CAVEOLINS: STRUCTURE AND FUNCTION IN SIGNAL …...CELL. MOL. BIOL. LETT. Vol. 9. No. 2. 2004 196...

CELLULAR & MOLECULAR BIOLOGY LETTERS Volume 9, (2004) pp 195 – 220 http://www.cmbl.org.pl

Received 12 December 2003 Accepted 3 March 2004

* Corresponding author, E-mail: [email protected]

CAVEOLINS: STRUCTURE AND FUNCTION IN SIGNAL

TRANSDUCTION

WANDA M. KRAJEWSKA* and IZABELA MASŁOWSKA University of Łódź, Department of Cytobiochemistry, Banacha 12/16,

90-237 Łódź, Poland Abstract: The caveolin family proteins are typically associated with microdomains that are found in the plasma membrane of numerous cells. These microdomains are referred to as/called caveolae. Caveolins are small proteins (18-24 kDa) that have a hairpin loop conformation with both the N and C termini exposed to the cytoplasm. Apart from having a structural function within caveolae, these proteins have the capacity to bind cholesterol as well as a variety of proteins, such as receptors, Src-like kinases, G-proteins, H-Ras, MEK/ERK kinases and nitric oxide synthases, which are involved in signal transduction processes. Considerable data allow the assumption to be made that the majority of the interactions with signaling molecules hold them in an inactive or repressed state. The activity of caveolins seems to be dependent on its specific post-translation modifications. It is suggested that caveolins fulfill a role in the modulation of cellular signaling cascades. Key Words: Caveolin, Caveolae, Membrane Domains, Signal Transduction INTRODUCTION The mammalian caveolin family proteins: caveolins-1, -2 and -3 (18-24 kDa) were discovered in the early 1990s, and are the major component of caveolae [1-4]. Caveolae, originally described in the 1950s, are nonclatrin-coated plasma membrane microdomains rich in cholesterol and glycosphingolipids. They can invaginate to form 50-100 nm vesicles [5-10]. They can exist as single caveolae or clusters of multiple caveolae. Caveolae are most abundant in terminally differentiated cells. High numbers of caveolae were found in endothelial and epithelial cells, adipocytes, pneumocytes, fibroblasts and smooth and striated muscle cells. Caveolae are attached to the plasma membrane via a short caveolar neck, but they may also appear as flat pits, assumed to be early invagination stages. They are anchored by the actin cytoskeleton [11]. In electron microscopic studies, caveolae appear as more or less static invaginations of the plasma

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membrane. However, studies of endothelial cells and fibroblasts showed that caveolae are dynamic structures that become internalized under special condition [5, 12-15]. Caveolae have been reported to contain various receptors, intracellular signaling molecules and proteins including growth-factor receptors, G-protein coupled receptors, integrins, Src-family kinases, G-proteins, Ras-related GTPases, adenylate cyclase, protein kinase A, protein kinase C isoforms, phospholipases and nitric oxide synthases [1, 2, 5, 7, 10, 16]. It has become evident that these structures play an important role in membrane traffic and cellular signal transduction. A number of function are proposed for caveolae, such as clathrin-independent endocytosis, potocytosis (the uptake of small molecules into cells), transcytosis of molecules across the cell, polonized trafficking of proteins (especially in epithelial cells), cholesterol transport, intracellular calcium concentration, and regulation of signal transduction [1, 2, 17-25]. Apart from these, the list of potential functions can be extended to include internalizations of toxins, bacteria and viruses, prion infection and multidrug resistance [15, 26-30]. Caveolae are considered to be multifunctional organelles with a biological role that varies depending on cell type and physiological status. CAVEOLIN GENE STRUCTURE The gene encoding human caveolin-1 colocalizes with the gene encoding human caveolin-2 to the q31.1 region of human chromosome 7, downstream of the D7S522 locus, in fragile site FRA7G. The marker D7S522 is located about 67 kb upstream of the CAV-2 gene, which is located about 19 kb upstream of the CAV-1 gene (Fig. 1) [31-34]. The human CAV-1 gene contains three exons, while the CAV-2 gene contains two exons. The boundaries of the last exon of the CAV-1 and CAV-2 genes are analogous, suggesting that they may have arisen through gene duplication. The first and second exons of the CAV-1 and -2 genes are embedded within CpG islands. This may suggest that the regulation of caveolin gene expression may be controlled, at least in part, by the methylation of these regions [33]. The CAV-1 and CAV-2 genes are independent transcriptional units lying in the same orientation. The transcriptional start site of the CAV-1 gene is localized at -62 bp, and the second promoter region was indicated within CAV-1 intron 1. Multiple transcriptional start sites spanning 35 bp upstream from the CAV-2 ATG translational start site were detected. The CAV-2 promoter region contains two putative SP1 binding sites and two SRE-like boxes [36, 37]. Human caveolin-3 gene is found on chromosome 3p25, and consists of two exons. It is localized to the microsatellite markers D3S18, D3S4163 and D3S4539 locus (Fig. 1) [32, 35].

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Fig. 1. The organization of the human caveolin-1, -2, and -3 loci. Microsatellite markers, the numbers of exons, the sizes of the exons and the distances between them are indicated [33, 35, 36]. CAVEOLIN PROTEINS Caveolin-1 Caveolin-1/VIP21 (a vesicular integral membrane protein of 21 kDa) is most abundantly expressed in terminally differentiated cells such as epithelial and endothelial cells, adipocytes, fibroblasts and smooth muscle cells [38-42]. Caveolin-1 is a integral membrane protein, and the principal component of caveolae. It is expressed by two isoforms, i.e., caveolin-1α of mol. wt 24 kDa and caveolin-1β of mol. wt 21 kDa. Caveolin-1α contains 178 and caveolin-1β 147 residues. The α and β isoforms start from methionine at positions 1 and 32, respectively. Caveolin-1β was thought to arise by internal initiation, but it has recently been shown that it is translated from different mRNA than caveolin-1α. The α and β isoforms of caveolin-1 have different potentials in caveola formation, and this is the reason why the molecular composition, the deep and shallow of caveolae may not be the same [36, 37, 43, 44]. Caveolin-1 forms hairpin-like structures with both the N and C termini oriented towards the cytoplasm. Structurally, caveolin can be divided into three distinct domains, i.e., the hydrophilic cytosolic N-terminal, the hydrophobic central stretch and the hydrophilic cytosolic C-terminal (Fig. 2). The N-terminal domain (residues 1-101) varies in length between the three mammalian caveolins and shows the highest level of diversity from species to species, particularly in the residues located at the extreme N terminus. The N-terminal region contains the caveolin scaffolding domain (CSD; residues 82-101), which is essential for the formation of caveolin oligomers and interaction with other proteins. The central domain (residues 102-134) consists of 33 mostly hydrophobic amino acids and resembles the membrane spanning segment of an integral membrane protein. It is suggested to form a hairpin-like loop into the membrane (TMD, transmembrane domain). Membrane attachment and caveolar localization was found to be mediated by two other regions, i.e.,


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N-MAD (the N-terminal membrane attachment domain, residues 82-101), and C-MAD (the C-terminal membrane attachment domain, residues 135-150). Recent studies suggest that TMD is not required for membrane attachment of caveolin-1 in vitro or in vivo, especially as this region is predicted to assume a β-sheet conformation rather than the typical α helix characteristic for transmembrane domains [45-47]. It seems that N-MAD and C-MAD confer membrane attachment, while TMD plays a critical role in specific interactions with caveolin-2 and other proteins [48]. The C-terminal domain (residues 135-178) is also fairly conserved in terms of length, and consists of almost 44 amino acids in all mammalian caveolins. It has two separate functions: membrane attachment and protein-protein interaction [49-53].

Fig. 2. A model of the membrane topology and functional domains identified in caveolin-1. OD – oligomerization domain involved in homooligomer formation; CSD – caveolin scaffolding domain involved in the binding to and inhibition of proteins containing a defined caveolin binding motif; N-MAD and C-MAD – N-terminal and C-terminal membrane attachment domains involved in caveolar localization; TMD – transmembrane or membrane spanning domain involved in interaction with caveolin-2; TD – terminal domain involved in oligomer interactions. The Src-induced phosphorylation site on Tyr 14 and palmitoylation sites on Cys 133, 143 and 156 are also indicated [45, 46, 48, 50, 77]. A 41-amino acid region of the N-terminal domain is the so-called oligomerization domain (OD; residues 61-101), which contains CSD and directs the formation of caveolin homooligomers (14-16 individual molecules) with a high molecular mass of about 350-450 kDa. These molecules have the capacity to interact with cholesterol and signaling molecules [51, 54, 55]. After synthesis


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in the endoplasmic reticulum, caveolins interact with themselves to form oligomers that increase in size upon transport through the Golgi apparatus. The oligomers interact with one another through contacts between the N-terminal (residues 61-101) and C-terminal regions (residues 168-178) in a side-by-side packing scheme, thereby forming a caveolar coat [46, 56]. Recent structural studies indicate that the N-terminal 101 amino acids assemble into heptameric subunits that appear to be the basic substructure of the caveolae coat filament [4]. Different regions in caveolin-1 appear to influence caveolin-1 intracellular traffic, i.e., transit from endoplasmic reticulum to the cell surface and recycling itinerary [57]. Amino acids 66-70 are necessary for exiting the endoplasmic reticulum, 71-80 control the incorporation of caveolin-1 oligomers into the Golgi apparatus, and 91-100 and 135-154 regulate oligomerization and exit from the Golgi. Caveolin-1 forms also a stable heterooligomeric complex with caveolin-2 in cell types in which they are coexpressed. The complex has a mol.wt of about 200-600 kDa. Caveolin-1 and caveolin-2 complex formation is mediated by interactions between their respective membrane spanning domains [48, 58]. These caveolin heterooligomers are thought to represent the assembly units that drive the formation of caveolae. However, caveolin-2 null mice show no defects in the formation of caveolae and little or no change in caveolin-1 protein trafficking [59]. The role of caveolin-1 in caveolae formation was confirmed in experiments using cells that normally lack caveolae (lymphocytes, Fischer rat thyroid cells, Caco-2 cells) or a mouse model with an ablation of the gene encoding the caveolin-1 protein. Expression of caveolin-1 in these cells induces caveolae formation [60-65]. It is suggested that caveolin-1 stabilizes caveolae at the plasma membrane and thereby acts as a negative regulator of the internalization of caveolae or lipid raft-like membrane domains [23]. It was found that the N terminus of caveolin binds to the C terminus of the filamin molecule that anchors the caveolae to the actin cytoskeleton [11]. Both the N-terminal and C-terminal domains of caveolin-1 undergo cytoplasmic post-translational modifications. The N-terminal domain of caveolin-1 is phosphorylated on tyrosine 14, while the C-terminal domain is palmitoylated on three cysteine residues at positions 133, 143 and 156 [50, 66]. The function of caveolin-1 palmitate chains is probably complex. They may anchor the C-terminal region to the membrane. They may increase the stability of the oligomers and therefore the scaffold structure of caveolae [56, 67, 68]. In addition, caveolin-1 palmitate residues seem to regulate its interaction with acylated signaling molecules. A palmitate deficient mutant of caveolin-1 exhibits normal caveolar localization, but its interaction with the G-protein α subunit is diminished greatly [50, 69]. The palmitoylation of caveolin-1 at a single site (Cys 156) was shown to be necessary for the coupling of caveolin-1 to c-Src tyrosine kinase [70]. Caveolin-1 strongly binds cholesterol and affects cholesterol homeostasis [54, 71-75]. It is suggested that at least two palmitate chains on caveolin-1 are required for the binding and transport of cholesterol [20, 76].


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In the human caveolin-1 molecule, there are nine tyrosine residues, three of which (at positions 6, 14 and 25) exist only in the α isoform. The α isoform is selectively phosphorylated on tyrosine 14, which is the major phosphorylation site for non-receptor tyrosine kinases including Src, Fyn, Abl. Activated Src induces the constitutive phosphorylation of caveolin on tyrosine 14 [77]. Lipid modification of c-Src is required for this phosphorylation event to occur in vivo [49, 66, 70, 77-79]. Caveolin-1 is phosphorylated not only on tyrosine 14 but also on other residues in v-Src expressing cells. These modifications lead to the flattening, aggregation and fusion of caveolae and/or caveolae-derived vesicles. Thus, the phosphorylation of caveolin-1 by Src-family kinases could affect caveolar functions through morphological changes [80]. In addition to the changes in caveolae morphology, caveolin-1 tyrosine phosphorylation is essential for protein-protein interaction. It has been shown that the mutation of tyrosine 14 residue that prevents phosphorylation undermines association with the Grb7 protein involved in signal transduction [77]. Caveolin-1β was found to be phosphorylated on serine residues in vivo [81]. The role of serine phosphorylation is less clear. Of the 12 residues conserved across all caveolin isoforms from all species examined till now, only the serine at positions 80 and 168 could serve as phosphorylation sites. Caveolin-1 phosphorylation on invariant serine residue 80 was found to be required for endoplasmic reticulum retention and entry into the regulated secretory pathway in exocrine cells [82]. Caveolae are not only the location for caveolin-1 in all cell types. In some cells, caveolin-1 is a soluble protein localized in multiple cellular compartments. Skeletal muscle cells and keratinocytes target caveolin-1 to the cytosol, while airway epithelial cells and hepatocytes target it to the mitochondria. In exocrine and endocrine cells, caveolin-1 accumulates in the lumen of secretory vesicles. In these cells, caveolin-1 behaves like an apolipoprotein [83-85]. Most known interactions between caveolins and other proteins have been mapped to the N-terminal cytosolic domain. This binding occurs within the juxtamembrane 20-amino acid region CSD of caveolin-1, and similarly in caveolin-3 [2, 52, 86]. This modular protein domain recognizes a conserved sequence of aromatic residues that is present in many distinct classes of signaling molecules. Two related caveolin binding motifs, i.e., ΦXΦXXXXΦ and ΦXXXXΦXXΦ, with Φ being Trp, Phe or Tyr, were elucidated. Caveolin-2 Caveolin-2 is coexpressed with caveolin-1 in most cell types, but similarly to caveolin-1, the expression of the caveolin-2 protein is mostly in endothelial cells, smooth muscle cells, skeletal myoblasts, fibroblasts and adipocytes [58, 87]. Caveolin-2 is about 38% identical and about 58% similar to caveolin-1, and is the most divergent member of the caveolin family. Caveolin-2 has a central (residues 87-119) hydrophobic domain and N-terminal (residues 1-86) and C-terminal (residues 120-162) hydrophilic domains. The central domain and residues 70-86 of the N-terminal and residues 120-150 of the C-terminal regions


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seem to be involved in membrane binding [88]. Caveolin-2, similarly to caveolin-1, has been found to exist in multiple isoforms that differ in the length of their N-terminal part. Three isoforms of caveolin-2: 2α (162 residues), 2β (149 residues), and 2γ (shorter, the least abundant) were identified [61, 87, 89, 90]. Alternate translation starts are present in the caveolin-2 mRNA, leading to the possible formation of the caveolin-2α and caveolin-2β isoforms from a single mRNA, although evidence also exists that alternative termination/poly-adenylation generates two different mRNAs [36, 58, 87]. Interestingly, caveolin-2γ is abundantly expressed in astrocytes. Caveolin-2 alone exists mainly as a monomer or homodimer that is retained at the level of the Golgi complex. It is unable to create high molecular mass homooligomers. To form stable high molecular mass oligomers (300-350 kDa) caveolin-2 requires caveolin-1 but not caveolin-3. Such heterooligomers have been found in the endoplasmic reticulum and Golgi apparatus. These oligomers mature into higher molecular mass complexes once they reach caveolae. The intracellular transport of caveolin-2 requires the presence of caveolin-1, and it has been proposed that caveolin-2 may function as an accessory protein to caveolin-1 [48, 58, 61, 90]. However, caveolin-2 deficient mice show evidence of severe pulmonary dysfunction without the disruption of caveolae indicating a selective role for caveolin-2 in mammalian physiology independent of caveolin-1 [59]. Unlike caveolin-1 and caveolin-3, caveolin-2 does not have the capacity to form caveolae by itself. In cells lacking caveolin-1 expression, caveolin-2 is retained intracellulary at the level of the Golgi complex, where it undergoes proteasomal degradation [59, 64, 91, 92]. Caveolin-2 is a phosphoprotein. It undergoes Src-induced phosphorylation on tyrosine 19. For this phosphorylation, as in the case of caveolin-1, lipid modification of Src kinase appears to be important. Phosphocaveolin-2 (pTyr19) remains associated with caveolae but no longer forms high molecular mass heterooligomers with caveolin-1 [93]. It is suggested that caveolin-2 tyrosine phosphorylation may contribute to the recruitment of signaling molecules to the cytoplasmic face of caveolae. Caveolin-2 is constitutively phosphorylated in vivo at two serine residues in the N terminus, i.e., at positions 23 and 36 in a casein kinase 2 (CK2)-dependent manner as well. Mutational analysis shows that the phosphorylation of caveolin-2 is necessary to modulate caveolin-1-dependent caveolae assembly [94]. Caveolin-3 Caveolin-3 (M-caveolin; a muscle specific member of the caveolin family), the most recently recognized member of the caveolin family, has been shown to be muscle specific. However, it was recently found to be expressed in astrocytes and chondrocytes as well [95-99]. Caveolin-3 is the major caveolar protein of differentiated skeletal, cardiac and smooth muscle cells. Several independent lines of evidence indicate that caveolin-3 localizes to the sarcolemma, where it associates with the muscle specific dystrophin-glycoprotein complex (DAGs)


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[48, 96]. Caveolin-3 consists of 151 amino acid residues and possesses domain structure. Based on protein sequence homology, caveolin-3 is most closely related to caveolin-1. Caveolin-1 and caveolin-3 are about 65% identical and about 85% similar. The N-terminal domain of caveolin-3 is shorter than that of caveolin-1 by 27 amino acid residues [97]. In caveolin-3, a central WW-like domain: W(X)18FXF(X)8W(X)3P involved in protein-protein interaction was identified [47]. Two characteristics for WW domain tryptophan residues, highly conserved in the case of caveolin-3 and caveolin-1 from different species, are separated by 29 amino acids. The second tryptophan is followed by a highly conserved proline residue. Interestingly, caveolin-2 lacks certain critical residues that are required to form a WW domain. That WW-like domain overlaps with a domain suggested to be a transmembrane spanning domain of caveolin-3. Caveolin-3 molecules homooligomerize both in vitro and in vivo and form high molecular mass multimers, which consist of 14-16 monomers [97]. This self assembly is thought to drive the caveolae formation. The expression of caveolin-3, like caveolin-1, is sufficient to cause the formation of caveolae, and appears to be essential for maintaining normal muscle homeostasis. Skeletal muscle fibers from caveolin-3 knock-out mice show a number of myopathic changes, consistent with a mild to moderate muscular dystrophy phenotype [100]. Loss of caveolin-3 expression is sufficient to induce cardiac myocyte hypertrophy and cardiomyopathy as well [101]. Caveolin-3 mutation that removes three amino acids within the caveolin scaffolding domain (ΔTFT) or missense mutation within the membrane spanning domain (P→L) were found to cause the retention of caveolin-3 at the level of the Golgi apparatus [102]. Analysis of skeletal muscle tissue from Duchenne muscular dystrophy (DMD) patients or transgenic mice overexpressing caveolin-3 revealed down-regulation of dystrophin and β-dystroglycan protein expression [47, 103]. A WW-like domain identified within caveolin-3 directly recognizes the extreme C terminus of β-dystroglycan, which contains a PPXY motif. As the WW domain of dystrophin recognizes the same site within β-dystroglycan, caveolin-3 can effectively block the interaction of dystrophin with β-dystroglycan suggesting the competitive regulation of the recruitment of dystrophin to the sarcolemma [47]. Caveolin-3 has been shown to associate with the T-tubule network. In cells lacking caveolin-3 expression, T-tubule abnormalities were found [98, 100]. CAVEOLINS AND SIGNAL TRANSDUCTION Caveolae have been suggested to function in signaling events through the compartmelization of signaling molecules that interact with caveolin proteins. Thus, in addition to the structural role of caveolins in the formation of caveolae, there is considerable evidence for their involvement in the modulation of cell signaling [2, 3, 10, 24, 104-107]. A wide variety of cellular signaling molecules have been shown to associate with caveolae including:


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– receptor tyrosine kinases and their downstream targets such as EGFR, c-Neu, PDGFR, insulin receptor, nerve growth factor receptor, neurotrophin receptor, H-Ras, Raf-1 and extracellular signal regulated kinases [72, 73, 108-116];

– non-receptor protein tyrosine kinases such as Src, Fyn, Yes, Bmx, Btk and Fak [66, 112, 117-119];

– receptor serine/threonine kinases such as TGFβ type I receptor [120]; – G-protein coupled receptors and their downstream signaling molecules, such

as various G-protein subunits, adenylyl cyclase, PKA and β2-adrenoreceptor [69, 121-127];

– steroid hormone receptors such as AR and ER [128-131]; – enzymes of NO signaling, such as endothelial and neuronal nitric oxide

synthase (NOS) [64, 132-145]. Tab. 1 summarizes caveolin interacting and regulated signaling molecules. There are some pieces of evidence that the binding of the signaling molecules to caveolins results in their inactivation. It was shown that binding to caveolin through the scaffolding domain is sufficient to repress the kinase activity of c-Src or the maintenance of the inactive conformation of G-proteins [86, 111]. The interaction of caveolin-1 with EGFR or c-Neu through the recognition of a conserved caveolin binding motif within the kinase domain (DVWSYGUTUWEL) is sufficient to inhibit autophosphorylation and activation of the receptor [111, 115, 146]. Functional interaction between caveolin-1 and the protein kinase A α catalytic subunits which inhibits its phosphorylation of the cAMP response element binding protein (CREB) in vivo, is mediated by and requires either scaffolding or C-terminal caveolin domains (the 38 C terminus residues). The CSD/C-terminal region mutant acts in a dominant negative fashion to disrupt the caveolin mediated inhibition of PKA signaling [147]. Similarly, in many cases, it has been shown that the mutational activation of signaling molecules (G-protein, H-Ras or Src-family kinases) prevents regulated interaction with the caveolin scaffolding domain [86, 110, 121]. These activating mutations include H-Ras (G12V) and Gαs (Q227L), which are found in human cancers. Targeted down-regulation of caveolin-1 expression is sufficient to hyperactivate signaling via the TGFβ receptor [120]. On the other hand, targeted overexpression of caveolin-1 blocks Neu mediated signal transduction from the growth factor receptor to the nucleus in vivo [115]. The reciprocal relationship between the Ras-p42/44 MAPK pathway (MEK 1/2 and ERK 1/2) and caveolin-1 has been established. Treatment with mitogens such as PDGF, Neu mediated signaling or the expression of constitutively activated H-Ras (G12V) in NIH 3T3 cells negatively regulates caveolin-1 expression at the transcriptional level [114, 115, 148, 149]. On the other hand, caveolin-1 and caveolin-3 can function as a negative regulator of the Ras-p42/44 MAPK cascade, probably through a direct interaction with MEK or ERK [114, 117, 148, 150]. Overexpression of caveolin-1 inhibits p42/44 MAPK activation, while targeted down-regulation of caveolin-1 results in the hyperactivation of the


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p42/44 MAPK cascade in NIH 3T3 fibroblasts [114, 148]. Furthermore, it was demonstrated that caveolin-1 and caveolin-3 deficient mice show hyperactivation of p42/44 MAPK signaling [101, 151]. Tab. 1. Caveolin interacting and regulated signaling molecules.

Signaling protein Reference(s) Adenylyl cyclase Adrenergic receptor β2 (β2AR) Androgen receptor (AR) Btk, Bmx Cox-2 Csk EGF receptor (EGFR) Estrogen receptor α (ERα) Fak G-protein α subunits G-protein-coupled receptor kinase (GRK 1, 2, 5) Grb7 Hedgehog receptor H-Ras Insulin receptor Integrins MEK/ERK Nerve growth factor receptor (TrkA) Neurothrophin receptor p75 Neu (c-Erb2) Neutral sphingomyelinase (nSMase)/ceramide eNOS nNOS PDGF receptor (PDGFR) PI3K PKA PKC isoforms PLC PLD Prion protein cellular form (PrPc) Prostacyclin synthase (P61S) Src Src-family kinases (Fyn, Lck, Lyn, Yes) TGFβ receptor type I (TGFβRI) Trp1/Gαq/11/IP3 receptor TNF receptor associated factor 2 (TRAF2) VEGF receptor 2 (VEGFR-2)

122, 124, 125, 166 127 129 119 153 167 109, 111, 146, 160, 168 128, 130, 131 118, 169 69, 97, 121, 125, 126, 166 170 70, 77 171 72, 73, 110 154, 157 117, 169 114, 150, 157 116 116 115 172 64, 132-138, 140-143, 145, 173 139, 143, 144 112, 174, 175. 112, 176 123, 147 111, 112, 177, 178 112, 125 152, 179 180 180 70, 77, 86, 112 112, 117, 118, 155 120 181 167, 182 165


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In some cases however, caveolin-1 has no effect at all [152, 153]. For insulin receptor signaling, caveolin has an activating function instead [154]. The insulin receptor was found to directly catalyze the phosphorylation of caveolin on tyrosine 14. This phosphorylation does not require the activation of PI3K, MAPK or Fyn [155, 156]. The case of insulin receptor status seems to be more complex. In adipocytes, both endogenous caveolin-1 and the insulin receptor have been found to be expressed at a very high level [157]. Fatty acylation may represent a common mechanism for targeting cytoplasmic signaling molecules to caveolae, where they can interact with caveolins. Many proteins that copurify with caveolins, like G-protein α subunits, Src-family kinases, Ras-related GTPases, or eNOS, undergo myristylation, palmitoylation, prenylation, or dual acylation [70, 77]. The N-terminal miristoyl moiety of the c-Src and palmitoyl group attached to caveolin-1 at cysteine 156, seems to be necessary for this interaction. However, the farnesylation of H-Ras appears to be unnecessary for its caveolar localization [110]. Thus, lipid modification of certain signaling molecules may not only serve to target them to caveolae, but may also function to modulate the balance of protein-protein interactions occurring within caveolae [69, 70]. The phosphorylation of caveolin-1 on tyrosine 14 is likely to be an intermediate step in a signaling cascade occurring within caveolae. Tyrosine 14 of caveolin-1 together with flanking region, closely resembles the known recognition motifs for tyrosine kinases KYVDSEGHLpY: R/K/QX2-4D/EX2-3pY. It was shown that tyrosine 14 phosphorylation of caveolin-1 occurs in a tightly regulated fashion during signaling. Epidermal growth factor, insulin and integrin ligation as well as osmotic shock induce the phosphorylation of caveolin-1 on tyrosine 14 [77, 158-160]. Epidermal growth factor receptor transactivation in response to G-protein coupled receptor stimuli releases it from caveolin. Activated EGFR and ERK 1/2 have appeared to localize at focal adhesion complexes along with phosphocaveolin [161--162]. It has been found that the low molecular weight phosphotyrosine protein phosphatase, which is involved in the regulation of several tyrosine kinase growth factor receptors, is localized in the caveolae and has the capacity to rapidly dephosphorylate phosphocaveolin [163]. Tyrosine-phosphorylated caveolin-1 has been suggested to provide a docking site for phosphotyrosine binding proteins, particularly for SH2-containing molecules, and to serve as a positive regulator of cell signaling through its specific localization in focal adhesions, a major site of tyrosine kinase signaling in vivo. It was shown that caveolin-1 binds the SH2 domain of adaptor molecule Grb7 following growth factor stimulated and Src catalyzed phosphorylation of caveolin-1 tyrosine 14 both in vitro and in vivo [70, 77]. The binding of Grb7 to tyrosine 14 phosphorylated caveolin-1 functionally augments anchorage-independent growth and EGF stimulated cell migration. There is also a possibility that the binding of phosphocaveolin-1 to the scaffolding domain would compete with caveolin binding signaling molecules and displace them from caveolin-1 or disrupt the attachment of caveolin-1 to the membrane. It has


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been demonstrated that phosphocaveolin-1 binds to the caveolin-1 residue 61-101 region and inhibits the activation of ERK in response to shear stress [150]. Tyrosine phosphorylation of caveolin-2 (Tyr 19) may also contribute to the signal transduction [93]. Insulin stimulation of adipocytes and integrin ligation of endothelial cells can both induce the tyrosine phosphorylation of caveolin-2. During integrin ligation, phosphocaveolin-2 colocalized with activated FAK at focal adhesions. Ras-GAP, c-Src and Nck proteins interact with caveolin-2 in a phosphorylation-dependent manner, suggesting that phosphocaveolin-2 may also function as a docking site for SH2 domain containing proteins during signal transduction. However, phosphocaveolin-2 did not show any binding activity towards the Grb7 adapter protein recognized by phosphocaveolin-1. Thus caveolin-1 and caveolin-2 may serve as binding partners for different SH2 domain containing proteins, which may lead to the recruitment and compartmentalization of distinct signaling cascades. Caveolin-1 may function as a plasma membrane platform to localize caveolin interacting signaling molecules within caveola membranes. However, since it was found that the activation of the caveolin interacting proteins depends on cholesterol, it may be speculated that caveolin-1 modulates signal transduction through an interaction with lipids rather than proteins. The implication of caveolin in the control of cholesterol level may be a way to exert its regulatory role on signal transduction. Cholesterol depletion of caveolae was found to cause a decline in several key signaling molecules of the MAP kinase pathway, including Ras, Grb2, ERK2 and Src, to inhibit EGFR transactivation by angiotensin II, and to modulate VEGFR-2 localization and signaling activity [161, 164, 165]. In hamster kidney cells, dominant negative caveolin-3 completely blocks Raf activation mediated by H-Ras. This inhibitory effect was found to be reversed by replenishing cell membranes with cholesterol [72]. It is suggested that the elevation of cellular cholesterol level could promote the translocation of caveolin-1 and its associated signaling molecules, such as Ras, into caveolae, where cell signaling is triggered [73]. CONCLUSIONS The caveolae comprise unique lipid and protein domains in the cell membrane, and fulfill a role in a wide range of processes. It has become quite clear that the constituent proteins of the caveolin family are involved in the modulation of signal transduction events. Aberrations in such pathways will ultimately result in the disturbance of normal cell functions and as a consequence, may lead to pathological processes. There is a growing body of evidence to indicate that the altered expression of caveolins contributes to such diseases as cancer, muscular dystrophy and Alzheimer’s dementia. Acknowledgements. We would like to thank J. Gierak M.Sc. for editing the manuscript.


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124. Schwencke, C., Yamamoto, M., Okumura, S., Toya, Y., Kim, S.-J. and Ishikawa, Y. Compartmentation of cyclic adenosine 3’,5’-monophosphate signaling in caveolae. Mol. Endocrinol. 13 (1999) 1061-1070.

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151. Cohen, A.W., Park, D.S., Woodman, S.E., Williams, T.M., Chandra, M., Shirani, J., Pereira de Souza, A., Kitsis, R.N., Russell, R.G., Weiss, L.M., Tang, B., Jelicks, L.A., Factor, S.M., Shtutin, V., Tanowitz, H.B. and Lisanti, M.P. Caveolin-1 null mice develop cardiac hyperthropy with hyperactivation of p42/44 MAP kinase in cardiac fibroblasts. Am. J. Physiol. Cell Physiol. 284 (2003) C457-C474.

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