Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

MAP/Microtubule Affinity-Regulating Kinase

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101717

Synonyms

Historical Background

Microtubule-associated protein (MAP)/microtubule affinity-regulating kinase [MARK] was first identified for its role in phosphorylating tau, a MAP implicated in Alzheimer’s disease [AD] (Drewes et al. 1995). Following this discovery, four MARK isoforms were identified in humans and rodents, all of which phosphorylate tau, MAP2, and MAP4 (Drewes et al. 1995; Illenberger et al. 1996; Drewes 2004). Phosphorylation of MAPs causes them to dissociate from microtubules [MTs] leading to MT destabilization (Drewes et al. 1997, 1998). Tau has been the subject of intensive studies because its phosphorylation is elevated in the AD brain. Since MARK phosphorylates tau, it is a candidate of prime interest as a possible therapeutic target in treating AD and other brain disorders (Drewes 2004; Naz et al. 2013). MARK has also been found to be involved in cancer, metabolic disorder and autism (Maussion et al. 2008), and possibly male infertility (Tang et al. 2013). MARK is the human ortholog of PAR-1 (partitioning defective 1, a polarity protein), which was first discovered for its role in cytoplasmic partitioning in the early embryo in C. elegans (Kemphues 2000; Goldstein and Macara 2007; Tang and Chisholm 2016). Like PAR-1, MARK belongs to the Ser/Thr protein kinase family and is involved in regulation of a number of cellular processes, such as regulation of cell polarity, microtubule dynamics (i.e., assembly, disassembly and stabilization), cell cycle control, and intracellular signaling (McDonald 2014; Black 2016).

Structure and Regulation

The MARK family are Ser/Thr kinases and consist of four proteins, MARK1, MARK2, MARK3, and MARK4 (hPAR-1c, hPAR-1b, hPAR-1a, and hPAR-1d, respectively), which arise from a family of four closely related genes, MARK1–4 (Drewes et al. 1998). The structure of MARK kinases is highly conserved, and they share 45% sequence homology overall based on a comparison of their open reading frames (Drewes et al. 1998). These isoforms form a subgroup of adenosine monophosphate-activated protein kinases (AMPK), which belong to the calcium/calmodulin-dependent protein kinase (CAMK) family (Drewes et al. 1998; Naz et al. 2013). MARK kinases are comprised of an N-terminal domain (N), followed by a catalytic kinase domain, linker/common docking (CD) domain, ubiquitin-associated domain (UBA), and spacer and tail domains, all of which are conserved (Marx et al. 2010) (Fig. 1). The function of the N-terminal head is unknown. The catalytic domain contains phosphorylation sites that can either activate or inactivate MARK activity. The linker/CD domain connects the catalytic domain to the UBA domain and may serve as a common docking site for binding partners of MAP kinases and other cofactors (Marx et al. 2010). The function of the UBA domain is unclear as its affinity to bind to ubiquitin is weak (Murphy et al. 2007). The UBA domain may simply serve to stabilize the neighboring kinase domains and has also been suggested to play inhibitory and activating roles based on phosphorylation state of MARK (Marx et al. 2010; Reiner and Sapir 2014). The spacer domain is the most variable region of MARK isoforms and it also contains sites of phosphorylation (Hurov et al. 2004; Suzuki et al. 2004). The tail domain of many MARK isoforms contains a kinase-associated 1 (KA1) domain. The role of the KA1 domain may help to target MARK to the plasma membrane by binding to phospholipids (Moravcevic et al. 2010). See Fig. 1.
MAP/Microtubule Affinity-Regulating Kinase, Fig. 1

Schematic diagram of MARK isoforms. There are four MARK isoforms in humans and they each have six domains: (1) N-terminal domain (N), (2) catalytic domain, (3) common docking (CD) site, (4) ubiquitin-associated domain (UBA), (5) spacer domain, and (6) C-terminal tail domain. MARK isoform lengths are based on UniProt entries for human MARK1–4 (Q9P0L2, Q7KZI7, P27448, and Q96L34, respectively). The corresponding polypeptide for MARK1, MARK2, MARK3, and MARK4 has 795, 788, 753, and 752 amino acid residues

MARK is regulated by a number of mechanisms through interactions of other proteins with its functional domains which are summarized in Table 1 (for reviews, see (Drewes 2004; Naz et al. 2013; Reiner and Sapir 2014)).
MAP/Microtubule Affinity-Regulating Kinase, Table 1

Function of different domains of MARKs

Domain

Regulatory mechanism

Effect

References

Catalytic

Binding of 14-3-3, PAK5

Inhibition

Matenia et al. (2005)

 

Phosphorylation by CaMKI

Activation

Uboha et al. (2007)

 

Phosphorylation by MARKK (TAO1), LKB1 at Thr208 (MARK2)

Activation

Lizcano et al. (2004)

 

Phosphorylation by GSK3ß at Ser212 (MARK2)

Inhibition

Timm et al. (2008)

Spacer

Phosphorylation of aPKC at Thr595 (MARK2)

Inhibition

Hurov et al. 2004 and Suzuki et al. (2004)

 

Binding of 14-3-3

Inhibition

Muller et al. (2003) and Hurov and Piwnica-Worms (2007)

UBA

Binding of polyubiquitin

Unclear

Al-Hakim et al. (2008)

Tail (KA1)

Intramolecular binding to catalytic domain

Inhibition

Elbert et al. (2005)

Function

MARK has diverse roles in the cell. Its ortholog, PAR-1, was originally identified in a screening study to uncover genes that were involved in asymmetric division in the embryo of C. elegans. PAR-1 was also found to localize asymmetrically in Drosophila oocytes (Shulman et al. 2000). In mammalian epithelial cells, MARK is excluded from the apical domain and is located basolaterally (Suzuki et al. 2004). These earlier findings thus establish its function as a polarity protein and it is conserved across species. MARK has also been well-studied for its regulation of MT dynamics, initially for its association in early AD pathogenesis (Drewes et al. 1998; Drewes 2004).

Microtubules are dynamic polymers comprised of α- and ß-tubulins. They are intrinsically polar, with ends designated plus and minus, in reference to fast and slow growth of MTs at those ends, respectively (Mitchison and Kirschner 1984; Desai and Mitchison 1997). In addition to providing cell structural support, MTs are involved in a host of cellular processes ranging from meiosis to vesicle/organelle trafficking. To accommodate their diverse roles, MTs need to be tightly regulated. MARK kinases regulate MT stability by phosphorylating MAP proteins, causing their detachment from MTs rendering them less stable.

As a regulator of MT dynamics and stability, MARK also affects cell migration (for reviews, see (McDonald 2014; Reiner and Sapir 2014)). Studies on the role of MARK during neuronal migration suggest that MARK is involved in cross talk between the MT and actin cytoskeletons. Actin remodeling is critical for cell migration and thus requires cross communication with the dynamic MT network (Matenia et al. 2005; Johne et al. 2008). Although MARK is a known regulator of MTs, not all MARK functions are mediated through the MTs.

As described earlier, MARK is the human ortholog of PAR-1. PAR proteins comprise a group of proteins originally discovered for their role in regulating cytoplasmic partitioning of the embryo of C. elegans. They can be localized asymmetrically and can form complexes with fellow PAR members (i.e., PAR-3/PAR-6/aPKC complex). Though discovered in C. elegans, they are also found in many other organisms in which they serve to help regulate cell polarization. PAR proteins have also been discovered to interact with other protein complexes involved in epithelial polarity such as CRB/PALS1/PATJ and DLG/SCRIB/LGL (McDonald 2014; Rodriguez-Boulan and Macara 2014; Gao et al. 2016).

Traditionally, MARK has been studied through its regulation of MAPs and interaction with other PAR polarity proteins. A wider range of roles of MARK kinases have emerged, such as their possible involvement in the planar cell polarity pathway, which helps to establish planar cell polarity of cells (Ossipova et al. 2005; Mamidi et al. 2012). MARK kinases are also involved in cell cycle control via regulation of CDC25C (Peng et al. 1998; Hurov and Piwnica-Worms 2007). More recently, MARK has been linked to the Hippo-YAP pathway, which regulates stem cell activity and organ size (Mohseni et al. 2014).

MARK in Health and Disease

Alzheimer’s Disease and Neurodegeneration

As the life expectancy of humans is increasing, understanding age-related neurodegenerative diseases is becoming ever more important. Microtubules are a major component of neurons and they form dense bundles arranged in parallel arrays to give neurons their unique structure and shape. MARK kinases are MT regulatory proteins which have been extensively studied in the brain. MARK was first identified by its ability to phosphorylate MAPs, leading to MT destabilization. Tau is a MAP protein that is enriched on the dynamic MTs of axons and is phosphorylated by MARK on their KXGS motifs. Phosphorylation of tau causes decreased affinity for MTs, making MTs less stable. The dissociated unbound tau forms aggregates of hyperphosphorylated tau, which are a hallmark of AD, and it has been found that MARK is upregulated at these neurofibrillary tangles (NFT). These NFTs are also common to other diseases referred to as tauopathies.

MARK has also been found to be involved in Parkinson’s disease (PD), another neurodegenerative disease (Fabbri et al. 2015). MARK2 was discovered as an interacting partner and upstream activator of phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1). Mutations in PINK1 have been linked to familial PD, and it was found that MARK2 phosphorylates a PINK1 mutation site linked to PD, affecting neuronal mitochondrial trafficking (Matenia et al. 2012; Matenia and Mandelkow 2014). Mitochondrial abnormalities are exhibited in the pathogenesis of neurodegenerative diseases such as AD and PD. These findings suggest that MARK kinases may provide a link in further understanding the signaling axis in such diseases.

Autism

Autism and autism spectrum disorders (ASD) are neurodevelopment disorders characterized by difficulties in social interaction, verbal and nonverbal communication, and repetitive behaviors (Folstein and Rosen-Sheidley 2001). MARK proteins are important for neuronal function since they regulate MT dynamics and trafficking, such as proper trafficking of neuronal mitochondria. In a screening to identify markers for autism and ASDs, MARK1 levels were elevated in ASD subjects (Maussion et al. 2008). Dendritic abnormalities are implicated in ASDs (Hutsler and Zhang 2010), and thus changes in MARK1 expression in ASDs suggest the possibility that this kinase regulates the function of neuronal dendrites.

Cancer

Few studies have examined the connection between MARK and cancer. However, there is growing evidence that MARK kinases play a role in cancer, adding to the variety of roles these kinases have in the cell. MARK3 was found to be overexpressed in human hepatocellular carcinoma and proposed to play a role in hepatocellular carcinogenesis by acting as a messenger in the Wnt signaling pathway (Kato et al. 2001). Additionally, MARK2 levels were elevated in cisplatin-resistant cancer cell lines, suggesting that MARK2 may respond to DNA damage incurred by the DNA damaging anticancer chemotherapy drug (Wu et al. 2010; Hubaux et al. 2015). MARK4, which has two spliced isoforms, MARK4L and MARK4S, has been studied for its potential role in gliomas. It was found that the MARK4L isoform was located in the nucleolus in glioma tumor cells, and its presence at that site is absent in normal cells. Thus, MARK4L isoform may serve as a nucleolar tumor marker and provide further insight into gliomagenesis (Magnani et al. 2011).

Metabolic Disorder

Studies using MARK knockout mice have demonstrated that MARK kinases are necessary for metabolic regulation (see Table 2). For example, MARK2-null mice were found to be hypermetabolic, as they were resistant to weight gain when placed on a high-fat diet (Hurov and Piwnica-Worms 2007). Likewise, MARK4 knockout mice were found to be hypermetabolic and were also protected from insulin resistance (Sun et al. 2012). Studies have also linked MARK4 to the regulation of mammalian target of rapamycin (mTOR) pathway; in particular, MARK4 acts as a negative regulator of mTORC1 (mTOR complex 1, which is formed when mTOR binds to Raptor) (Sun et al. 2012). mTOR is an intracellular signaling protein that is found in virtually all mammalian cells, and it is involved in energy metabolism that regulates cell metabolism, growth, and proliferation (Laplante and Sabatini 2009). Disruption of mTORC1 is associated with metabolic disorder and a variety of diseases such as cancer. Since MARK4 is involved in mTOR regulation, it may be a potential drug target for metabolic diseases (Liu et al. 2016).
MAP/Microtubule Affinity-Regulating Kinase, Table 2

Phenotypes of MARK knockout micea

Gene deletion

Phenotype

References

MARK2

Subfertility, dwarfism, immune system dysfunction, impairment of spatial learning and memory

Bessone et al. (1999), Hurov et al. (2001), and Segu et al. (2008)

MARK3

Subfertility, hypermetabolism, reduced adiposity, protection against high-fat diet-induced obesity, normal insulin sensitivity

Lennerz et al. (2010)

MARK4

Normal fertility, hyperactivity, hypermetabolism, hyperphagia, protection from high-fat diet-induced obesity, protection from obesity and insulin resistance induced by high-fat diet

Sun et al. (2012)

aNo information available on MARK1 knockout mice

Male Fertility

While the precise function of MARKs in spermatogenesis remains to be better elucidated, studies have shown that MARK, specifically MARK4, is important for spermatogenesis. It is known that MARK4 is prominently expressed at the Sertoli-spermatid (steps 8–19) interface and also at the Sertoli cell-cell interface in the testis-specific actin- and MT-rich ultrastructure known as apical and basal ectoplasmic specialization (ES), respectively (Tang et al. 2012). The ES was previously shown to be crucial in supporting germ cell transport across the seminiferous epithelium during spermatogenesis (Mruk and Cheng 2004). MARK4 was found to be tightly co-localized with MTs in the testis, which provide the track-like structures across the epithelium that support spermatid transport (Tang et al. 2012; Tang et al. 2016). However, treatment of adult rats with a single dose of adjudin, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide, a potential male contraceptive known to induce germ cell exfoliation, leading to male infertility (Cheng et al. 2005; Cheng 2014), was found to perturb the organization of MTs and the localization of MARK4 in the seminiferous epithelium. For instance, the MT tracks and the MARK4 expression along the MT tracks were considerably disrupted and/or undetectable following adjudin treatment (Tang et al. 2012). As such, developing spermatids found near the edge of the adluminal compartment were emptied into the tubule lumen at spermiation; however, spermatids that were still developing inside the epithelium could no longer be transported across the epithelium to undergo their release at spermiation due to the loss of the track. This thus leads to aspermatogenesis and infertility or subfertility, illustrating the significance of MARK4 and MTs to support spermatogenesis and fertility.

Summary

MARK kinases are involved in a number of cellular processes, with new roles still emerging. There are four MARK (MARK1/MARK2/MARK3/MARK4; hPAR-1c/hPAR-1b/hPAR-1a/hPAR-1d) isoforms in mammals, which may share some redundancy, as knockout mouse models have shown, as compared to a single PAR-1 in C. elegans and Drosophila. Studies on PAR-1 focused on the importance of this protein in regulation of cell polarity and migration and revealed that these major roles are conserved across species. MARK kinases were first discovered for their role in the pathogenesis of Alzheimer’s disease via regulation of MAPs and MTs. MARK kinases do in fact regulate MT dynamics; however, their diverse roles are not all mediated through the MT cytoskeleton. They are regulated by phosphorylation on Ser and/or Thr residues located in their catalytic domain, as well as spacer domain. Additional regulatory mechanisms have been proposed, such as binding of the tail domain to the catalytic domain to induce a conformational change, which still need to be further confirmed. The study of MARK kinases in disease has brought to light their extensive roles, as they are implicated in, for example, neurodegenerative disease, autism, cancer, metabolic disorder, and male fertility. Much progress has been made in identifying unique properties and roles of individual MARK isoforms; however, more work is needed to further distinguish them from each other.

Notes

Acknowledgments

This work was supported by grants from the National Institutes of Health, NICHD, R01 HD056034 to C.Y.C., and U54 HD029990 Project 5 to C.Y.C.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population CouncilNew YorkUSA