Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

RASSF Family

  • Leanne Bradley
  • Delia Koennig
  • Maria Laura Tognoli
  • Jelte van der Vaart
  • Eric O’Neill
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101852

Synonyms

Historical Background

The RASSF (Ras Association Domain Family) protein family is a group of ten proteins which has been expanding and gaining interest due to their roles in human pathology. The family is named due to the presence of an RA (Ras-association) domain, the location of which is used to classify the RASSF proteins as C- or N-terminal RASSF proteins (Fig. 1). Interest in the family is fueled by the tumor-suppressive roles displayed by several RASSF members. RASSF7 was arguably the first of the family to be described as HRC-1 (Weitzel et al. 1992); however, it has only recently been renamed to join the ranks of the RASSF family. Therefore, NORE1 (RASSF5) is often considered the founding member following its identification as a Ras effector (Vavvas et al. 1998), joined shortly afterwards by RASSF1, which was originally discovered in the hunt for a lung cancer tumor suppressor on the short arm of chromosome 3 (Dammann et al. 2000). As studies continue, it is clear that the RASSF family proteins have much more widespread and diverse roles than originally anticipated. Here we will review each member of the RASSF family and their isoforms in turn, describing their major cellular functions and their links to human disease.
RASSF Family, Fig. 1

Schematic representation of the RASSF family. RASSF family members 1 to 10 are shown here alongside two biologically relevant splice variants (RASSF1C and RASSF5C). Depicted domains are the Protein Kinase C conserved region (C1 domain) in yellow, RAS-association (RA) domain in green, Savaldor/RASSF/Hippo (SARAH) domain in red and the coiled-coil motif in purple. Consensus sequences in RASSF1A and RASSF1C for ATM phosphorylation are depicted in light blue. RASSF1-6 are grouped due to their C-terminal RA domain while RASSF7-10 are grouped given their N-terminal RA domain

Classical RASSF Proteins

RASSF1 Family, Ras Association Domain Family Member 1

Loss of heterozygosity (LOH) studies in lung, breast, and kidney tumors identified several loci in chromosome 3p likely to harbor one or more tumor suppressor genes (TSGs). Particularly, the 3p21.3 region was suspected to be the home for a TSG because instability of this region is the earliest and most frequently detected deficiency in lung cancer (Hung et al. 1995; Kok et al. 1997; Sekido et al. n.d.; Sundaresan et al. 1992; Wistuba et al. 1999; Wistuba et al. 2000). This 120 kb region was found to be gene rich and eight genes were identified: CACNA2D2, PL6/placental protein 6, CYB561D2/101F6, TUSC4/NPRL2/G21, ZMYND10/BLU, RASSF1/123F2, TUSC2/FUS1, and HYAL2/LUCA2. However, none of these candidate genes are frequently mutated in cancer (Agathanggelou et al. 2005; Lerman and Minna 2000). The RASSF1 gene was identified in a yeast two-hybrid screen as an interacting partner of the DNA damage repair protein Xeroderma Pigmentosum Complementation Group A (XPA) (Dammann et al. 2003a). The RASSF1 gene became of interest because it mapped in the critical 3p21.3 region, according to Genebank database, it shared high sequence homology with the Ras effector in mouse Nore1 (human RASSF5) and also because expression of one of its isoforms, RASSF1A, was lost in most lung tumor cell lines (Dammann et al. 2003a; Agathanggelou et al. 2005). The name Ras-association domain family member 1 was assigned after identification of a Ras association domain (RA) in the RASSF1 sequence.

The RASSF1 Gene Locus

The RASSF1 locus spans about 11 kb of the human genome and it includes eight exons. Differential promoter usage and alternative splicing generate eight isoforms (A-H). Two CpG islands are associated with the promoter regions of RASSF1. The smaller of the two spans the promoter region of RASSF1A, 1D, 1E, 1F, 1G, 1H, and methylation at this CpG island has been shown to be one of the most common events in human cancers (Donninger et al. 2007; Hesson et al. 2007; Jones and Baylin 2007). The second CpG island surrounds the promoter regions for RASSF1B and 1C. Isoforms A and C are the major transcripts of the gene and are ubiquitously expressed (Richter et al. 2009). The B isoform is expressed mainly in hematopoietic cells and D and E are present in cardiac and pancreatic tissue, respectively. Little information is available regarding the functions of splice variants B, D, E, F, G, and H (Donninger et al. 2007).

RASSF1A, Ras Association Domain Family Member 1A

The 1.9 kb RASSF1A transcript initiates from a promoter located in the first CpG island of the RASSF1 gene and translates to a 340 amino acids protein. Transcription initiates with exon 1α followed by exon 2αβ. These exons encode for a diacylglycerol/phorbol ester domain (DAG), also called protein kinase C conserved region (C1) which encodes for amino acids 51–101 in RASSF1A (Newton 1995). In vitro studies have revealed a sequence within exon 3 that is an ataxia telangiectasia mutated (ATM) kinase phosphorylation site, conserved in RASSF1A, 1C, 1D, 1E, and 1H (Kim et al. 1999).

A Ras association (RA) or RalGDS/AF-6 domain is encoded by exon 4 and 5, and it generates residues 194–288 of RASSF1A. This domain is located at the COOH terminus of isoforms A-E. The RA domain mediates interactions with Ras and Ras-like small GTPases. It shares similarity in structure with the RasGTP binding domain of Raf1 kinase, a well-established RasGTP effector (Ponting and Benjamin 1996; Yamamoto et al. 1999).

The last 47 amino acids on the COOH terminus of RASSF1A are part of the so-called SARAH (Sav/RASSF/Hpo) domain. The SARAH domain mediates protein-protein interactions and facilitates the formation of both homo- and heterodimers of RASSF isoforms and other Hippo pathway components such as protein salvador homolog 1 (SAV1) and mammalian sterile 20-like protein kinase (MST) (Hwang et al. 2007; Scheel and Hofmann 2003).

The isoforms A, D-H are expressed from the same promoter within the same CpG island. Therefore, these isoforms are commonly missing in various tumors due to epigenetic inactivation.

RASSF1A Functions

RASSF1A has been categorized by many studies as a bona fide tumor suppressor gene (TSG), and the biological functions that RASSF1A performs in the cell are tightly related to its TSG role. The most studied functions of RASSF1A include involvement in cell cycle, microtubule organization, induction of apoptosis, control of tissue size/proliferation via the Hippo pathway, and maintenance of genomic stability.

RASSF1A and Apoptosis

The apoptotic cascade plays a pivotal role in determining cell fate. Notably, one of the hallmarks of cancer cells is their ability to escape apoptotic processes and develop high-grade malignancy and resistance to therapy (Hanahan and Weinberg 2011). Many RASSF family members have been described as proapoptotic (Khokhlatchev et al. 2002; Eckfeld et al. 2004; Vos et al. 2000, 2003a, b). RASSF1A has been documented to regulate apoptosis via the death receptor signaling pathway as well as to work as an effector protein of KRas-driven induction of apoptosis. In the first scenario, RASSF1A has been shown to be required for death receptor-induced Bax conformational change and mediation of apoptosis (Baksh et al. 2005). Briefly, death receptor stimulation by tumor necrosis factor α (TNFα) or TNFα-related apoptosis-inducing ligand (TRAIL) resulted in recruitment of RASSF1A and the modulator of apoptosis 1 (MOAP1) proteins to the receptors and formation of a complex between RASSF1A and MOAP1. This complex allowed MOAP1 to associate with the proapoptotic protein Bax and eventually resulted in apoptotic signaling activation (Baksh et al. 2005; Foley et al. 2008; Vos et al. 2006). Concomitant loss of RASSF1A and MOAP1 has been recently correlated to tumorigenesis (Law et al. 2015).

In the KRas-driven apoptosis scenario, RASSF1A (and its homologue NORE1/RASSF5) has been proposed to be a driver of the proapoptotic Hippo pathway component MST1 (Praskova et al. 2004). Various publications also demonstrated RASSF1A-mediated apoptosis with engagement of the Hippo signaling pathway, with RASSF1A enhancing MST2 interaction with its substrate, large tumor suppressor homolog 1 (LATS1). Subsequently, activated LATS1 phosphorylates and releases the transcriptional regulator Yes associated protein 1 (YAP1), allowing YAP1 to translocate to the nucleus and associate with p73, resulting in transcription of the proapoptotic target gene puma (Matallanas et al. 2007). A later study documented the importance of Ras signaling in the activation of the apoptotic MST2-LATS1 cascade. Interestingly, mutant but not wild-type KRas directly binds to the tumor suppressor RASSF1A to activate the MST2-LATS1 pathway. In this pathway LATS1 binds to and sequesters the ubiquitin ligase MDM2 causing stabilization of the tumor suppressor p53 and apoptosis (Matallanas et al. 2011). Always in the mutant KRas scenario, another scaffold protein, the connector enhancer of KSR (CNK1) has been shown to participate to the apoptotic response and to require a direct interaction with RASSF1A (and MST1) in order to enhance cell death (Rabizadeh et al. 2004).

RASSF1A in Mitosis and Cell Cycle Control

RASSF1A plays a major role in the regulation and progression of mitosis and the cell cycle. Perhaps the mitotic role most frequently attributed to RASSF1A is its association with microtubules (MTs). RASSF1A interacts with MTs via microtubule associated proteins (MAPs) (Dallol et al. 2004) and localizes with the spindle and centrosomes during mitosis (Liu et al. 2003). RASSF1A’s localization with tubulin has been shown to influence MT stability via RAN-GTPase (Dallol et al. 2009), as well as increasing stability by inhibiting HDAC6 (histone deacetylase 6) activity (Jung et al. 2013). The ability of RASSF1A to associate with the MTs correlates with its tumor suppressive functions, and loss of this property can lead to apoptotic defects (Matallanas et al. 2007), centrosomal/spindle errors (Liu et al. 2003), and tubulin instability (Vos et al. 2004) (which has been linked to cancer cell invasion/metastasis (Kaverina and Straube 2011)). Of note, the MT binding sites of RASSF1A have been found to interact specifically with nondynamic regions of MTs which are crucial for Golgi integrity and the establishment of polarity during cell migration (Arnette et al. 2014).

Given its importance at the mitotic spindle, it is unsurprising that RASSF1A is involved in regulating the cell cycle and has been shown to induce cell cycle arrest in all its phases (Rong et al. 2004). Importantly, the cell cycle control role of RASSF1A is impaired upon loss of MT association (Donninger et al. 2014). Various mechanisms by which RASSF1A exerts its cell cycle regulatory functions have been described, including its role as a death domain-associated protein 6 (DAXX) dependent mitotic stress checkpoint (Giovinazzi et al. 2012), its inhibition of cyclin D accumulation at the G1/S transition checkpoint (Shivakumar et al. 2002), and as an S-phase progression (and inducing senescence) regulator via a distinct p21Cip1/Waf1-dependent pathway (Thaler et al. 2009). It has been proposed that RASSF1A can modulate the activity of the APC-Cdc20 complex (which is necessary for mitotic progression). Conflicting reports have explored RASSF1A’s inhibition of, and interaction with, this complex (Sup Song et al. 2004; Liu and Katrin Baier RHD & GPP 2007) with the most recent studies showing that Aurora A phosphorylates RASSF1A on Ser203 and uncouples it from APC/Cdc20 at the centrosomes (Rong et al. 2007; Song et al. 2009). Interestingly, Ser203 is located within the microtubule binding domain of RASSF1A and phosphorylation of this site disrupts the microtubule binding ability of RASSF1A and abrogates RASSF1A-mediated mitotic arrest (Rong et al. 2007) concomitant with the need for MT association in RASSF1A-mediated cell cycle regulation.

RASSF1A and Stem Cells

RASSF1A interacts with and induces activation of the core kinases MST1 and MST2 of the Hippo pathway via its SARAH domain. The Hippo pathway is a highly conserved developmental signaling pathway, first described in Drosophila melanogaster, that regulates organ growth (Heallen et al. 2011), stem cell function and tissue regeneration in the mammalian system (reviewed in Wang et al. (2017)). Crosstalk between the Hippo and TGFβ/BMP pathway has been found to regulate self-renewal and differentiation in mouse (Lian et al. 2010) and human embryonic stem cells (James et al. 2005) by mediating SMAD signaling via the Hippo effectors YAP/ TAZ (Varelas et al. 2008). RASSF1A has been shown to be targeted for degradation in response to TGFβ signaling allowing nuclear localization of YAP/SMAD and transcription of TGFβ target genes (Pefani et al. 2016).

Interestingly, epigenetic inactivation of RASSF1A in addition to hypermethylated in cancer 1 protein (HIC1) was sufficient to induce a tumorigenic phenotype of human mesenchymal stem cells (hMSCs) (Teng et al. 2011) suggesting that loss of function of RASSF1A contributes to the transitioning of stem to cancer-like stem cells.

RASSF1A and Genome Stability

In 2009, Hamilton et al. identified the ATM-dependent phosphorylation of RASSF1A at Ser131 in response to DNA damage (Hamilton et al. 2009). Upon phosphorylation RASSF1A dimerizes and stimulates the kinase activity of MST2, resulting in stabilization of p73 (Hamilton et al. 2009) and expression of YAP/p73 apoptotic target genes (Strano et al. 2005). In 2014, Pefani et al. established an MST2-LATS1-dependent role for RASSF1A in response to replication stress. Phosphorylation of RASSF1A by ataxia telangiectasia and Rad3-related protein (ATR) promotes replication fork stability by restricting cyclin-dependent kinase 2 (CDK2) binding to LATS1 and therefore decreasing breast cancer type 2 susceptibility protein 2 (BRCA2) phosphorylation to enhance DNA repair protein RAD51 homolog 1 (RAD51) nucleofilament formation at stalled forks (Pefani et al. 2014). Additionally, Donninger et al. showed that RASSF1A has a direct role in DNA repair by modulating sirtuin 1 (SIRT1)-dependent deacetylation of XPA and therefore enhancing its nucleotide excision repair (NER) activity in response to UV-induced DNA damage (Donninger et al. 2015a). However, the RASSF1A single nucleotide polymorphism variant (RASSF1 c.397G > T, p.Ala133Ser, rs2073498) fails to get phosphorylated and is associated with early cancer onset (Kanzaki et al. 2006; Bergqvist et al. 2010) particularly in patients with BRCA mutations (Gao et al. 2008), supporting that RASSF1A loss of function contributes to genomic instability and subsequently to tumorigenesis. Notably, RASSF1A has been shown to promote p53 activity and stability by disrupting the MDM2-DAXX-ubiquitin carboxyl-terminal hydrolase 7 (HAUSP) complex and therefore destabilizing MDM2, the p53 E3 ubiquitin ligase (Song et al. 2008).

RASSF1A in Cancer

Epigenetic Inactivation of RASSF1A

Silencing of putative tumor suppressor genes (TSG) is one of the hallmarks of carcinogenesis (Jones and Baylin 2007). Downregulation of TSGs may occur via genetic mutation or epigenetic silencing (e.g., through gene methylation). RASSF1A is one of the most frequently epigenetically inactivated tumor suppressor genes in sporadic human malignancies (Donninger et al. 2007; Hesson et al. 2007; van der Weyden and Adams 2007; Grawenda and O’Neill 2015). Methylation of the RASSF1A gene is rare in normal tissues, whereas the frequency of methyl-cytosine in the promoter spanning CpG island increases in tumor tissue and is one of the highest described. It has been reported over the years in a number of malignancies with the highest frequencies being reported in lung, breast, and prostate cancers (Donninger et al. 2007; Grawenda and O’Neill 2015).

Given the link between RASSF1A and Ras signaling pathways, several studies have investigated a correlation between KRas mutation and RASSF1A inactivation in cancer. An inverse, and thus synergetic for the tumor, correlation has been shown for colorectal (van Engeland et al. 2002), pancreatic (Dammann et al. 2003b), nonsmall cell lung cancer (NSCLC) (Li et al. 2003), and melanoma (Reifenberger et al. 2004), even though conflicting results are proposed in a different study on NSCLC (Kim et al. 2003).

RASSF1A Epigenetic Inactivation as a Marker for Tumor Diagnosis and Prognosis

Given the strong correlation between RASSF1A promoter methylation and cancer onset, RASSF1A methylation status has a compelling clinical utility potential as a biomarker for cancer risk and prognosis (Grawenda and O’Neill 2015). An apparent correlation of RASSF1A methylation with clinical characteristics of invasive tumors is evident in both breast and lung cancer (Donninger et al. 2007; Grawenda and O’Neill 2015). Correlation of RASSF1A methylation with cancer risk is also best validated in gastrointestinal (GI) cancer (Grawenda and O’Neill 2015). Intriguingly, the fact that RASSF1A promoter methylation occurs rarely in normal tissues also makes RASSF1A a candidate diagnostic marker (Agathanggelou et al. 2005). Furthermore, detection of methylated DNA in samples obtained with noninvasive techniques such as plasma, sputum, urine, throat washing, and nipple aspirates (Chang et al. 2003; de Caceres et al. 2004; Topaloglu et al. 2004; Hoque et al. 2004; Fiegl et al. 2004) makes this approach clinically relevant.

RASSF1A Mutations

Loss of RASSF1A expression is mainly attributed to promoter methylation, as somatic mutations are uncommon. Analysis of lung, breast, kidney, nasopharyngeal carcinomas, and related cell lines identified only one frame-shift mutation (at codon 277 in the RA domain) and one missense mutation (at codon 201 in the RA domain) (Dammann et al. 2000; Burbee et al. 2001; Astuti et al. 2001; Dreijerink et al. 2001; Lo et al. 2001). However, various somatic polymorphisms have been reported in tumors. Most of them localize in RASSF1A functional domains. Namely, five reside in the C1 domain, four in the ATM phosphorylation site, and five in the RA domain, the most commonly reported actually being a germline Ala133Ser SNP (Dammann et al. 2003a; Gordon et al. 2012). The functional significance of these alterations is not yet fully understood, but data suggests that they are defective mutants. For instance, the Ser131Phe and Ala133Ser mutants reside on the ATM phosphorylation site. Both mutants are unable to induce cell cycle arrest by blocking cyclin D1 accumulation and the Ser131Phe mutant shows reduced phosphorylation which causes a less efficient inhibition of cell proliferation (Shivakumar et al. 2002). Moreover, the Ala133Ser mutant leads to a disrupted conformation of the ATM phosphorylation site and this event leads to a failure in activating p73-dependent apoptotic response upon DNA damage (Yee et al. 2012). Interestingly, the findings on the Ala133Ser mutant correlated with poor outcome and early age onset of sarcoma in patients bearing this SNP (Yee et al. 2012). An independent study also found a correlation between the Ala133Ser polymorphism and early onset of breast cancer in patients carrying a BRCA1/2 mutation (Gao et al. 2008).

RASSF1A in Heart Disease

RASSF1A is a candidate gene in heart disease. As in other tissues, RASSF1A activates MST1 in the heart (Delre and Clark 2010); however, it seems to play contradicting roles depending on which cell type the activation occurs in. In cardiomyocytes, RASSF1A activation of MST1 promotes apoptosis, a detrimental event in the heart; however, in cardiac fibroblasts RASSF1A elicits a positive response by downregulating TNFα expression, which drives cardiac failure via hypertrophy and fibrosis (Bryant et al. 1998; Yokoyama et al. 1997; Sun et al. 2007). Furthermore, studies performed in hypertrophic mouse hearts show that RASSF1A expression is significantly reduced (Oceandy et al. 2009) and RASSF1A expression shows a protective role during pressure overload in cardiac fibroblasts (Delre and Clark 2010). Overall, RASSF1A is a potential cell-type specific therapeutic target in heart disease, but more research is necessary to elucidate its utility.

RASSF1 Knockout Mouse Studies

Knockout mice have been generated for total Rassf1 (all isoforms), as well as for Rassf1A specifically. Rassf1 knockout mice have been shown to be both viable and fertile and to date no other obvious phenotypes have been reported (Liu et al. 2003). However, Rassf1-/- MEFs isolated from the mice displayed smaller overall size as well as an increased sensitivity to MT destabilizing agents, confirming the role of Rassf1 in MT stability. In 2005, two groups separately generated Rassf1A knockout mice (van der Weyden et al. 2005; Tommasi et al. 2005). Once again, the Rassf1A-/- mice were healthy with no obvious abnormalities. Following analysis of the Rassf1A-/- MEFs and lymphocyte populations, it was reported that Rassf1A absence did not grossly affect genome stability and the data further supported the MT stabilizing effects of Rassf1A (van der Weyden et al. 2005). It has also been shown that Rassf1A-/- MEFs have delayed mitotic progression and cytokinesis defects (Guo et al. 2007) displaying the importance of RASSF1A in maintaining mitotic integrity.

The absence of major phenotypes in these mice is surprising given the widespread anti-tumorigenic roles that have been proposed for RASSF1(A). However, when the effect on tumor development was analyzed, the ablation of Rassf1A expression led to a higher susceptibility of malignant disease (van der Weyden et al. 2005; Tommasi et al. 2005) which is in line with the view of Rassf1A as a tumor suppressor. Concomitant with a role for RASSF1A in the heart, it was reported that Rassf1a null mice showed a higher susceptibility to cardiac failure (van der Weyden et al. 2005). Furthermore, there is speculation that the activities of Rassf1A may be compensated for by the Rassf5A/Nore1A protein which has highly similar sequence identity (Dammann et al. 2000; Tommasi et al. 2002), but further study is necessary to fully understand the physiology.

RASSF1B, Ras Association Domain Family Member 1B

The RASSF1B transcript is transcribed from the same promoter as RASSF1A but uses a different 5’ exon resulting in a minor variant lacking the C1 domain. RASSF1B is specifically expressed in hematopoietic cells (Dammann et al. 2003a).

RASSF1C, Ras Association Domain Family Member 1C

RASSF1C is the second ubiquitously expressed isoform of the RASSF1 gene. RASSF1C is transcribed from a different CpG island promoter, 3.5 kb distant from the RASSF1A one. RASSF1C transcription starts at exon 2γ and then continues with four C-terminal exons (3–6) shared with RASSF1A. The main difference to RASSF1A is the lack of the N-terminal C1 domain resulting in a shorter isoform of 270 amino acids. RASSF1C, however, retains the other two C-terminal domains, the RA and SARAH domains (van der Weyden and Adams 2007) (Fig. 1). Like RASSF1A, RASSF1C contains an ATM phosphorylation consensus sequence at Ser61, but data on the phosphorylation has not been shown yet (Kim et al. 1999). Conversely to RASSF1A, a clear role for RASSF1C in tumor suppression has not yet been defined, as reports on its activity show varied outcomes and potential tissue-specificity (Li et al. 2004). RASSF1C does not show promoter hypermethylation and is expressed in almost all lung, breast, pediatric and pancreatic endocrine tumors and cancer cell lines analyzed to date (Dammann et al. 2003a; Burbee et al. 2001; Harada et al. 2002; Malpeli et al. 2011; Reeves et al. 2013). However, in the renal cell carcinoma cell line KRC/Y, RASSF1C was almost undetectable (Dreijerink et al. 2001) suggesting a tissue-specific expression.

RASSF1C Functions

One of RASSF1A’s characteristics is to be associated with and stabilize microtubules (Liu et al. 2003; Vos et al. 2004). RASSF1C has also been found to colocalize with tubulin structures in the cell but is not able to stabilize them to the same extent as RASSF1A (Vos et al. 2004).

RASSF1C has been shown to associate with active Ras. In the embryonic kidney cell line HEK293T and in the human lung cancer cell line NCI-H1299, RASSF1C overexpression suppresses the destabilizing effects on genomic integrity of overexpressed mutant RasG12V. The aforementioned protective effect of wild-type RASSF1C was lost when its defective mutant (RASSF1C Ser61Phe) was expressed (Vos et al. 2004). Collectively these data show a potential protective role for RASSF1C in DNA damage response.

The RASSF1C binding to active KRas was also reported to elicit cell death via canonical apoptotic pathway activation (Vos et al. 2000).

Moreover, RASSF1C has been recently reported as a DAXX binding partner (Kitagawa et al. 2006; Escobar-Cabrera et al. 2010), and this could potentially define a role for RASSF1C in apoptosis in response to stress stimuli. In ovarian cancer cells, RASSF1C was found to sensitize cells to cisplatin treatment and induce apoptosis and its activity could be halted by expression of the cellular apoptosis susceptibility CAS/CSE1L gene (Lorenzato et al. 2012). Conversely, other reports supported the evidence of RASSF1C being phosphorylated by glycogen synthase kinase 3 (GSK3) and being targeted for degradation under stress conditions in a AKT-dependent fashion (Zhou et al. 2012). Since AKT promotes RASSF1C upregulation, this would characterize RASSF1C as an oncogene. These findings are in agreement with reports showing that RASSF1C increased cell proliferation in osteoblasts and lung cancer cells and migration in breast cancer cell lines (Amaar et al. 2006; Reeves et al. 2010).

RASSF1C in Cancer

The aforementioned role of RASSF1C as a promoter of cell proliferation in osteoblasts is mediated by the extracellular signal-regulated kinase (ERK) 1/2 and the insulin-like growth factor binding partner 5 (IGFBP5) (Amaar et al. 2005). In lung cancer cells, IGFBP5 seems to play a negative role in RASSF1C promotion of cell proliferation (Reeves et al. 2014).

The variety of downstream genes upregulated upon RASSF1C overexpression also suggests an oncogenic role for the protein. For example, overexpression of RASSF1C in breast cancer cell lines leads to C-X-C chemokine receptor type 4 (CXCR4) upregulation, which enhances cell proliferation and metastasis (Reeves et al. 2010). Interestingly, it has been suggested that RASSF1C modulates the expression of the stem cell renewal gene Piwi-like protein 1 (PIWIL1) in lung cancer (Reeves et al. 2012).

Interplay between the two major isoforms RASSF1A and RASSF1C has been reported in breast cancer cells. In the report, both isoforms alternatively regulate SRC activity and β-catenin/YAP-mediated invasion (Vlahov et al. 2015).

Other reports confirm that RASSF1C induces nuclear β-catenin translocation and transcriptional activation via inhibition of the βTrCP receptor subunit of SCFβ-TrCP, a ubiquitin ligase known to target β-catenin for proteasomal degradation (Estrabaud et al. 2007).

Furthermore, the oncogenic role of RASSF1C has been supported by clinical evidence. Several groups have shown RASSF1C upregulation in a variety of cancers, such as pancreatic endocrine tumors, large cell neuroendocrine carcinomas, small cell lung carcinomas, and esophageal squamous cell carcinoma (Malpeli et al. 2011; da Costa et al. 2011; Pelosi et al. 2010; Guo et al. 2014).

RASSF1D, RASSF1E, Ras Association Domain Family Member 1D and 1E

The RASSF1D and RASSF1E isoforms are both considered RASSF1A splice variants specifically expressed in the cardiac and pancreatic tissue, respectively (van der Weyden and Adams 2007). Both isoforms are encoded by exon 1α. In RASSF1D four additional amino acids 5’ of exon 2αβ are encoded, whereas the RASSF1E transcript has additional four amino acids 3’ of exon 2αβ, for a total of 344 amino acids in both cases.

RASSF1F, Ras Association Domain Family Member 1F

RASSF1F is produced by alternative splicing from RASSF1D where the 2αβ exon is excluded. The RASSF1F protein differs from the canonical sequence by exchange of the amino acids 85–91 (LSADCKF → RACGVGD) and is missing amino acids 93–344. The truncated protein of 92 amino acids terminates within the C1 domain.

RASSF1G, Ras Association Domain Family Member 1G

RASSF1G transcript skips exon 2αβ and 3. The protein differs from the canonical sequence by exchange of the amino acids 84–149 (RLSADCKFTC…EQKIKEYNAQ → QQGRFLHRLH …PACAVTHKGT) and is missing amino acids 150–344 resulting in a short protein lacking the RA and SARAH domain.

RASSF1H, Ras Association Domain Family Member 1H

The RASSF1H transcript variant misses the alternate coding exon from isoform D resulting in a frameshift that translates into isoform RASSF1B. The protein is missing amino acids 1–74 and 140–344. It differs from the canonical sequence by exchange of the amino acids 75–123 ( VVRKGLQCAR…EPAVERDTNV → MGEAEAPSFE…SLARRPRRDQ).

RASSF2, Ras Association Domain Family Member 2, Rasfadin

RASSF2, located at human chromosomal region 20p13, was originally called Rasfadin and was first identified as a novel gene in close proximity to the bovine prion gene (Comincini et al. 2001). The first report showed high nucleotide (88%) and amino acid similarity (95%) with a previously described human cDNA, KIAA0168. In silico characterization of RASSF2 reported three isoforms (namely RASSF2A, RASSF2B, and RASSF2C). All three isoforms contain predicted RA domains, although RASSF2B mRNA produces a much shorter protein with a truncated RA domain. RASSF2A and RASSF2C contain a C-terminal coiled coil SARAH domain that is absent in RASSF2B and share identical sequence (Hesson et al. 2005) (Fig. 1).

The longest isoform RASSF2A contains a 5’ CpG island and a predicted promoter region (Hesson et al. 2005). It is a 326 amino acids protein with the RA domain sharing 28% identity to that of RASSF1A and 31% to that of RASSF5 (van der Weyden and Adams 2007)

RASSF2 Functions

RASSF2 has been described as a nuclear protein (Cooper et al. 2008). Interaction has been shown with KRas in a GTP-dependent manner via the RA domain (Vos et al. 2003a) and this interaction could explain at least partially the RASSF2 tumor suppressive role. The idea that silencing of RASSF2 plays a key role in KRas-mediated transformation is supported by reports that KRAS/BRAF mutations are found more frequently in colorectal carcinomas (CRCs) with RASSF2 methylation than in those without (Akino et al. 2005; Nosho et al. 2007; Park et al. 2007). Yeast two-hybrid screens have also proved an association between RASSF2 and RASSF5, MST1/2 and RASSF3. Particularly, interaction with the core Hippo pathway kinase MST2 leads to its stabilization, enhancing MST2 proapoptotic potential (Cooper et al. 2009). Moreover, another report demonstrated a role for MST1 in maintaining RASSF2 protein stability and a proapoptotic activation of MST1 after complexing with RASSF2 (Song et al. 2010). Further links to apoptotic signaling have been made with the observation that RASSF2 was required for the prostate apoptotic response protein 4 (PAR4) to translocate to the nucleus and promote apoptosis (Donninger et al. 2010). Independent groups also observed reduced cell proliferation upon RASSF2 overexpression in lung and colorectal cancer cells and the mechanistic basis for growth inhibition have been related to apoptosis and cell cyce arrest (Vos et al. 2003a; Akino et al. 2005.

RASSF2 in Cancer

Similarly to its homolog RASSF1A, RASSF2 undergoes promoter methylation in a variety of cancers such as breast (Cooper et al. 2008), lung (Cooper et al. 2008; Kaira et al. 2007), colorectal (Vos et al. 2003a; Hesson et al. 2005; Akino et al. 2005), and gastric cancer (Endoh et al. 2005), among others. Particularly strong evidence in CRC shows that RASSF2 promoter methylation is an early event during CRC development as it has been reported in a high proportion of colon adenomas and it is a specific marker of tumor status, since the normal mucosa is found unmethylated (Hesson et al. 2005; Akino et al. 2005). RASSF2A promoter methylation has been positively correlated in some of these studies to KRAS, BRAF, or PIK3CA mutations (Akino et al. 2005; Nosho et al. 2007; Park et al. 2007). It has also been detected in nasopharyngeal carcinoma, in which it positively correlates to lymph node metastasis (Zhang et al. 2007).

RASSF3, Ras Association Domain Family Member 3

The RASSF3 gene, located at 12q14.1, is predicted to produce three transcripts (RASSF3A, RASSF3B, and RASSF3C) due to alternative splicing of the exons. Particularly, RASSF3A contains three exons and translates a 238-residue protein. The last four exons encode a consensus RA domain with a 44% identity (59% homology) to the C-terminus of RASSF1 (both A and C isoforms) and 46% identity to the mouse Rassf5 protein (Tommasi et al. 2002) (Fig. 1). The protein sequence translated from the first exon of RASSF3 shares high homology with the translated sequence of the first exon of RASSF1C (van der Weyden and Adams 2007; Tommasi et al. 2002).

RASSF3 Functions

Although there are indications that RASSF3 may act as a tumor suppressor, to date no systematic functional characterization has been performed and mechanisms supporting its tumor suppressor role are still lacking. Recently, RASSF3 has been reported to stabilize p53 and induce p53-dependent apoptosis, thus playing a role both in cell cycle and DNA repair mechanisms (Kudo et al. 2012) In agreement with this data, RASSF3 overexpression in HER2/Neu positive breast cancer cell lines (both mouse and human) inhibited cell proliferation (Jacquemart et al. 2009) and RASSF3 knockdown in NSCLC cells increased migration rate (Fukatsu et al. 2014), thus reinforcing the hypothesis that RASSF3 acts a tumor suppressor gene.

RASSF3 in Cancer

The protein has been found both in normal and cancer cells (Tommasi et al. 2002) Interestingly, RASSF3 has been reported to be downregulated in NSCLC patients, even though the downregulation was not due to promoter methylation, unlike other RASSF family members (Fukatsu et al. 2014). Consistent with the NSCLC data, two independent studies on gliomas and colorectal tumor cell lines also reported no evidence for RASSF3 silencing via promoter methylation (Hesson et al. 2005; Hesson et al. 2004).

RASSF4, Ras Association Domain Family Member 4, AD037

The RASSF4 gene is located on chromosome 10q11.21. It has 12 transcripts variants resulting from alternative splicing from which 5 transcripts are protein coding. RASSF4 contains a RA and a SARAH domain but lacks the ATM phosphorylation site (Fig. 1). It shows 60% identity with RASSF2 and 25% with RASSF1A.

RASSF4 Functions

RASSF4 is a potential tumor suppressor that binds the KRas effector protein in a GTP-dependent manner via its association domain (Eckfeld et al. 2004), and it has been shown to bind also other Ras family members. RASSF4 is expressed in various human tissues. It has been shown to play a role in apoptosis (Eckfeld et al. 2004) and cell cycle arrest and is frequently downregulated in numerous cancers (Han et al, 2016). Eckfeld et al. reported that with exogenous expression RASSF4 interacts with MST1 of the Hippo pathway, but data were not presented in the publication (Eckfeld et al. 2004).

RASSF4 in Cancer

Downregulation or loss of RASSF4 is often correlated with promoter methylation (Eckfeld et al. 2004; Chow et al. 2004). Interestingly, no RASSF4 promoter methylation was observed in pheochromocytomas (Richter et al. 2015). RASSF4 has been shown to inhibit growth by suppression of the MAPK pathway in human oral squamous cell carcinoma (Michifuri et al. 2013). Its overexpression inhibits proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and Wnt signaling in osteosarcoma cells (Zhang et al. 2017).

RASSF5, Ras Association Domain Family Member 5, NORE1, RAPL, Maxp1

RASSF5 is often considered the founding member of the RASSF family. It was originally identified in a yeast-2-hybrid system as an interaction partner of mutant RasG12V and therein named and classified as NORE1 (Novel Ras Effector 1) (Vavvas et al. 1998). It is located on chromosome 1q32.1 and has four transcript variants (RASSF5A-D) which are expressed via differential promoter usage and alternative splicing. RASSF5A/NORE1A is the canonical RASSF5 sequence encoding a 418 amino acid protein (Fig. 1). The two predominant isoforms RASSF5A and RASSF5C (NORE1A and NORE1B respectively) are expressed by differential promoter expression (RASSF5A and C have separate CpG islands) leading to a shorter RASSF5C isoform. RASSF5B is expressed from the same promoter as RASSF5A but does not have the SARAH domain due to exon skipping. Its function has not been demonstrated yet (Hesson et al. 2003). RASSF5 interacts via its RA domain with active (GTP-bound) Ras and various other Ras family/subfamily GTPases (mostly with KRas) (Avruch et al. 2006; Rodriguez-Viciana et al. 2004) and its heterodimerization with RASSF1A is essential for RASSF1A association with RasG12V (Ortiz-Vega et al. 2002). Interestingly, the RASSF5 transcripts display 40–60% homology to RASSF1A (Dammann et al. 2000; Tommasi et al. 2002), suggesting functional overlap between the encoded proteins.

RASSF5A Functions

RASSF5A and Apoptosis
Given its sequence similarity to, and interaction with, RASSF1A, it is unsurprising that apoptosis is an important cellular function of NORE1A (Fig. 2). This is largely mediated via its ability to bind the apoptotic kinases MST1/2 and act as part of a proapoptotic Ras effector complex (Hwang et al. 2007; Khokhlatchev et al. 2002; Zhou et al. 2014). The affinity of RASSF5A for the MST kinases depends of TNFα and TRAIL stimulation (Park et al. 2010), proving that it elicits apoptosis in a death receptor ligand mediated manner. Recent studies suggest that RASSF5A is important in regulating the balance of p53 mediated apoptosis and senescence (Donninger et al. 2015b). It does this via a Ras-dependent interaction with homeodomain-interacting protein kinase 2 (HIPK2), which inhibits the proapoptotic phosphorylation of p53 while promoting its pro-senescent acetylation. Furthermore, RASSF5A can directly modulate p53 protein levels (and in turn, apoptosis) by targeting the p53 negative regulator MDM2 for degradation (Schmidt et al. 2016).
RASSF Family, Fig. 2

Schematic representation of general RASSF family functions. Overlapping major biological functions of RASSF family proteins are shown. Each family member is linked to relevant processes by specific coloured lines

RASSF5A and Cell Cycle/Growth

Like RASSF1A, RASSF5A is localized at the centrosomes and binds MTs via its RA domain (Moshnikova et al. 2006) The cytoskeletal interactions of RASSF5A are considered essential for RASSF5’s cell cycle inhibitory roles, which were found to be mediated via negative ERK signaling (Moshnikova et al. 2006) (Fig. 2). RASSF5A can induce MT nucleation via direct interaction with tubulin in a mechanism that is negatively regulated by Aurora A phosphorylation and the binding of RASSF5 to active Ras (Bee et al. 2010). The growth suppression roles of RASSF5 are well documented, with its nuclear localization reported to be essential for this function (Kumari et al. 2007). RASSF5A has been shown to restrict tumor cell line growth in an apoptotic (Kumari et al. 2010) Ras and MST1/2 independent manner (Vos et al. 2003b; Aoyama et al. 2004).

Other Biological Roles of RASSF5A

The role of RASSF proteins in cell fate decisions has been gaining considerable interest. Of note, RASSF5A was found to be important for the specification of axons, allowing neuronal polarization through the small GTPase, Rap1B (Nakamura et al. 2013). Interestingly, RASSF5A displays antiviral activity (Arora et al. 2017) which is specifically targeted and inhibited by the hepatitis C virus (HCV) infection.

RASSF5C Functions

RASSF5C (NORE1B, RAPL), like RASSF1A, has been shown to have tumor suppressor functions and is epigenetically silenced in various tumors (Macheiner et al. 2006; Lee et al. 2010). Additionally, it modulates the immune system in response to T-cell receptor (TCR) activation. RASSF5C binds to activated RAP1 to increase lymphocyte-function-associated antigen 1 (LFA1) activity and induce lymphocyte polarization through integrin activation (Katagiri et al. 2003). Furthermore, it has been reported that RASSF5C binds to MST1 in a RAP1-GTP dependent manner. It regulates the activity and localization of MST1 to induce cell polarity and lymphocyte adhesion (Katagiri et al. 2006). Interestingly, Praskova et al. showed that RASSF5A inhibits MST1 activity (Praskova et al. 2004) suggesting different functions for the two isoforms. RASSF5C is predominantly expressed in lymphoid tissue where activation of MST1 is required for lymphocyte adhesion and polarization (Katagiri et al. 2006). Upon TCR activation, RASSF5C mediates NFkB signaling by recruiting active Ras to the plasma membrane and Carma1 (an essential lipid raft-associated regulator of TCR) into the immune synapse (Ishiguro et al. 2006). RASSF5C also localizes to microtubules (Fujita et al. 2005).

RASSF5 and Cancer

Typical of several of the RASSF family members, RASSF5 has been found to be downregulated in a variety of tumors (Vos et al. 2003b; Tommasi et al. 2002) and is a proven bona fide tumor suppressor. Like other RASSF family members, epigenetic inactivation of RASSF5 has been reported in several cancers, including neuroblastoma (Djos et al. 2012; Geli et al. 2008), thyroid (Nakamura et al. 2005), lung (Vos et al. 2003b), colorectal (Lee et al. 2010), and kidney (Steiner et al. 1996; Morris et al. 2003a). However, such silencing is absent in several tumor types (Tommasi et al. 2002; Chow et al. 2004; Nakamura et al. 2005; Foukakis et al. 2006) and deletion is rare (Steiner et al. 1996). RASSF5 has subsequently been reported to be downregulated by proteasomal degradation in transformed cells. The E3 ubiquitin ligase, ITCH, has been shown to interact with RASSF5 and regulate its tumor suppressive activities by downregulation of the protein (Suryaraja et al. 2013). Given the association of HCV infection with the onset of liver cancer, the inhibition of RASSF5A by the HCV protein NS5B (Arora et al. 2017) may also be considered a contributing factor to tumorigenesis in this context.

A number of studies have investigated the consequence of RASSF5 downregulation in tumorigenesis. RASSF5A has been shown to be an inhibitor of the oncoprotein HIPK1 (Lee et al. 2012) by inducing its MDM2-mediated proteasomal degradation, thus displaying further tumor suppressive activities independent of its apoptotic and cell cycle roles. Rassf5-null mice were found to be resistant to TNFα/TRAIL-mediated apoptosis as they could not activate Mst1, and MEFs isolated from the animals displayed more tumorigenic traits than their Rassf5 expressing counterparts (Park et al. 2010). Notably, RASSF5 downregulation has also been linked to the presence of other alterations in specific cancer types. For example, the reduction of RASSF5A in follicular thyroid tumors was shown to be dramatically reduced in cases with a PAX8-PPAR11 translocation as well as being mutually exclusive with the presence of Ras mutations (Foukakis et al. 2006), while in other tumor types there was no correlation (Vos et al. 2003b).

RASSF6, Ras Association Domain Family Member 6

The RASSF6 gene is located on chromosome 4q13.3. There are five known splice variants of the RASSF6 gene, four of them are protein coding. All RASSF6 isoforms contain a RA and a SARAH domain. Additionally, they have a C-terminal PDZ-binding motif, which distinguishes RASSF6 from other RASSF proteins (Fig. 1).

RASSF6 Functions

Conflicting data exists regarding RASSF6 and its binding to Ras. Ikeda et al. showed that RASSF6, despite harboring a RA domain, does not bind to Ras proteins under the same conditions as RASSF5 (Ikeda et al. 2007). However, Allen et al. found that RASSF6 specifically binds to activated KRas via its effector domain and that cotransfection with KRas leads to increased apoptosis (Allen et al. 2007). RASSF6 has been shown to induce apoptosis dependent on MDM2 and p53 (Iwasa et al. 2013) and MST1/2, but not the canonical Hippo pathway (Ikeda et al. 2009). Interestingly, it inhibits MST2 activation and therefore Hippo signaling. Upon dissociation from MST2, RASSF6 binds to MOAP1 (Allen et al. 2007) to induce apoptosis. RASSF6 expression is frequently epigenetically silenced in cancer cells and primary tumors (Djos et al. 2012; Hesson et al. 2009; Mezzanotte et al. 2014) and has been shown to have prognostic value (Guo et al. 2016; Wen et al. 2011).

Additionally, RASSF6 has been shown to inhibit NFκB in response to respiratory syncytial virus (RSV) therefore mediating an inflammatory response.

N-Terminal RASSF Proteins

The N-terminus RASSF proteins are a distinct group, as they contain their RA/Ub folds at the N-terminus and none contain a C1 or SARAH domain (Fig. 1).

RASSF7, Ras Association Domain Family Member 7, C11orf13, HRC1

RASSF7 is the most studied member of the N-terminal members of the RASSF proteins. RASSF7 is located at 11p15.5 and the RA/Ub fold of the protein is near the N-terminus and there are two coiled coil regions at the C-terminus (Fig. 1). There are three known splice variants of the protein, with isoform 1 referred to as the canonical sequence. RASSF7 was originally discovered in 1992, when the genome close to the HRas gene was screened for nearby genes (Weitzel et al. 1992) and a new gene was identified and named HRC1 (HRas cluster 1). The gene has since been officially renamed to RASSF7.

RASSF7 Functions

The role of RASSF7 in the cell is only just beginning to be uncovered. RASSF7 expression has been recorded in several tissues, including the developing Xenopus (Sherwood et al. 2008) and mouse (Recino et al. 2010) embryos and in many human tissues/cells (Recino et al. 2010). Given its embryonic expression, the developmental role of RASSF7 has been investigated and was recently found to work in concert with DISC1 (Disrupted in schizophrenia 1 protein) in the regulation of astrogenesis (Morris et al. 2003b; Wang et al. 2016), which may suggest a role for RASSF7 in brain development.

RASSF7 has been reported to localize with the centrosome via its coiled coil domain (Sherwood et al. 2008; Gulsen et al. 2016) and its interaction with DISC1 in yeast also indicates a centrosomal role (Porteous et al. 2011). It has been found to be essential for the completion of mitosis (Sherwood et al. 2008; Recino et al. 2010), due to its role as an activator of Aurora B and a regulator of microtubule dynamics (Recino et al. 2010). The protein has also been shown to have an antiapoptotic role via its interactions with NRas and MKK7, to negatively regulate proapoptotic JNK signaling (Takahashi et al. 2011), a role which may be developmentally important in human invertebral disc degeneration (Liu et al. 2015).

RASSF7 in Cancer

Recently, RASSF7 involvement in cancer has only begun to be uncovered. It has been shown to be upregulated in several cancers including pancreatic ductal adenocarcinomas (Vasseur et al. 2003; Logsdon et al. 2003; Friess et al. 2003), pancreatic islet cell tumors (Lowe et al. 2007), endometrial carcinomas (Mutter et al. 2001), malignant thyroid neoplasms (Li et al. 2013), and ovarian clear cell carcinomas (Tan et al. 2009), while a truncated form has been identified and suggested to act as an oncogene (Gulsen et al. 2016). Notably, RASSF7 has been suggested as potential diagnostic marker for islet cell (Lowe et al. 2007) and endometrial (Mutter et al. 2001) tumor identification, given its specific upregulated expression in these cancers. Furthermore, RASSF7 expression is increased in hypoxic conditions (Camps et al. 2008; Liang et al. 2009), a common feature of solid tumors. In contrast, RASSF7 has been shown to be epigenetically silenced in neuroblastomas (Djos et al. 2012).

RASSF8, Ras Association Domain Family Member 8, HoJ-1, C12ORF2

Similarly to RASSF7, which maps close to the HRAS1 gene, RASSF8 is located in close proximity to the KRAS2 locus, 70.8 kb from KRAS2 on chromosome 12p11 (van der Weyden and Adams 2007). RASSF8 has been implicated in a complex type of synpolydactyly by the reciprocal chromosomal translocation t(12;22) (p11.2;q13.3), which involves genes RASSF8 and FBLN1 (Debeer et al. 2002). RASSF8 contains an N-terminal RA domain and lacks the SARAH domain (Lock et al. 2010). Bioinformatic programs (Vega, Ensembl (van der Weyden and Adams 2007)) primarily predict transcripts which differ due to premature truncation at the C-terminus (exons 4–6). To date, seven transcripts have been predicted from the RASSF8 locus (most of which remain to be experimentally confirmed). RASSF8A and RASSF8B share high similarity, differing only in the C-terminal exon. RASSF8C-E transcripts prematurely terminate at the 5’ end of exon 4 and translate shorter proteins that consist almost entirely of the RA domain. RASSF8F and RASSF8G translate for much shorter proteins with no identifiable functional domains (van der Weyden and Adams 2007).

RASSF8 Functions

RASSF8 has been showed to inhibit cell growth and to promote adherent junction formation in lung cancer and particularly it has been found to interact with E-cadherin and β-catenin at the adherent junctions (Lock et al. 2010). RASSF8 has been also reported to interact with the ubiquitous scaffolding protein 14-3-3 (Jin et al. 2004) which regulates various molecular mechanisms, such as cell cycle progression and apoptosis (van Hemert et al. 2001).

RASSF8 in Cancer

RASSF8’s initial tumor suppressor role was proposed due to decreased expression in lung adenocarcinomas (Falvella et al. 2006). Moreover, a recent study on melanoma has shown positive correlation between RASSF8 methylation and tumor progression (Wang et al. 2015). In the aforementioned report, RASSF8 significantly inhibited cell growth, cell migration and invasion, whereas its knockdown had an opposing effect by increasing expression of p65 and its downstream target IL6. Additionally, RASSF8 was found to induce apoptosis in melanoma cells by activating the p53-p21 pathway (Wang et al. 2015). A report on childhood leukemia, however, highlighted infrequent methylation of the RASSF8 promoter, thus proving that the methylation status may vary among cancer types (Hesson et al. 2009). A contrasting report on breast cancer identified, among others, RASSF8 mRNA to be enriched in patients’ blood, thus suggesting a role for RASSF8 in cancer progression in this scenario (Rykova et al. 2008).

RASSF9, Ras Association Domain Family Member 9, PAMCI, PCIP1

RASSF9 is located at 12q21.31. It has two isoforms and is the only member of the N-terminal RASSF family that lacks a coiled coil domain and the only one not to be transcribed from a CpG island (Richter et al. 2009) (Fig. 1). It was originally identified in a yeast two-hybrid screen as an interactor of peptidylglycine alpha-amidating monooxygenase (PAM) and was thus named PCIP1 (PAM C-terminal interactor 1) (Alam et al. 1996). In 2008, PCIP1 was renamed RASSF9 given its structural similarities to RASSF7/8 (Sherwood et al. 2008). Interestingly, RASSF9 has been implicated in regulating the trafficking of PAM as it associates with recycling endosomes (Chen 1998). It is also the only member of the N-terminal RASSF proteins that has been shown to interact with Ras proteins (N-,K- and RRas) (Rodriguez-Viciana et al. 2004). While the precise molecular functions of RASSF9 remain unclear, studies suggest that it may be important in epidermal homeostasis. Rassf9-null mice show signs of accelerated aging and defects in epidermal epithelial cell proliferation and differentiation (Lee et al. n.d.). Genetic variants of RASSF9 have been identified that are associated with UV-exposure levels, suggesting that the gene may have recently been evolutionarily selected for (Kita and Fraser n.d.).

RASSF9 in Cancer

To date, there is no clear evidence that RASSF9 has an effect on cancer development. In fact, it was considered a good candidate for colorectal cancer based on its chromosomal localization but was recently ruled out as an influential gene (Sánchez-Tomé et al. 2015). However, there is generally very little data on RASSF9 and given its emerging role in skin development and differentiation; it may yet be uncovered that RASSF9 can play a role in tumorigenesis.

RASSF10, Peptidylglycine Alpha-Amidating Monooxygenase COOH-Terminal Interactor-Like

RASSF10 was discovered by the Chalmers group at locus 11p15.2 and named at the same time as RASSF9 (Sherwood et al. 2008); it contains a RA domain and one coiled coil region (Fig. 1). The molecular functions of RASSF10 remain relatively unknown but the expression of the gene has been found in several tissues (Hesson et al. 2009; Schagdarsurengin et al. 2009; Reeves and Posakony 2005; Hill et al. 2011) and reduction of RASSF10 function has been shown to impair Hedgehog signaling in Drosophila (Nybakken et al. 2005).

RASSF10 in Cancer

Like several of the RASSF genes, the RASSF10 gene has a large CpG island which appears to be the most frequently methylated of the N-terminal family (Underhill-Day et al. 2011) and, following the discovery of its epigenetic silencing in childhood acute lymphocytic leukemia (Hesson et al. 2009), it has been considered a putative tumor suppressor. More recent studies have further supported this notion, as RASSF10 has been found to be epigenetically inactivated in a plethora of cancers including, thyroid (Schagdarsurengin et al. 2009), melanoma (Helmbold et al. 2012), glioma (Hill et al. 2011), lung (Richter et al. 2012), head and neck (Richter et al. 2012), sarcoma (Richter et al. 2012), and pancreatic (Richter et al. 2012).

Concluding Remarks

The RASSF family of proteins is involved in a plethora of physiological functions, such as apoptosis, cytoskeleton dynamics, mitosis, genome stability, and tissue homeostasis. Loss of function, specifically via promoter methylation, of various members of the family has been reported in different tumor types, thus suggesting that some RASSF members could become valuable diagnostic and prognostic markers for cancer onset. However, it is fundamental to further elucidate the roles of RASSFs in physiological and pathological conditions.

References

  1. Agathanggelou A, Cooper WN, Latif F. Role of the Ras-association domain family 1 tumor suppressor gene in human cancers. Cancer Res. 2005;65(9):3497–508. doi:10.1158/0008-5472.CAN-04-4088.PubMedCrossRefGoogle Scholar
  2. Akino K, Toyota M, Suzuki H, et al. The Ras effector RASSF2 is a novel tumor-suppressor gene in human colorectal cancer. Gastroenterology. 2005;129(1):156–69. doi:10.1053/j.gastro.2005.03.051.PubMedCrossRefGoogle Scholar
  3. Alam MR, Caldwell BD, Johnson RC, Darlington DN, Mains RE, Eipper BA. Novel proteins that interact with the COOH-terminal cytosolic routing determinants of an integral membrane peptide-processing enzyme. J Biol Chem. 1996;271(45):28636–40. doi:10.1074/jbc.271.45.28636.PubMedCrossRefGoogle Scholar
  4. Allen NPC, Donninger H, Vos MD, et al. RASSF6 is a novel member of the RASSF family of tumor suppressors. Oncogene. 2007;26(42):6203–11. doi:10.1038/sj.onc.1210440.PubMedCrossRefGoogle Scholar
  5. Amaar YG, Baylink DJ, Mohan S. Ras-association domain family 1 protein, RASSF1C, is an IGFBP-5 binding partner and a potential regulator of osteoblast cell proliferation. J Bone Min Res. 2005;20(8):1430–9. doi:10.1359/JBMR.050311.CrossRefGoogle Scholar
  6. Amaar YG, Minera MG, Hatran LK, Strong DD, Mohan S, Reeves ME. Ras association domain family 1C protein stimulates human lung cancer cell proliferation. Am J Physiol Lung Cell Mol Physiol. 2006;291(6):1185–1190Google Scholar
  7. Aoyama Y, Avruch J, Zhang X. Nore1 inhibits tumor cell growth independent of Ras or the MST1/2 kinases. Oncogene. 2004;23(19):3426–33. doi:10.1038/sj.onc.1207486.PubMedCrossRefGoogle Scholar
  8. Arnette C, Efimova N, Zhu X, Clark GJ, Kaverina I. Microtubule segment stabilization by RASSF1A is required for proper microtubule dynamics and Golgi integrity. Mol Biol Cell. 2014;25(6):800–10. doi:10.1091/mbc.E13-07-0374.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Arora P, Basu A, Schmidt ML, et al. NS5B promotes degradation of the NORE1A tumor suppressor to facilitate hepatitis C virus replication. Hepatology. 2017. doi:10.1002/hep.29049.PubMedGoogle Scholar
  10. Astuti D, Agathanggelou A, Honorio S, et al. RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours. Oncogene. 2001;20(51):7573–7. doi:10.1038/sj.onc.1204968.PubMedCrossRefGoogle Scholar
  11. Avruch J, Praskova M, Ortiz-Vega S, Liu M, Zhang X-FF. Nore1 and RASSF1 regulation of cell proliferation and of the MST1/2 kinases. Methods Enzym. 2006;407(2002):290–310. doi:10.1016/S0076-6879(05)07025-4.CrossRefGoogle Scholar
  12. Baksh S, Tommasi S, Fenton S, et al. The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to Bax conformational change and cell death. Mol Cell. 2005;18(6):637–50. doi:10.1016/j.molcel.2005.05.010.PubMedCrossRefGoogle Scholar
  13. Bee C, Moshnikova A, Mellor CD, et al. Growth and tumor suppressor NORE1A is a regulatory node between Ras signaling and microtubule nucleation. J Biol Chem. 2010;285(21):16258–66. doi:10.1074/jbc.M109.081562.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bergqvist J, Latif A, Roberts SA, et al. RASSF1A polymorphism in familial breast cancer. Fam Cancer. 2010;9(3):263–5. doi:10.1007/s10689-010-9335-8.PubMedCrossRefGoogle Scholar
  15. Bryant D, Becker L, Richardson J, et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-α. Circulation. 1998;97(14):1375–1381Google Scholar
  16. Burbee DG, Forgacs E, Zöchbauer-Müller S, et al. Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst. 2001;93(9):691–9. doi:10.1093/JNCI/93.9.691.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Camps C, Buffa FM, Colella S, et al. hsa-miR-210 is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res. 2008;14(5):1340–8. doi:10.1158/1078-0432.CCR-07-1755.PubMedCrossRefGoogle Scholar
  18. Chang HW, Chan A, Kwong DLW, Wei WI, Sham JST, Yuen APW. Evaluation of hypermethylated tumor suppressor genes as tumor markers in mouth and throat rinsing fluid, nasopharyngeal swab and peripheral blood of nasopharygeal carcinoma patient. Int J Cancer. 2003;105(6):851–5. doi:10.1002/ijc.11162.PubMedCrossRefGoogle Scholar
  19. Chen L. P-CIP1, a novel protein that interacts with the cytosolic domain of peptidylglycine alpha -amidating monooxygenase, is associated with endosomes. J Biol Chem. 1998;273(50):33524–32. doi:10.1074/jbc.273.50.33524.PubMedCrossRefGoogle Scholar
  20. Chow LS, Lo KW, Kwong J, Wong AY, Huang DP. Aberrant methylation of RASSF4/AD037 in nasopharyngeal carcinoma. Oncol Rep. 2004;12(4):781–7. https://www.ncbi.nlm.nih.gov/pubmed/15375500.
  21. Comincini S, Castiglioni BM, Foti GM, Del Vecchio I, Ferretti L. Isolation and molecular characterization of rasfadin, a novel gene in the vicinity of the bovine prion gene. Mamm Genome. 2001;12(2):150–6.PubMedCrossRefGoogle Scholar
  22. Cooper WN, Dickinson RE, Dallol A, et al. Epigenetic regulation of the ras effector/tumour suppressor RASSF2 in breast and lung cancer. Oncogene. 2008;27(12):1805–11. doi:10.1038/sj.onc.1210805.PubMedCrossRefGoogle Scholar
  23. Cooper WN, Hesson LB, Matallanas D, et al. RASSF2 associates with and stabilizes the proapoptotic kinase MST2. Oncogene. 2009;28(33):2988–98. doi:10.1038/onc.2009.152.PubMedPubMedCentralCrossRefGoogle Scholar
  24. da Costa PE, Cavalli LR, Rainho CA. Evidence of epigenetic regulation of the tumor suppressor gene cluster flanking RASSF1 in breast cancer cell lines. Epigenetics. 2011;6(12):1413–24. doi:10.4161/epi.6.12.18271.CrossRefGoogle Scholar
  25. Dallol A, Agathanggelou A, Fenton SL, et al. RASSF1A interacts with microtubule-associated proteins and modulates microtubule dynamics RASSF1A interacts with microtubule-associated proteins and modulates microtubule dynamics. Cancer Res. 2004;16:4112–6.CrossRefGoogle Scholar
  26. Dallol A, Hesson LB, Matallanas D, et al. RAN GTPase is a RASSF1A effector involved in controlling microtubule organization. Curr Biol. 2009;19(14):1227–32. doi:10.1016/j.cub.2009.05.064.PubMedCrossRefGoogle Scholar
  27. Dammann R, Li C, Yoon J-HH, Chin PL, Bates S, Pfeifer GP. Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3. Nat Genet. 2000;25(3):315–9. doi:10.1038/77083.PubMedCrossRefGoogle Scholar
  28. Dammann R, Schagdarsurengin U, Strunnikova M, et al. Epigenetic inactivation of the Ras-association domain family 1 (RASSF1A) gene and its function in human carcinogenesis. Histol Histopathol. 2003a;18(2):665–77. http://www.ncbi.nlm.nih.gov/pubmed/12647816.
  29. Dammann R, Schagdarsurengin U, Liu L, et al. Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma. Oncogene. 2003b;22(24):3806–12. doi:10.1038/sj.onc.1206582.PubMedCrossRefGoogle Scholar
  30. de Caceres II, Battagli C, Esteller M, et al. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res. 2004;64(18):6476–81. doi:10.1158/0008-5472.CAN-04-1529.CrossRefGoogle Scholar
  31. Debeer P, Schoenmakers EFPM, Twal WO, et al. The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly. J Med Genet. 2002;39(2):98–104. doi:10.1136/JMG.39.2.98.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Delre D, Clark GJ. Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice. J Clin Invest. 2010;120. doi:10.1172/JCI43569.Google Scholar
  33. Djos A, Martinsson T, Kogner P, Carén H. The RASSF gene family members RASSF5, RASSF6 and RASSF7 show frequent DNA methylation in neuroblastoma. Mol Cancer. 2012;11:40. doi:10.1186/1476-4598-11-40.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Donninger H, Vos MD, Clark GJ. The RASSF1A tumor suppressor. J Cell Sci. 2007;120(Pt 18):3163–72. doi:10.1242/jcs.010389.PubMedCrossRefGoogle Scholar
  35. Donninger H, Hesson L, Vos M, et al. The Ras effector RASSF2 controls the PAR-4 tumor suppressor. Mol Cell Biol. 2010;30(11):2608–20. doi:10.1128/MCB.00208-09.PubMedPubMedCentralCrossRefGoogle Scholar
  36. Donninger H, Clark JA, Monaghan MK, Schmidt ML, Vos M, Clark GJ. Cell cycle restriction is more important than apoptosis induction for RASSF1A protein tumor suppression. J Biol Chem. 2014;289(45):31287–95. doi:10.1074/jbc.M114.609537.PubMedPubMedCentralCrossRefGoogle Scholar
  37. Donninger H, Clark J, Rinaldo F, et al. The RASSF1A tumor suppressor regulates XPA-mediated DNA repair. Mol Cell Biol. 2015a;35(1):277–87. doi:10.1128/MCB.00202-14.PubMedCrossRefGoogle Scholar
  38. Donninger H, Calvisi DF, Barnoud T, et al. NORE1A is a Ras senescence effector that controls the apoptotic/senescent balance of p53 via HIPK2. J Cell Biol. 2015b;208(6):777–89.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Dreijerink K, Braga E, Kuzmin I, et al. The candidate tumor suppressor gene, RASSF1A, from human chromosome 3p21.3 is involved in kidney tumorigenesis. Proc Natl Acad Sci U S A. 2001;98(13):7504–9. doi:10.1073/pnas.131216298.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Eckfeld K, Hesson L, Vos MD, Bieche I, Latif F, Clark GJ. RASSF4/AD037 is a potential ras effector/tumor suppressor of the RASSF family. Cancer Res. 2004;64(23):8688–93. doi:10.1158/0008-5472.CAN-04-2065.PubMedCrossRefGoogle Scholar
  41. Endoh M, Tamura G, Honda T, et al. RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer. Br J Cancer. 2005;93(12):1395–9. doi:10.1038/sj.bjc.6602854.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Escobar-Cabrera E, Lau DKW, Giovinazzi S, Ishov AM, McIntosh LP. Structural characterization of the DAXX N-terminal helical bundle domain and its complex with Rassf1C. Structure. 2010;18(12):1642–53. doi:10.1016/j.str.2010.09.016.PubMedCrossRefGoogle Scholar
  43. Estrabaud E, Lassot I, Blot G, et al. RASSF1C, an isoform of the tumor suppressor RASSF1A, promotes the accumulation of -catenin by interacting with TrCP. Cancer Res. 2007;67(3):1054–61. doi:10.1158/0008-5472.CAN-06-2530.PubMedCrossRefGoogle Scholar
  44. Falvella FS, Manenti G, Spinola M, et al. Identification of RASSF8 as a candidate lung tumor suppressor gene. Oncogene. 2006;25(28):3934–8. doi:10.1038/sj.onc.1209422.PubMedCrossRefGoogle Scholar
  45. Fiegl H, Gattringer C, Widschwendter A, et al. Methylated DNA collected by tampons – a new tool to detect endometrial cancer. Cancer Epidemiol Biomarkers Prev. 2004;13(5):882–8.PubMedGoogle Scholar
  46. Foley CJ, Freedman H, Choo SL, et al. Dynamics of RASSF1A/MOAP-1 association with death receptors. Mol Cell Biol. 2008;28(14):4520–35. doi:10.1128/MCB.02011-07.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Foukakis T, Au AYM, Wallin G, et al. The Ras effector NORE1A is suppressed in follicular thyroid carcinomas with a PAX8-PPAR γ fusion. J Clin Endocrinol Metab. 2006;91(3):1143–9. doi:10.1210/jc.2005-1372.PubMedCrossRefGoogle Scholar
  48. Friess H, Ding J, Kleeff J, et al. Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancer. Cell Mol Life Sci C. 2003;60(6):1180–99. doi:10.1007/s00018-003-3036-5.CrossRefGoogle Scholar
  49. Fujita H, Fukuhara S, Sakurai A, et al. Local activation of Rap1 contributes to directional vascular endothelial cell migration accompanied by extension of microtubules on which RAPL, a Rap1-associating molecule, localizes. J Biol Chem. 2005;280(6):5022–31. doi:10.1074/jbc.M409701200.PubMedCrossRefGoogle Scholar
  50. Fukatsu A, Ishiguro F, Tanaka I, et al. RASSF3 downregulation increases malignant phenotypes of non-small cell lung cancer. Lung Cancer. 2014;83(1):23–9. doi:10.1016/j.lungcan.2013.10.014.PubMedCrossRefGoogle Scholar
  51. Gao BN, Xie XJ, Huang CX, et al. RASSF1A polymorphism A133S is associated with early onset breast cancer in BRCA1/2 mutation carriers. Cancer Res. 2008;68(1):22–5. doi:10.1158/0008-5472.Can-07-5183.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Geli J, Kogner P, Lanner F, et al. Assessment of NORE1A as a putative tumor suppressor in human neuroblastoma. Int J Cancer. 2008;123(2):389–94. doi:10.1002/ijc.23533.PubMedCrossRefGoogle Scholar
  53. Giovinazzi S, Lindsay CR, Morozov VM, et al. Regulation of mitosis and taxane response by Daxx and Rassf1. Oncogene. 2012;31(1):13–26. doi:10.1038/onc.2011.211.PubMedCrossRefGoogle Scholar
  54. Gordon M, El-Kalla M, Baksh S. RASSF1 polymorphisms in cancer. Mol Biol Int. 2012;2012:365213. doi:10.1155/2012/365213.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Grawenda AM, O’Neill E. Clinical utility of RASSF1A methylation in human malignancies. Br J Cancer. 2015;113(3):372–81. doi:10.1038/bjc.2015.221.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Gulsen T, Hadjicosti I, Li Y, Zhang X, Whitley PR, Chalmers AD. Truncated RASSF7 promotes centrosomal defects and cell death. Dev Biol. 2016;409(2):502–17. doi:10.1016/j.ydbio.2015.11.001.PubMedCrossRefGoogle Scholar
  57. Guo C, Tommasi S, Liu L, Yee J-K, Dammann R, Pfeifer GP. RASSF1A is part of a complex similar to the Drosophila Hippo/Salvador/Lats tumor-suppressor network. Curr Biol. 2007;17(8):700–5. doi:10.1016/j.cub.2007.02.055.PubMedCrossRefGoogle Scholar
  58. Guo W, Cui L, Wang C, et al. Decreased expression of RASSF1A and up-regulation of RASSF1C is associated with esophageal squamous cell carcinoma. Clin Exp Metastasis. 2014;31(5):521–33. doi:10.1007/s10585-014-9646-5.PubMedCrossRefGoogle Scholar
  59. Guo W, Dong Z, Guo Y, et al. Decreased expression and frequent promoter hypermethylation of RASSF2 and RASSF6 correlate with malignant progression and poor prognosis of gastric cardia adenocarcinoma. Mol Carcinog. 2016;55(11):1655–66. doi:10.1002/mc.22416.PubMedCrossRefGoogle Scholar
  60. Hamilton G, Yee KS, Scrace S, O’Neill E. ATM regulates a RASSF1A-dependent DNA damage response. Curr Biol. 2009;19(23):2020–5. doi:10.1016/j.cub.2009.10.040.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Han Y, Dong Q, Hao J, et al. RASSF4 is downregulated in nonsmall cell lung cancer and inhibits cancer cell proliferation and invasion. Tumour Biol. 2016;37(4):4865–71. doi:10.1007/s13277-015-4343-9.PubMedCrossRefGoogle Scholar
  62. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.PubMedCrossRefGoogle Scholar
  63. Harada K, Toyooka S, Maitra A, et al. Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines. Oncogene. 2002;21(27):4345–9. doi:10.1038/sj.onc.1205446.PubMedCrossRefGoogle Scholar
  64. Heallen T, Zhang M, Wang J, et al. Hippo pathway inhibits wnt signaling to restrain cardiomyocyte proliferation and heart size. Science (80- ). 2011;332(6028):458–61. doi:10.1126/science.1199010.CrossRefGoogle Scholar
  65. Helmbold P, Richter AM, Walesch S, et al. RASSF10 promoter hypermethylation is frequent in malignant melanoma of the skin but uncommon in nevus cell nevi. J Invest Dermatol. 2012;132(3):687–94. doi:10.1038/jid.2011.380.PubMedCrossRefGoogle Scholar
  66. Hesson L, Dallol A, Minna JD, Maher ER, Latif F. NORE1A, a homologue of RASSF1A tumour suppressor gene is inactivated in human cancers. Oncogene. 2003;22(6):947–54. doi:10.1038/sj.onc.1206191.PubMedCrossRefGoogle Scholar
  67. Hesson L, Bièche I, Krex D, et al. Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas. Oncogene. 2004;23(13):2408–19. doi:10.1038/sj.onc.1207407.PubMedCrossRefGoogle Scholar
  68. Hesson LB, Wilson R, Morton D, et al. CpG island promoter hypermethylation of a novel Ras-effector gene RASSF2A is an early event in colon carcinogenesis and correlates inversely with K-ras mutations. Oncogene. 2005;24(24):3987–94. doi:10.1038/sj.onc.1208566.PubMedCrossRefGoogle Scholar
  69. Hesson LB, Cooper WN, Latif F. Evaluation of the 3p21.3 tumour-suppressor gene cluster. Oncogene. 2007;26(52):7283–301. doi:10.1038/sj.onc.1210547.PubMedCrossRefGoogle Scholar
  70. Hesson LB, Dunwell TL, Cooper WN, et al. The novel RASSF6 and RASSF10 candidate tumour suppressor genes are frequently epigenetically inactivated in childhood leukaemias. Mol Cancer. 2009;8(1):42. doi:10.1186/1476-4598-8-42.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Hill VK, Underhill-Day N, Krex D, et al. Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis. Oncogene. 2011;30(8):978–89. doi:10.1038/onc.2010.471.PubMedCrossRefGoogle Scholar
  72. Hoque MO, Begum S, Topaloglu O, et al. Quantitative detection of promoter hypermethylation of multiple genes in the tumor, urine, and serum DNA of patients with renal cancer. Cancer Res. 2004;64(15):5511–7. doi:10.1158/0008-5472.CAN-04-0799.PubMedCrossRefGoogle Scholar
  73. Hung J, Kishimoto Y, Sugio K, et al. Allele-specific chromosome 3p deletions occur at an early stage in the pathogenesis of lung carcinoma. JAMA. 1995;273(7):558. doi:10.1001/jama.1995.03520310056030.PubMedCrossRefGoogle Scholar
  74. Hwang E, Ryu K-S, Pääkkönen K, et al. Structural insight into dimeric interaction of the SARAH domains from Mst1 and RASSF family proteins in the apoptosis pathway. Proc Natl Acad Sci U S A. 2007;104(22):9236–41. doi:10.1073/pnas.0610716104.PubMedPubMedCentralCrossRefGoogle Scholar
  75. Ikeda M, Hirabayashi S, Fujiwara N, et al. Ras-association domain family protein 6 induces apoptosis via both caspase-dependent and caspase-independent pathways. Exp Cell Res. 2007;313(7):1484–95. doi:10.1016/j.yexcr.2007.02.013.PubMedCrossRefGoogle Scholar
  76. Ikeda M, Kawata A, Nishikawa M, et al. Hippo pathway-dependent and -independent roles of RASSF6. Sci Signal. 2009;2(90):ra59. doi:10.1126/scisignal.2000300.PubMedCrossRefGoogle Scholar
  77. Ishiguro K, Avruch J, Landry A, et al. Nore1B regulates TCR signaling via Ras and Carma1. Cell Signal. 2006;18(10):1647–54. doi:10.1016/j.cellsig.2006.01.015.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Iwasa H, Kudo T, Maimaiti S, et al. The RASSF6 tumor suppressor protein regulates apoptosis and the cell cycle via MDM2 protein and p53 protein. J Biol Chem. 2013;288(42):30320–9. doi:10.1074/jbc.M113.507384.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Jacquemart IC, Springs AEB, Chen WY. Rassf3 is responsible in part for resistance to mammary tumor development in neu transgenic mice. Int J Oncol. 2009;34(2):517–28.PubMedGoogle Scholar
  80. James D, Levine AJ, Besser D, Hemmati-Brivanlou A. TGF beta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem. Development. 2005;132(6):1273–82. doi:10.1242/dev.01706.PubMedCrossRefGoogle Scholar
  81. Jin J, Smith FD, Stark C, et al. Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. Curr Biol. 2004;14(16):1436–50. doi:10.1016/j.cub.2004.07.051.PubMedCrossRefGoogle Scholar
  82. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128(4):683–92. doi:10.1016/j.cell.2007.01.029.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Jung HY, Jung JS, Whang YM, Kim YH, Jung Hae-Yun Jung Jun Seok WYMKYH. RASSF1A suppresses cell migration through inactivation of HDAC6 and increase of acetylated alpha-tubulin. Cancer Res Treat. 2013;45(2):134–44. doi:10.4143/crt.2013.45.2.134.PubMedPubMedCentralCrossRefGoogle Scholar
  84. Kaira K, Sunaga N, Tomizawa Y, et al. Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers. Int J Oncol. 2007. doi:10.3892/ijo.31.1.169.PubMedGoogle Scholar
  85. Kanzaki H, Hanafusa H, Yamamoto H, et al. Single nucleotide polymorphism at codon 133 of the RASSF1 gene is preferentially associated with human lung adenocarcinoma risk. Cancer Lett. 2006;238(1):128–34. doi:10.1016/j.canlet.2005.07.006.PubMedCrossRefGoogle Scholar
  86. Katagiri K, Maeda A, Shimonaka M, Kinashi T. RAPL, a Rap1-binding molecule that mediates Rap1-induced adhesion through spatial regulation of LFA-1. Nat Immunol. 2003;4(8):741–8. doi:10.1038/ni950.PubMedCrossRefGoogle Scholar
  87. Katagiri K, Imamura M, Kinashi T. Spatiotemporal regulation of the kinase Mst1 by binding protein RAPL is critical for lymphocyte polarity and adhesion. Nat Immunol. 2006;7(9):919–28. doi:10.1038/ni1374.PubMedCrossRefGoogle Scholar
  88. Kaverina I, Straube A. Regulation of cell migration by dynamic microtubules. Semin Cell Dev Biol. 2011;22(9):968–74. doi:10.1016/j.semcdb.2011.09.017.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Khokhlatchev A, Rabizadeh S, Xavier R, et al. Identification of a novel Ras-regulated proapoptotic pathway. Curr Biol. 2002;12(4):253–65. doi:10.1016/S0960-9822(02)00683-8.PubMedCrossRefGoogle Scholar
  90. Kim ST, Lim DS, Canman CE, Kastan MB. Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem. 1999;274(53):37538–43.PubMedCrossRefGoogle Scholar
  91. Kim D-H, Kim JS, Park J-H, et al. Relationship of Ras association domain family 1 methylation and K-ras mutation in primary non-small cell lung cancer. Cancer Res. 2003;63(19):6206–11.PubMedGoogle Scholar
  92. Kita R, Fraser HB. Local adaptation of sun-exposure-dependent gene expression regulation in human skin. Tishkoff SA, ed. PLOS Genet. 2016;12(10):e1006382. doi:10.1371/journal.pgen.1006382.Google Scholar
  93. Kitagawa D, Kajiho H, Negishi T, et al. Release of RASSF1C from the nucleus by Daxx degradation links DNA damage and SAPK/JNK activation. EMBO J. 2006;25(14):3286–97. doi:10.1038/sj.emboj.7601212.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Kok K, Naylor SL, Buys CH. Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res. 1997;71:27–92.PubMedCrossRefGoogle Scholar
  95. Kudo T, Ikeda M, Nishikawa M, et al. The RASSF3 candidate tumor suppressor induces apoptosis and G1-S cell-cycle arrest via p53. Cancer Res. 2012;72(11):2901–11. doi:10.1158/0008-5472.CAN-12-0572.PubMedCrossRefGoogle Scholar
  96. Kumari G, Singhal PK, Rao MRKS, Mahalingam S. Nuclear transport of Ras-associated tumor suppressor proteins: different transport receptor binding specificities for arginine-rich nuclear targeting signals. J Mol Biol. 2007;367(5):1294–311. doi:10.1016/j.jmb.2007.01.026.PubMedCrossRefGoogle Scholar
  97. Kumari G, Singhal PK, Suryaraja R, Mahalingam S. Functional interaction of the Ras effector RASSF5 with the tyrosine kinase lck: critical role in nucleocytoplasmic transport and cell cycle regulation. J Mol Biol. 2010;397(1):89–109. doi:10.1016/j.jmb.2010.01.005.PubMedCrossRefGoogle Scholar
  98. Law J, Salla M, Zare A, et al. Modulator of apoptosis 1 (MOAP-1) is a tumor suppressor protein linked to the RASSF1A protein. J Biol Chem. 2015;290(40):24100–18. doi:10.1074/jbc.M115.648345.PubMedPubMedCentralCrossRefGoogle Scholar
  99. Lee CK, Lee J-H, Lee M-G, et al. Epigenetic inactivation of the NORE1 gene correlates with malignant progression of colorectal tumors. BMC Cancer. 2010;10:577. doi:10.1186/1471-2407-10-577.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Lee C-M, Yang P, Chen L-C, et al. A novel role of RASSF9 in maintaining epidermal homeostasis. Beier F, ed. PLoS One. 2011;6(3):e17867. doi:10.1371/journal.pone.0017867.Google Scholar
  101. Lee D, Park S-J, Sung KS, et al. Mdm2 associates with Ras effector NORE1 to induce the degradation of oncoprotein HIPK1. EMBO Rep. 2012;13(2):163–9. doi:10.1038/embor.2011.235.PubMedCrossRefGoogle Scholar
  102. Lerman MI, Minna JD. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res. 2000;60(21):6116–33.PubMedGoogle Scholar
  103. Li J, Zhang Z, Dai Z, et al. RASSF1A promoter methylation and Kras2 mutations in non small cell lung cancer. Neoplasia. 2003;5(4):362–6.PubMedPubMedCentralCrossRefGoogle Scholar
  104. Li J, Wang F, Protopopov A, et al. Inactivation of RASSF1C during in vivo tumor growth identifies it as a tumor suppressor gene. Oncogene. 2004;23(35):5941–9. doi:10.1038/sj.onc.1207789.PubMedCrossRefGoogle Scholar
  105. Li X, Zhao G, Wang Y, Zhang J, Duan Z, Xin S. RASSF7 and RASSF8 proteins are predictive factors for development and metastasis in malignant thyroid neoplasms. J Cancer Res Ther. 2013;9 (Suppl 7):S173–7. doi:10.4103/0973–1482.122519.Google Scholar
  106. Lian I, Kim J, Okazawa H, et al. The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev. 2010;24(11):1106–18. doi:10.1101/gad.1903310.PubMedPubMedCentralCrossRefGoogle Scholar
  107. Liang G-P, Su Y-Y, Chen J, Yang Z-C, Liu Y-S, Luo X-D. Analysis of the early adaptive response of endothelial cells to hypoxia via a long serial analysis of gene expression. Biochem Biophys Res Commun. 2009;384:415–9. doi:10.1016/j.bbrc.2009.04.160.PubMedCrossRefGoogle Scholar
  108. Liu L, Katrin Baier RHD & GPP. The tumor suppressor RASSF1A does not interact with Cdc20, an activator of the anaphase promoting complex. Cell Cycle. 2007;6(13):1663–5.PubMedCrossRefGoogle Scholar
  109. Liu L, Tommasi S, Lee D-H, Dammann R, Pfeifer GP. Control of microtubule stability by the RASSF1A tumor suppressor. Oncogene. 2003;22(50):8125–36. doi:10.1038/sj.onc.1206984.PubMedCrossRefGoogle Scholar
  110. Liu Z-H, Huo J-L, Wu Z-G, et al. RASSF7 expression and its regulatory roles on apoptosis in human intervertebral disc degeneration. Int J Clin Exp Pathol. 2015;8(12):16097–103.PubMedPubMedCentralGoogle Scholar
  111. Lo KW, Kwong J, Hui AB, et al. High frequency of promoter hypermethylation of RASSF1A in nasopharyngeal carcinoma. Cancer Res. 2001;61(10):3877–81.PubMedGoogle Scholar
  112. Lock FE, Underhill-Day N, Dunwell T, et al. The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways. Oncogene. 2010;29(30):4307–16. doi:10.1038/onc.2010.192.PubMedCrossRefGoogle Scholar
  113. Logsdon CD, Simeone DM, Binkley C, et al. Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. Cancer Res. 2003;63(10):2649–57.PubMedGoogle Scholar
  114. Lorenzato A, Martino C, Dani N, et al. The cellular apoptosis susceptibility CAS/CSE1L gene protects ovarian cancer cells from death by suppressing RASSF1C. FASEB J. 2012;26(6):2446–56. doi:10.1096/fj.11-195982.PubMedCrossRefGoogle Scholar
  115. Lowe AW, Olsen M, Hao Y, et al. Gene expression patterns in pancreatic tumors, cells and tissues. PLoS One. 2007;2(3):1–11. doi:10.1371/journal.pone.0000323.CrossRefGoogle Scholar
  116. Macheiner D, Heller G, Kappel S, et al. NORE1B, a candidate tumor suppressor, is epigenetically silenced in human hepatocellular carcinoma. J Hepatol. 2006;45(1):81–9. doi:10.1016/j.jhep.2005.12.017.PubMedCrossRefGoogle Scholar
  117. Malpeli G, Amato E, Dandrea M, et al. Methylation-associated down-regulation of RASSF1A and up-regulation of RASSF1Cin pancreatic endocrine tumors. BMC Cancer. 2011;11(1):351. doi:10.1186/1471-2407-11-351.PubMedPubMedCentralCrossRefGoogle Scholar
  118. Matallanas D, Romano D, Yee K, et al. RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein. Mol Cell. 2007;27(6):962–75. doi:10.1016/j.molcel.2007.08.008.PubMedPubMedCentralCrossRefGoogle Scholar
  119. Matallanas D, Romano D, Al-Mulla F, et al. Mutant K-Ras activation of the proapoptotic MST2 pathway is antagonized by wild-type K-Ras. Mol Cell. 2011;44(6):893–906. doi:10.1016/j.molcel.2011.10.016.PubMedCrossRefGoogle Scholar
  120. Mezzanotte JJ, Hill V, Lee Schmidt M, et al. RASSF6 exhibits promoter hypermethylation in metastatic melanoma and inhibits invasion in melanoma cells. Epigenetics. 2014;9(11):1496–503. doi:10.4161/15592294.2014.983361.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Michifuri Y, Hirohashi Y, Torigoe T, et al. Small proline-rich protein-1B is overexpressed in human oral squamous cell cancer stem-like cells and is related to their growth through activation of MAP kinase signal. Biochem Biophys Res Commun. 2013;439(1):96–102. doi:10.1016/j.bbrc.2013.08.021.PubMedCrossRefGoogle Scholar
  122. Morris MR, Hesson LB, Wagner KJ, et al. Multigene methylation analysis of Wilms’ tumour and adult renal cell carcinoma. Oncogene. 2003a;22(43):6794–801. doi:10.1038/sj.onc.1206914.PubMedCrossRefGoogle Scholar
  123. Morris JA, Kandpal G, Ma L, Austin CP. DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet. 2003b;12(13):1591–608. doi:10.1093/hmg/ddg162.PubMedCrossRefGoogle Scholar
  124. Moshnikova A, Frye J, Shay JW, Minna JD, Khokhlatchev AV. The growth and tumor suppressor NORE1A is a cytoskeletal protein that suppresses growth by inhibition of the ERK pathway. J Biol Chem. 2006;281(12):8143–52. doi:10.1074/jbc.M511837200.PubMedCrossRefGoogle Scholar
  125. Mutter GL, Baak JPA, Fitzgerald JT, et al. Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. Gynecol Oncol. 2001;83(2):177–85. doi:10.1006/gyno.2001.6352.PubMedCrossRefGoogle Scholar
  126. Nakamura N, Carney JA, Jin L, et al. RASSF1A and NORE1A methylation and BRAFV600E mutations in thyroid tumors. Lab Investig. 2005;85(9):1065–75. doi:10.1038/labinvest.3700306.PubMedCrossRefGoogle Scholar
  127. Nakamura T, Yasuda S, Nagai H, et al. Longest neurite-specific activation of Rap1B in hippocampal neurons contributes to polarity formation through RalA and Nore1A in addition to PI3-kinase. Genes to Cells. 2013;18(11):1020–31. doi:10.1111/gtc.12097.PubMedCrossRefGoogle Scholar
  128. Newton AC. Protein kinase C. Seeing two domains. Curr Biol. 1995;5(9):973–6. doi:10.1016/S0960-9822(95)00191-6.PubMedCrossRefGoogle Scholar
  129. Nosho K, Yamamoto H, Takahashi T, et al. Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers. Carcinogenesis. 2007;28(6):1364–70. doi:10.1093/carcin/bgl246.PubMedCrossRefGoogle Scholar
  130. Nybakken K, Vokes SA, Lin TY, McMahon AP, Perrimon N. A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway. Nat Genet. 2005;37. doi:10.1038/ng1682.Google Scholar
  131. Oceandy D, Pickard A, Prehar S, et al. Tumor suppressor Ras-association domain family 1 isoform A is a novel regulator of cardiac hypertrophy. Circulation. 2009;120(7):607–U125. doi:10.1161/Circulationaha.109.868554.PubMedCrossRefGoogle Scholar
  132. Ortiz-Vega S, Khokhlatchev A, Nedwidek M, et al. The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1. Oncogene. 2002;21(9):1381–90. doi:10.1038/sj.onc.1205192.PubMedCrossRefGoogle Scholar
  133. Park H-W, Kang HC, Kim I-J, et al. Correlation between hypermethylation of theRASSF2A promoter and K-ras/BRAF mutations in microsatellite-stable colorectal cancers. Int J Cancer. 2007;120(1):7–12. doi:10.1002/ijc.22276.PubMedCrossRefGoogle Scholar
  134. Park J, Kang SI, Lee S-Y, et al. Tumor suppressor ras association domain family 5 (RASSF5/NORE1) mediates death receptor ligand-induced apoptosis. J Biol Chem. 2010;285(45):35029–38. doi:10.1074/jbc.M110.165506.PubMedPubMedCentralCrossRefGoogle Scholar
  135. Pefani DE, Latusek R, Pires I, et al. RASSF1A-LATS1 signalling stabilizes replication forks by restricting CDK2-mediated phosphorylation of BRCA2. Nat Cell Biol. 2014. doi:10.1038/ncb3035.PubMedPubMedCentralGoogle Scholar
  136. Pefani DE, Pankova D, Abraham AG, et al. TGF-beta targets the hippo pathway scaffold RASSF1A to facilitate YAP/SMAD2 nuclear translocation. Mol Cell. 2016;63(1):156–66. doi:10.1016/j.molcel.2016.05.012.PubMedCrossRefGoogle Scholar
  137. Pelosi G, Fumagalli C, Trubia M, et al. Dual role of RASSF1 as a tumor suppressor and an oncogene in neuroendocrine tumors of the lung. Anticancer Res. 2010;30(10):4269–81. http://www.ncbi.nlm.nih.gov/pubmed/21036752.
  138. Ponting CP, Benjamin DR. A novel family of Ras-binding domains. Trends Biochem Sci. 1996;21(11):422–5. http://www.ncbi.nlm.nih.gov/pubmed/8987396.
  139. Porteous DJ, Millar JK, Brandon NJ, Sawa A. DISC1 at 10: connecting psychiatric genetics and neuroscience. Trends Mol Med. 2011;17(12):699–706. doi:10.1016/j.molmed.2011.09.002.PubMedPubMedCentralCrossRefGoogle Scholar
  140. Praskova M, Khoklatchev A, Ortiz-Vega S, Avruch J. Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem J. 2004;381(Pt 2):453–62. doi:10.1042/BJ20040025.PubMedPubMedCentralCrossRefGoogle Scholar
  141. Rabizadeh S, Xavier RJ, Ishiguro K, et al. The scaffold protein CNK1 interacts with the tumor suppressor RASSF1A and augments RASSF1A-induced cell death. J Biol Chem. 2004;279(28):29247–54. doi:10.1074/jbc.M401699200.PubMedCrossRefGoogle Scholar
  142. Recino A, Sherwood V, Flaxman A, et al. Human RASSF7 regulates the microtubule cytoskeleton and is required for spindle formation, Aurora B activation and chromosomal congression during mitosis. Biochem J. 2010;430(2):207–13. doi:10.1042/BJ20100883.PubMedPubMedCentralCrossRefGoogle Scholar
  143. Reeves N, Posakony JW. Genetic programs activated by proneural proteins in the developing Drosophila PNS. Dev Cell. 2005;8. doi:10.1016/j.devcel.2005.01.020.Google Scholar
  144. Reeves ME, Baldwin SW, Baldwin ML, et al. Ras-association domain family 1C protein promotes breast cancer cell migration and attenuates apoptosis. BMC Cancer. 2010;10:562. doi:10.1186/1471-2407-10-562.PubMedPubMedCentralCrossRefGoogle Scholar
  145. Reeves ME, Baldwin ML, Aragon R, et al. RASSF1C modulates the expression of a stem cell renewal gene, PIWIL1. BMC Res Notes. 2012;5:239. doi:10.1186/1756-0500-5-239.PubMedPubMedCentralCrossRefGoogle Scholar
  146. Reeves ME, Firek M, Chen S-TT, Amaar Y. The RASSF1 gene and the opposing effects of the RASSF1A and RASSF1C isoforms on cell proliferation and apoptosis. Mol Biol Int. 2013;2013:145096. doi:10.1155/2013/145096.PubMedPubMedCentralCrossRefGoogle Scholar
  147. Reeves MME, Firek M, Chen S-TS-TTS, et al. Evidence that RASSF1C stimulation of lung cancer cell proliferation depends on IGFBP-5 and PIWIL1 expression levels. Pallante P, ed. PLoS One. 2014;9(7):e101679. doi:10.1371/journal.pone.0101679.PubMedPubMedCentralCrossRefGoogle Scholar
  148. Reifenberger J, Knobbe CB, Sterzinger AA, et al. Frequent alterations of Ras signaling pathway genes in sporadic malignant melanomas. Int J Cancer. 2004;109(3):377–84. doi:10.1002/ijc.11722.PubMedCrossRefGoogle Scholar
  149. Richter AM, Pfeifer GP, Dammann RH. The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim Biophys Acta. 2009;1796(2):114–28. doi:10.1016/j.bbcan.2009.03.004.PubMedGoogle Scholar
  150. Richter AM, Walesch SK, Würl P, Taubert H, Dammann RH. The tumor suppressor RASSF10 is upregulated upon contact inhibition and frequently epigenetically silenced in cancer. Oncogenesis. 2012;1(6):e18. doi:10.1038/oncsis.2012.18.PubMedPubMedCentralCrossRefGoogle Scholar
  151. Richter AM, Zimmermann T, Haag T, Walesch SK, Dammann RH. Promoter methylation status of Ras-association domain family members in pheochromocytoma. Front Endocrinol. 2015;6:21. doi:10.3389/fendo.2015.00021.CrossRefGoogle Scholar
  152. Rodriguez-Viciana P, Sabatier C, McCormick F. Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol Cell Biol. 2004;24(11):4943–54. doi:10.1128/MCB.24.11.4943-4954.2004.PubMedPubMedCentralCrossRefGoogle Scholar
  153. Rong R, Jin W, Zhang J, Saeed Sheikh M, Huang Y. Tumor suppressor RASSF1A is a microtubule-binding protein that stabilizes microtubules and induces G2/M arrest. Oncogene. 2004;23(50):8216–30. doi:10.1038/sj.onc.1207901.PubMedCrossRefGoogle Scholar
  154. Rong R, Jiang LY, Sheikh MS, Huang Y. Mitotic kinase Aurora-A phosphorylates RASSF1A and modulates RASSF1A-mediated microtubule interaction and M-phase cell cycle regulation. Oncogene. 2007;26(55):7700–8. doi:10.1038/sj.onc.1210575.PubMedCrossRefGoogle Scholar
  155. Rykova EY, Skvortsova TE, Hoffmann AL, et al. Breast cancer diagnostics based on extracellular DNA and RNA circulating in blood. Biochem Suppl Ser B Biomed Chem. 2008;2(2):208–13. doi:10.1134/S1990750808020133.Google Scholar
  156. Sánchez-Tomé E, Rivera B, Perea J, et al. Genome-wide linkage analysis and tumoral characterization reveal heterogeneity in familial colorectal cancer type X. J Gastroenterol. 2015;50(6):657–66. doi:10.1007/s00535-014-1009-0.PubMedCrossRefGoogle Scholar
  157. Schagdarsurengin U, Richter AM, Wöhler C, Dammann RH. Frequent epigenetic inactivation of RASSF10 in thyroid cancer. Epigenetics. 2009;4(8):571–6. doi:10.4161/epi.4.8.10056.PubMedCrossRefGoogle Scholar
  158. Scheel H, Hofmann K. A novel inter action motif, SARAH, connects three classes of tumor suppressor. Curr Biol. 2003;13(23):R899–900. doi:10.1016/j.cub.2003.11.007.PubMedCrossRefGoogle Scholar
  159. Schmidt M, Calvisi D, Clark G. NORE1A regulates MDM2 via β-TrCP. Cancers (Basel). 2016;8(4):39. doi:10.3390/cancers8040039.CrossRefGoogle Scholar
  160. Sekido, Y., Ahmadian, M., II, W., Latif, F., Bader, S., Wei, M. H., … Minna, J. D. Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene. Oncogene, 1998;16(24):3151–3157. http://doi.org/10.1038/sj.onc.1201858.
  161. Sherwood V, Manbodh R, Sheppard C, ADC. RASSF7 is a member of a new family of RAS association domain-containing proteins and is required for completing mitosis. Mol Biol Cell. 2008;19(4):1772–82.PubMedPubMedCentralCrossRefGoogle Scholar
  162. Shivakumar L, Minna J, Sakamaki T, Pestell R, White MA. The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation. Mol Cell Biol. 2002;22(12):4309–18. http://www.ncbi.nlm.nih.gov/pubmed/12024041.
  163. Song MS, Song SJ, Kim SY, Oh HJ, Lim DS. The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex. EMBO J. 2008;27(13):1863–74. doi:10.1038/emboj.2008.115.PubMedPubMedCentralCrossRefGoogle Scholar
  164. Song SJ, Song MS, Kim SJ, et al. Aurora A regulates prometaphase progression by inhibiting the ability of RASSF1A to suppress APC-Cdc20 activity. Cancer Res. 2009;69(6):2314–23.PubMedCrossRefGoogle Scholar
  165. Song H, Oh S, Oh HJ, Lim D-S. Role of the tumor suppressor RASSF2 in regulation of MST1 kinase activity. Biochem Biophys Res Commun. 2010;391(1):969–73. doi:10.1016/j.bbrc.2009.11.175.PubMedCrossRefGoogle Scholar
  166. Steiner G, Cairns P, Polascik TJ, et al. High-density mapping of chromosomal arm 1q in renal collecting duct carcinoma: region of minimal deletion at 1q32.1–32.2. Cancer Res. 1996;56(21):5044–6.PubMedGoogle Scholar
  167. Strano S, Monti O, Pediconi N, et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA damage. Mol Cell. 2005;18(4):447–59. doi:10.1016/j.molcel.2005.04.008.PubMedCrossRefGoogle Scholar
  168. Sun M, Chen M, Dawood F, et al. Tumor necrosis factor-α mediates cardiac remodeling and ventricular dysfunction after pressure overload state. Circulation. 2007;115(11):1398–1407Google Scholar
  169. Sundaresan V, Ganly P, Hasleton P, et al. p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus. Oncogene. 1992;7(10):1989–97.PubMedGoogle Scholar
  170. Sup Song M, Sook Chang J, Jeong Song S, Hong Yang T, Lee H, Lim D-S. The centrosomal protein RAS association domain family protein 1A (RASSF1A)-binding protein 1 regulates mitotic progression by recruiting RASSF1A to spindle poles. J Biol Chem. 2004. doi:10.1074/jbc.M409115200.Google Scholar
  171. Suryaraja R, Anitha M, Anbarasu K, Kumari G, Mahalingam S, Ca I. The E3 ubiquitin ligase Itch regulates tumor suppressor protein RASSF5/NORE1 stability in an acetylation-dependent manner. Cell Death Dis. 2013;4(3):e565. doi:10.1038/cddis.2013.91.PubMedPubMedCentralCrossRefGoogle Scholar
  172. Takahashi S, Ebihara A, Kajiho H, Kontani K, Nishina H, Katada T. RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7. Cell Death Differ. 2011;18(4):645–55. doi:10.1038/cdd.2010.137.PubMedCrossRefGoogle Scholar
  173. Tan DSP, Lambros MBK, Rayter S, et al. PPM1D is a potential therapeutic target in ovarian clear cell carcinomas. Clin Cancer Res. 2009;15(7):2269–80. doi:10.1158/1078-0432.CCR-08-2403.PubMedCrossRefGoogle Scholar
  174. Teng IW, Hou PC, Lee KD, et al. Targeted methylation of two tumor suppressor genes is sufficient to transform mesenchymal stem cells into cancer stem/initiating cells. Cancer Res. 2011;71(13):4653–63. doi:10.1158/0008-5472.CAN-10-3418.PubMedCrossRefGoogle Scholar
  175. Thaler S, Hähnel PS, Schad A, Dammann R, Schuler M. RASSF1A mediates p21Cip1/Waf1-dependent cell cycle arrest and senescence through modulation of the Raf-MEK-ERK pathway and inhibition of Akt. Cancer Res. 2009;69(5):1748–57.PubMedCrossRefGoogle Scholar
  176. Tommasi S, Dammann R, Jin S-GG, Zhang XF, Avruch J, Pfeifer GP. RASSF3 and NORE1: identification and cloning of two human homologues of the putative tumor suppressor gene RASSF1. Oncogene. 2002;21(17):2713–20. doi:10.1038/sj/onc/1205365.PubMedCrossRefGoogle Scholar
  177. Tommasi S, Dammann R, Zhang Z, et al. Tumor susceptibility of Rassf1a knockout mice. Cancer Res. 2005;65(1):92 LP-98.Google Scholar
  178. Topaloglu O, Hoque MO, Tokumaru Y, et al. Detection of promoter hypermethylation of multiple genes in the tumor and bronchoalveolar lavage of patients with lung cancer. Clin Cancer Res. 2004;10(7):2284–8.PubMedCrossRefGoogle Scholar
  179. Underhill-Day N, Hill V, Latif F. N-terminal RASSF family: RASSF7-RASSF10. Epigenetics. 2011;6(3):284–92. doi:10.4161/epi.6.3.14108.PubMedPubMedCentralCrossRefGoogle Scholar
  180. van der Weyden L, Adams DJ. The Ras-association domain family (RASSF) members and their role in human tumourigenesis. Biochim Biophys Acta. 2007;1776(1):58–85. doi:10.1016/j.bbcan.2007.06.003.PubMedPubMedCentralGoogle Scholar
  181. van der Weyden L, Tachibana KK, Gonzalez MA, et al. The RASSF1A isoform of RASSF1 promotes microtubule stability and suppresses tumorigenesis. Mol Cell Biol. 2005;25(18):8356–67. doi:10.1128/MCB.25.18.8356-8367.2005.PubMedPubMedCentralCrossRefGoogle Scholar
  182. van Engeland M, Roemen GM, Brink M, et al. K-ras mutations and RASSF1A promoter methylation in colorectal cancer. Oncogene. 2002;21(23):3792–5. doi:10.1038/sj.onc.1205466.PubMedCrossRefGoogle Scholar
  183. van Hemert MJ, Steensma HY, van Heusden GPH. 14-3-3 proteins: key regulators of cell division, signalling and apoptosis. BioEssays. 2001;23(10):936–46. doi:10.1002/bies.1134.PubMedCrossRefGoogle Scholar
  184. Varelas X, Sakuma R, Samavarchi-Tehrani P, et al. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol. 2008;10(7):837–48. doi:10.1038/ncb1748.PubMedCrossRefGoogle Scholar
  185. Vasseur S, Malicet C, Calvo EL, et al. Gene expression profiling by DNA microarray analysis in mouse embryonic fibroblasts transformed by rasV12 mutated protein and the E1A oncogene. Mol Cancer. 2003;2(1):19. doi:10.1186/1476-4598-2-19.PubMedPubMedCentralCrossRefGoogle Scholar
  186. Vavvas D, Li X, Avruch J, Zhang X-F. Identification of Nore1 as a potential Ras effector. J Biol Chem. 1998;273(10):5439–42. doi:10.1074/jbc.273.10.5439.PubMedCrossRefGoogle Scholar
  187. Vlahov N, Scrace S, Soto MS, et al. Alternate RASSF1 transcripts control SRC activity, E-cadherin contacts, and YAP-mediated invasion. Curr Biol. 2015;25:1–16. doi:10.1016/j.cub.2015.09.072.Google Scholar
  188. Vos MD, Ellis CA, Bell A, Birrer MJ, Clark GJ. Ras uses the novel tumor suppressor RASSF1 as an effector to mediate apoptosis. J Biol Chem. 2000;275(46):35669–72. doi:10.1074/jbc.C000463200.PubMedCrossRefGoogle Scholar
  189. Vos MD, Ellis CA, Elam C, Ulku AS, Taylor BJ, Clark GJ. RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor. J Biol Chem. 2003a;278(30):28045–51. doi:10.1074/jbc.M300554200.PubMedCrossRefGoogle Scholar
  190. Vos MD, Martinez A, Ellis CA, Vallecorsa T, Clark GJ. The pro-apoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung. J Biol Chem. 2003b;278(24):21938–43. doi:10.1074/jbc.M211019200.PubMedCrossRefGoogle Scholar
  191. Vos MD, Martinez A, Elam C, et al. A role for the RASSF1A tumor suppressor in the regulation of tubulin polymerization and genomic stability. Cancer Res. 2004;64(12):4244–4250.Google Scholar
  192. Vos MD, Dallol A, Eckfeld K, et al. The RASSF1A tumor suppressor activates Bax via MOAP-1. J Biol Chem. 2006;281. doi:10.1074/jbc.M512128200.Google Scholar
  193. Wang J, Hua W, Huang SK, et al. RASSF8 regulates progression of cutaneous melanoma through nuclear factor-κb. Oncotarget. 2015;6(30):30165–77. doi:10.18632/oncotarget.5030.PubMedPubMedCentralCrossRefGoogle Scholar
  194. Wang S, Liang Q, Qiao H, et al. DISC1 regulates astrogenesis in the embryonic brain via modulation of RAS/MEK/ERK signaling through RASSF7. Development. 2016;143(15):2732–40. doi:10.1242/dev.133066.PubMedCrossRefGoogle Scholar
  195. Wang Y, Yu A, Yu F-X. The Hippo pathway in tissue homeostasis and regeneration. Protein Cell. 2017. doi:10.1007/s13238-017-0371-0.Google Scholar
  196. Weitzel JN, Kasperczyk A, Mohan C, Krontiris TG. The HRAS1 gene cluster: two upstream regions recognizing transcripts and a third encoding a gene with a leucine zipper domain. Genomics. 1992;14(2):309–19. doi:10.1016/s0888-7543(05)80221-6.PubMedCrossRefGoogle Scholar
  197. Wen Y, Wang Q, Zhou C, et al. Decreased expression of RASSF6 is a novel independent prognostic marker of a worse outcome in gastric cancer patients after curative surgery. Ann Surg Oncol. 2011;7–11. doi:10.1245/s10434–011–1668-5.Google Scholar
  198. Wistuba II, Bryant D, Behrens C, et al. Comparison of features of human lung cancer cell lines and their corresponding tumors. Clin Cancer Res. 1999;5(5):991–1000.PubMedGoogle Scholar
  199. Wistuba II, Behrens C, Virmani AK, et al. High resolution chromosome 3p allelotyping of human lung cancer and preneoplastic/preinvasive bronchial epithelium reveals multiple, discontinuous sites of 3p allele loss and three regions of frequent breakpoints. Cancer Res. 2000;60(7):1949–60.PubMedGoogle Scholar
  200. Yamamoto T, Taya S, Kaibuchi K. Ras-induced transformation and signaling pathway. J Biochem. 1999;126(5):799–803. http://www.ncbi.nlm.nih.gov/pubmed/10544270.
  201. Yee KS, Grochola L, Hamilton G, et al. A RASSF1A polymorphism restricts p53/p73 activation and associates with poor survival and accelerated age of onset of soft tissue sarcoma. Cancer Res. 2012;72(9):2206–17. doi:10.1158/0008-5472.CAN-11-2906.PubMedPubMedCentralCrossRefGoogle Scholar
  202. Yokoyama T, Nakano M, Bednarczyk JL, McIntyre BW, Entman M, Mann DL. Tumor necrosis factor-α provokes a hypertrophic growth response in adult cardiac myocytes. Circulation. 1997;95(5):1247–1252Google Scholar
  203. Zhang Z, Sun D, Van DN, Tang A, Hu L, Huang G. Inactivation of RASSF2A by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma. Int J Cancer. 2007;120(1):32–8. doi:10.1002/ijc.22185.PubMedCrossRefGoogle Scholar
  204. Zhang M, Wang D, Zhu T, Yin R. RASSF4 overexpression inhibits the proliferation, invasion, EMT, and wnt signaling pathway in osteosarcoma cells. Oncol Res. 2017;25(1):83–91. doi:10.3727/096504016X14719078133447.PubMedCrossRefGoogle Scholar
  205. Zhou X, Li T-T, Feng X, et al. Targeted polyubiquitylation of RASSF1C by the Mule and SCFβ-TrCP ligases in response to DNA damage. Biochem J. 2012;441(1):227–236Google Scholar
  206. Zhou X-H, Yang C-Q, Zhang C-L, Gao Y, Yuan H-B, Wang C. RASSF5 inhibits growth and invasion and induces apoptosis in osteosarcoma cells through activation of MST1/LATS1 signaling. Oncol Rep. 2014. doi:10.3892/or.2014.3387.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Leanne Bradley
    • 1
  • Delia Koennig
    • 1
  • Maria Laura Tognoli
    • 1
  • Jelte van der Vaart
    • 1
  • Eric O’Neill
    • 1
  1. 1.Department of Oncology, CRUK/MRC Oxford Institute for Radiation OncologyUniversity of OxfordOxfordUK