Caveolins, a Family of Scaffolding Proteins for Organizing “Preassembled Signaling Complexes” at the Plasma Membrane

Abstract

Caveolae are vesicular invaginations of the plasma membrane. The chief structural proteins of caveolae are the caveolins. Caveolins form a scaffold onto which many classes of signaling molecules can assemble to generate preassembled signaling complexes. In addition to concentrating these signal transducers within a distinct region of the plasma membrane, caveolin binding may functionally regulate the activation state of caveolae-associated signaling molecules. Because the responsibilities assigned to caveolae continue to increase, this review will focus on: (i) caveolin structure/function and (ii) caveolae-associated signal transduction. Studies that link caveolae to human diseases will also be considered.The Caveolin Gene Family: Caveolin-1, -2, and -3 Molecular cloning has identified three distinct caveolin genes (1-6), caveolin-1, caveolin-2, and caveolin-3. Two isoforms of caveolin-1 (Cav-1␣ and Cav-1␤) are derived from alternate initiation during translation. Caveolin-1 and -2 are most abundantly expressed in adipocytes, endothelial cells, and fibroblastic cell types, whereas the expression of caveolin-3 is muscle-specific.Caveolin proteins interact with themselves to form homo-and hetero-oligomers (7-9), which directly bind cholesterol (10) and require cholesterol for insertion into model lipid membranes (10,11). Caveolin oligomers may also interact with glycosphingolipids (12). These protein-protein and protein-lipid interactions are thought to be the driving force for caveolae formation (7). In addition, the caveolin gene family is structurally and functionally conserved from worms (Caenorhabditis elegans) to man (13), supporting the idea that caveolins play an essential role.Caveolin-1 assumes an unusual topology. A central hydrophobic domain (residues 102-134) is thought to form a hairpin-like structure within the membrane. As a consequence, both the N-terminal domain (residues 1-101) and the C-terminal domain (residues 135-178) face the cytoplasm. A 41-amino acid region of the N-terminal domain (residues 61-101) directs the formation of caveolin homooligomers (7), whereas the 44-amino acid C-terminal domain acts as a bridge to allow these homo-oligomers to interact with each other, thereby forming a caveolin-rich scaffold (14).Recent co-immunoprecipitation and dual labeling experiments directly show that caveolin-1 and -2 form a stable hetero-oligomeric complex and are strictly co-localized (9). Caveolin-2 localization corresponds to caveolae membranes as visualized by immunoelectron microscopy (9). Thus, caveolin-2 may function as an "accessory protein" in conjunction with caveolin-1. Caveolin-interacting ProteinsA number of studies support the hypothesis that caveolin proteins provide a direct means for resident caveolae proteins to be sequestered within caveolae microdomains. These caveolin-interacting proteins include G-protein ␣ subunits, Ha-Ras, Src family tyrosine kinases, endothelial NOS, 1 EGF-R and related receptor tyrosine kinases, and protein kinase C isoforms (11, 15-18, 20 -32).Heterotri...

Csk-binding protein (Cbp) negatively regulates epidermal growth factor-induced cell transformation by controlling Src activation

“…Interestingly, we found that Cbp interacted constitutively with caveolin-1, which is likely to be mediated by the FVITFLIF motif in the Cbp transmembrane domain, matching well with the published caveolin-binding motif cXXXXcXXc (c is an aromatic residue, like Trp, Phe, or Tyr) (Couet et al, 1997). Caveolin-1, which is the structural protein of caveolae, appears to be a scaffold protein used for assembling multiple signaling molecules, including heterotrimeric G-proteins, Src family tyrosine kinases, endothelial nitric oxide synthase, Ha-Ras, and the EGF receptor (Okamoto et al, 1998). The biological significance of the caveolin-Cbp interaction is currently unknown.…”

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

“…Caveolin-1 recruits b-catenin to caveolae membranes for its link with E-cadherin and thus promotes cell adhesion and effectively inhibits b-catenin TCF/LEF-1 signaling (Galbiati et al, 2000;Torres et al, 2007). In addition, caveolin-1 was reported to colocalize with a variety of lipid-modified signaling molecules, including G proteins, Src-like kinases, HaRas and eNOS on caveolae membranes, and function as a negative regulator of these proteins (Li et al, 1996;Couet et al, 1997;Okamoto et al, 1998). In our study, caveolin-1 was upregulated when the function of xCT was disrupted (Figure 3a).…”

Molecular pathways mediating mechanical signaling in bone

“…Lipid rafts can be categorized into caveolar and noncaveolar forms (Anderson, 1998;Cho et al, 2003). Unlike noncaveolar rafts, caveolae contain caveolins as their structural and functional molecules (Anderson, 1998;Okamoto et al, 1998). Both forms of detergent-resistant organized membrane have been shown to be critical to the integration of mechanical information at the plasma membrane surface (Anderson, 1998).…”

“…The protein structure of caveolins allows both amino and carboxyl termini to remain in the cell cytoplasm and interact with proteins that kink around the central hydrophobic domain. Many pro teins found in caveolae contain caveolinbinding motifs that may represent a mechanism for membrane sequestration (Okamoto et al, 1998). The tendency of caveolin to form homooligomers that associate with lipid-modified signaling molecules suggests that caveolin serves as a scaffold protein (Couet et al, 1997).…”