Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Caveolin-1

  • Samapika Routray
  • Niharika Swain
  • Rashmi Maruti Hosalkar
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101931

Synonyms

 BSCL3;  CAV-1;  CGL3;  LCCNS;  MSTP085;  PPH3;  VIP21

Historical Background

Caveolin-1 or Cav-1, one of three members of caveolin family, is a structural component of caveolae or “little cave”-like vesicular invaginations of plasma membrane. Based on their lipid composition and biophysical features, caveolae are considered subtypes of lipid rafts that form invaginations and are capable of endocytosis (Fig. 1). Cav-1 is the first member and true protein marker of caveolin family to be identified as tyrosine phosphorylated in Rous sarcoma virus-transformed fibroblasts in 1989 (Glenney 1989). Subsequently, other two members of the family, Caveolin-2 (Cav-2) and Caveolin-3 (Cav-3), were discovered in various experimental studies in 1996. Cav-2 was found to be colocalized and coexpressed with Cav-1 in adipocyte-derived caveolar membrane, whereas Cav-3 (M-Caveolin) was identified as an attempt to find Cav-1 homologs through database search and cDNA library screening (Williams and Lisanti 2004; Stan 2005).
Caveolin-1, Fig. 1

Cav-1 as an oligomeric structural unit of caveolae. Hairpin loop-like structure of Cav-1 in cholesterol-rich plasma membrane

Gene Transcription

Though a range of homologs have been identified in various species, the three mammalian genes encoding members of caveolin family are similar in sequence. In human, Cav-1 and Cav-2 genes are located in very close proximity on chromosome 7q31.1, while Cav-3 is located on a different chromosome (3p25). Cav-1 gene contains a TATA-less promoter with adjacent E2F/DP-1 and Sp1 consensus sequences and sterol regulatory elements. Cav-1 is composed of three exons which are highly conserved in structure and sequence across species (Cohen et al. 2004) (Fig. 2). Recent genetic evidences attempted to reveal detailed organization of caveolin genes. According to them, human Cav-1 and Cav-2 genes map at maximum distance of 100–200 kb from DLS522 locus, which is the center of smallest common deleted region and thought to carry a presumed tumor suppressor gene. Engelman et al. identified two adjacent contigs covering approximately 250 kb which consists of Cav-1 and Cav-2 and DLS522 region along with their tentative locations. DLS522 region is located ~67 kb upstream of Cav-2 gene, whereas Cav-2 gene is mapped ~19 kb upstream of the Cav-1 gene (Engelman et al. 1999).
Caveolin-1, Fig. 2

Structure of Cav-1 with its exons and introns involved in its gene transcription

Transcription Regulator

Various studies on transcriptional regulation of Cav-1 indicate its involvement in both physiological and pathological processes. In physiology, lactation regulates Cav-1 transcription via prolactin–Ras-dependent signaling, likewise PPARγ (peroxisome-proliferator-activated receptor γ), a member of nuclear hormone receptor family, the largest family of transcription factors, can upregulate Cav-1 expression in adipogenesis and differentiation of adipocytes. In addition, certain cell cycle regulators like p53 and p16ink4a can regulate FOXO (forkhead box class O)-mediated Cav-1 transcription. Furthermore, cellular cholesterol and low-density lipoprotein depletion upregulates Cav-1 transcription via sterol regulatory element-like sequences. In the contrary, components of many oncogenic pathway, i.e., c-Myc-Protein kinase Cε and Ras-p-42/44MAPK signaling pathway, have been observed to alter Cav-1 expression in various studies of human cancer cell line like prostate and breast cancer (Van den Heuvel et al. 2005).

Structure and Distribution

Cav-1 is considered being an integral membrane protein as it was resistant to extraction with sodium carbonate and high salt concentrations. It has been suggested that Cav-1 is comprised of 178 amino acids and has a membrane-spanning hairpin loop-like configuration with cytoplasmic amino (N-) and carboxyl (C-) termini and a hydrophobic domain inserted into the plasma membrane. Its amino-terminal domain comprises the first 101 residues, whereas the putative intramembrane domain occupying 33 amino acids and the carboxy-terminal domain contains 43–44 amino acids. Posttranslational modifications like palmitoylation of C-terminal at cys133, cys143, and cys156 and tyrosine phosphorylation of N-terminal at tyr14 are essential for structural organization of this molecule (cytoplasmic facing of C- and N-termini). Other membrane attachment domain (MAD) on both termini such as N-MAD (82–101 residue) and C-MAD (135–150 residue) present on either sides of intramembrane domain is thought to be involved in functions like membrane binding and cholesterol recognition. Interestingly, function like oligomerization of Cav-1 to form complex comprised of approximately 14–16 monomers could be contributed by oligomerization domain to residues 61–101 (Hoop et al. 2012; Williams and Lisanti 2004) (Figs. 1 and 2). Cav-1, a 22-kDa phosphoprotein, also independently cloned as VIP21 (a component of the trans-Golgi-derived vesicles), occurs in two isoforms, i.e., Cav-1α and Cav-1β. Cav-1α is comprised of 1–178 residues, whereas Cav-1β contains 32–178 residues. Difference between distribution of both isoforms in caveolae, i.e., deeply invaginated caveolae contains Cav-1α and Cav-1β, whereas caveolae with lesser invagination or flat membrane contains Cav-1β, dictates their functional differences. Experimental studies observed the requirement of both Cav-1α and Cav-1β and lesser efficacy of Cav-1β in the induction of caveolae formation (Stan 2005).

Cav-1 is predominantly found in plasma membrane of terminally differentiated cells or mechanically stressed cells such as adipocytes, epithelial cells, endothelial cells, smooth cell cells, and type-1 pneumocytes except in lymphocytes and neuronal cells. Intracellular localization of Cav-1 is extended to the Golgi apparatus, endoplasmic reticulum, and trans-Golgi-derived transport vesicles. In addition to membrane form, soluble form of Cav-1 also exists in cytosol which is predicted to have putative role in lipid transport (Liu et al. 2002). Cav-3 is expressed mainly in various muscle cells such as smooth, skeletal, and cardiac muscle cells, whereas Cav-2 normally colocalizes with Cav-1 (Echarri and Del Pozo 2015).

Caveolin-1 in Health

Since its discovery, caveolae gained much attention because of is multifacial role in physiology like vesicular transport (endocytosis and transcytosis), cholesterol homeostasis, and cellular signaling (Liu et al. 2002; Cohen et al. 2004).

Vesicular Transport

Due to their ultrastructural appearance as plasma membrane invaginations, caveolae were initially thought to have primary function of vesicular transport of macromolecule by a mechanism called pinocytosis. But later on, their function was expanded to other mechanisms like transcytosis and endocytosis. Extensive experimental studies on caveolar transcytosis in endothelial cells suggested about their involvement in selective transportation of specific macromolecules, i.e., gold and albumin, whereas in endocytosis, the role of caveolae seems to have an alternative pathway to the principal clathrin-mediated internalization. An exhaustive list of pathogenic agents including viruses, bacteria, fungi, and toxins are thought to be transported by caveolar endocytosis. Binding of pathogen to caveolae through their interaction with glycolipid moieties clusters could contribute in understanding the mechanism of caveolae-mediated cellular invasion.

Cholesterol Hemostasis

Structural alliance of caveolae with cholesterol has denoted about their functional interrelationship. Various studies targeted in this aspect have several observations like regulation of cholesterol levels by Cav-1 through regulation on efflux and influx of cholesterol, regulation of Cav-1 transcription by cholesterol via steroid binding regulatory elements on Cav-1 promoter, intracellular distribution and stabilization of Cav-1 by cellular cholesterol levels. However, various clinical and experimental studies support extracellular and intracellular lipid transport as primary function of Cav-1 in account of its consistent and strong expression in adipocytes and related abnormality in lipid metabolism in Cav-1 knockout experimental animals. Cav-1 has shown to have potent role in transportation of newly synthesized cholesterol from endoplasmic reticulum to membrane caveolae where it is delivered to plasma high-density lipoproteins (HDL). During entry of extracellular cholesterol to cells, significant contribution of caveolae is noticed as an adjunct to clathrin-mediated endocytosis of low-density lipoproteins. Influx of cholesterol via caveolae from HDL particles is principally by way of the scavenger receptor B1 (SR-B1), which is found to be colocalized with membrane form of Cav-1 (Hoop et al. 2012; Liu et al. 2002).

Signal Transduction

Though exact concept of Cav-1 in cellular signal transduction has not been clarified yet, many have been led down on the basis of observations like: (a) abundant presence of signaling molecules like Src-like tyrosine kinases and heterotrimeric G proteins within caveolae microdomain indicating putative role of Cav-1 in compartmentalization of signaling molecules, localizing them within cell in the view of rapid and selective modulation of cellular events. Thus, it is believed to behave as a docking point for various signaling molecules. According to few authors, Cav-1 behaves as both positive and negative regulator for cellular signal transduction. Cav-1 acts as a scaffolding protein by binding to various proteins involved in signal transduction pathways. One of the functional domains of Cav-1, Caveolin-1 scaffolding domain (CSD) with residue 82–101, mediates the interaction and inhibition of certain molecules like protein tyrosine kinases, G-protein-coupled receptors, molecules of MAPK/ERK pathway, members of protein kinase C family, and endothelial isoform of nitric oxide synthetase. Furthermore, proteosome-mediated degradation is hypothesized as an additional mechanism of the inhibitory effect of CSD on target protein like inducible form of nitric oxide synthetase (iNOS). In addition, inhibition of oncoprotein β-Catenin-Tcf/Lef-dependent transcription of genes like cyclin D1 and survivin designated Cav-1 as tumor suppressor genes (Torres et al. 2007). In contrast, for certain molecules like insulin receptor and integrin signaling to MAPK/ERK pathway via focal adhesion kinase (FAK) and Src family kinases (SFKs), positive signaling via tyrosine phosphorylation (tyr14) is mediated by Cav-1 (Lee et al. 2000; Quest et al. 2008).

Caveolin in Tumorogenesis

Besides few nonneoplastic diseases like dilated cardiomyopathy, pulmonary hypertension, and fibrotic diseases in knock-out experimental animals, altered expression of Cav-1 has been growingly reported in various human cancers like breast, lung, gastric, colon cancer, and oral cancer including human melanoma. Cumulative evidences suggested both tumor suppressive and pro-tumorogenic role of Cav-1 depending on the stage of tumor progression and tumor type studied (Fig. 3). For example, in early stages of carcinogenesis, loss of Cav-1 is necessary and sufficient to promote cell transformation supporting its tumor suppressor hypothesis, whereas elevated expression of Cav-1 correlates with negative predictive factors including advanced pathological stage in non-small cell lung cancer and esophageal carcinoma. Similarly, in breast cancer and ovarian carcinoma, Cav-1 appears to exhibit tumor suppressor activity, whereas Cav-1 seems to be a proto-oncogene in gastrointestinal cancer and pancreatic cancer.
Caveolin-1, Fig. 3

Prominent mechanisms elucidating the putative tumor promoter/tumor suppression role of Cav-1 in tumorogenesis. The caveolin scaffolding domain (CSD) plays a vital role in tumor suppression as it inhibits oncogenic activity of several signaling molecules like β-catenin and members of RAS–MAPK pathway. On the other hand, Cav-1 with tyrosine phosphorylation at N-terminus (tyr14) can serve as scaffolding protein, a cascade for growth stimulatory mechanism

Tumor Suppressive Role of Cav-1

Since its discovery, the growing evidences have been primarily revolved around the tumor suppressive role of Cav-1. As it was discovered as heavily tyrosine phosphorylated substrate in Rous sarcoma virus-transformed fibroblasts, the ability of Cav-1 in cellular transformation process was suspected. Later on, a series of experimental cell line research studies documented not only the putative role of Cav-1 in promotion of cell transformation but also supported its functions as a tumor suppressor at least in some cell lines. In majority of human cancers, observed tumor suppressive activity of Cav-1 could be explained through several mechanisms like: its initial loss induced increased cell proliferation via inhibition of mitogenic molecules, i.e., members of Ras-p42/44 MAPK pathway, reduction in apoptosis mainly intrinsic pathway, and also through enhanced β catenin-dependent transcription. Few authors also suggested Cav-1 as tumor susceptible rather than tumor suppressor gene as its experimental elimination led to promote susceptibility for tumor initiation in response to an additional stimulus. In addition, Lobos-González L et al. also revealed the synergistic tumor suppressive role of E-cadherin and Cav-1 in human melanoma cell lines. In the presence of E-cadherin, Cav-1 promotes recruitment of β-catenin to the plasma membrane, which also coincides with re-establishment of Cav-1-dependent regulation of survivin and COX-2 expression in tumor cells (Rodriguez et al. 2009).

Tumor Promoting Role of Cav-1

Beyond its well-documented tumor suppressive role, recent clinical and experimental cell line culture studies also demonstrated the pro-tumorigenic role of Cav-1 like tumor initiation, tumor progression, metastasis and multimodality therapeutic resistance in few cancers like pancreatic, breast cancer, and melanoma (Huang et al. 2012; Lobos-González et al. 2013; Arpaia et al. 2012). Altered expression/transcription of Cav-1 seems to involve in well-established oncogenic/proliferation pathways, i.e., src-JAK/STAT3 and JNK signaling (Chatterjee et al. 2015). Furthermore, Luanpitpong et al. also demonstrated the overexpression of Cav-1 in cancer stem cells, which was correlated with tumor initiation and aggressiveness exhibiting apoptosis resistance, enhanced cell invasion, and metastatic potential (Luanpitpong et al. 2014).

Downregulation of Cav-1 in the tumor microenvironment, especially cancer-associated fibroblasts, is a consistent finding in recent years which is explained by its ability to decrease tumor cell apoptosis, enhance cancer cell proliferation, and stimulate tumor angiogenesis (Routray 2014). Chen and Che hypothesized three possible mechanisms of Cav-1 dysregulation, i.e., firstly, activation of oncogenes or inactivation of tumor suppressor genes; secondly, the activation of the TGF-β signaling pathway; and thirdly, adjacent cancer cells may cause downregulation of Cav-1 via increased oxidative stress to the tumor microenvironment (Chen and Che 2014).

Summary

Till now, it has been clearly established that Cav-1 has potential tumor suppressor/modulating activity, though its putative tumor promotion role yet needs further exploration. Future studies should be targeted to reveal its novel association with prominent signaling pathways, so that it could contribute in predicting tumor prognosis and development of targeted anticancer therapies both in primary and metastatic tumors. In addition, caveolae-mediated endocytosis can attribute in augmentation of the current drug delivery system if selective and suitable ligands could be developed for the proteins of caveolar or raft domain.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Samapika Routray
    • 1
  • Niharika Swain
    • 2
  • Rashmi Maruti Hosalkar
    • 3
    • 4
  1. 1.Department of Dental SurgeryAll India Institute of Medical SciencesBhubaneswarIndia
  2. 2.MGM Dental College and HospitalNavi MumbaiIndia
  3. 3.Indian Association of Oral and Maxillofacial PathologistsMumbaiIndia
  4. 4.Maharashtra State Dental CouncilMumbaiIndia