Determinants of Membrane Raft Caveolae Localization

In spite of the localization of certain GPCR and post-receptor signaling components in rafts or caveolae (as we shall discuss in more detail subsequently), the precise determinants of this localization are not known. Certain GPCR and post-receptor signaling components show cell-selective patterns of localization in those microdomains, but no generally accepted explanation for such patterns is as yet available. Possible explanations for these patterns include:

Protein-protein interaction: Interactions of particular proteins might be favored because of charge, size and/or steric factors, but why such factors should differ in a cell-type-selective manner is not clear. For GPCR, the ability to form oligomers with different composition may contribute to such localization (Nichols 2003). It has been proposed that the localization of receptor tyrosine kinases (RTK) in membrane microdomains is attributable to protein-protein binding by sequences in the extracellular domain of the receptors; for the EGFR a 60-amino-acid region mediates targeting to rafts/caveolae (Pike 2005; Yamabhai and Anderson 2002).

Lipid-protein interaction: Lipid composition is important for rafts and caveolae with differences among different cell types or in the nature of the lipids in different portions of the plasma membrane (Park et al. 2004; Rothberg et al. 1992). Although such differences might contribute to changes in localization of proteins during states of altered lipid composition, or perhaps to cell-specific patterns of localization, direct evidence for this idea has not been provided. Lipid modification of proteins, perhaps most importantly palmitoylation and myristoylation, contribute to the localization of G-protein-signaling components in raft/caveolae domains (Ratajczak et al. 2003; Razzaq et al. 2004; Resh 2006; Rodgers et al. 2005).

Caveolin-associated proteins: Caveolin-associated proteins might also contribute to differences in the localization of signaling molecules. The caveolin scaffolding domain (CSD), a hydrophobic region in the cytoplasmic amino terminal tail that interacts with protein "partners" through hydrophobic interactions, has been proposed as a - or perhaps the - critical region by which signaling proteins interact with caveolins (Becher and Mcllhinney 2005; Chini and Parenti 2004), but it is difficult to fathom how such an ~20-amino-acid domain accommodates such a large number and array of proteins (see below). Are there other regions on caveolins that bind signaling proteins or is there a supramolecular assembly, whereby multiple signaling proteins create a "caveolin signaling particle," akin to protein complexes involved in other cellular events (transcription, translation, secretion, etc.)? Use of proteomic methods to analyze caveolin-bound proteins in cells treated under various experimental conditions should prove useful in defining the existence (or not) of "caveolin signaling particles." Proteomic methods have shown that a large number of proteins localize to caveolae (Banfi et al. 2006; Durr et al. 2004; Foster et al. 2003; McMahon et al. 2006; Sprenger and Horrevoets 2007), either via their interaction with the CSD or by localization in the caveolar lipid microenvironment. Proteomic approaches should prove useful in revealing the full range of protein partners in caveolae, as well as changes in the amount and nature of these partners that occur in physiological states, with drug treatment or in disease.

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