Caveolin -1, mechanistic insights into subcellular traffic and regulation of estrogen receptor signaling
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Caveolin-1 is the principal coat protein of caveolae membranes. This protein is also a component of the cell's transport machinery, contributing to the bi-directional traffic of cholesterol to and from caveolae. Third, caveolin-1 is a regulator of many signaling proteins that reside in caveolae as part of their activation cycle.;Caveolin-1 has a short, central hydrophobic domain predicted to anchor the protein to membranes. A panel of deletion mutants was used to show that this putative transmembrane domain (TMD) is dispensable for membrane binding. The two domains flanking the TMD can anchor heterologous reporter proteins to membranes in vitro and in vivo. These two domains target green fluorescent protein to different subcellular compartments, with the domain N-terminal to the TMD (the caveolin scaffolding domain, or N-terminal membrane attachment domain, N-MAD) targeting to caveolae membranes, and the domain C-terminal to the TMD (the C-terminal membrane attachment domain, C-MAD) targeting to the trans-Golgi network.;The role of serine phosphorylation, a long standing observation of previously unappreciated significance, was examined by mutational analysis as well. Mutation of invariant (i.e. conserved across all caveolin isoforms in all species examined to date) serine residue 80 to glutamate (Cav-1(S80E), mimicking phosphorylation, caused caveolin-1 to target to the cytoplasmic face of endoplasmic reticulum membranes in fibroblast cells. In contrast, Cav-1(S80A), a mutant that is not phosphorylated, targeted to caveolae. Mutation of the other invariant serine residue Ser168 to either alanine or glutamate had no effect on caveolae targeting.;Caveolin-1 is secreted by the exocrine pancreas. Cav-1(S80E) was secreted to a greater extent than wildtype caveolin-1, while Cav-1(S80A) was not secreted at all when the secretory phenotype of AR42J rat pancreatic adenocarcinoma cells was elicited with dexamethasone. Thus, caveolin-1 serine phosphorylation regulates caveolin-1 entry into the secretory pathway by targeting the protein to the endoplasmic reticulum.;In addition to these studies, the role of caveolin-1 in estrogen receptor alpha (ERalpha) signaling was examined. Caveolin-1 potentiated the transcriptional activity of ERalpha, and conferred resistance to tamoxifen. These effects are due to a direct interaction between these proteins, and increased level of ERalpha phosphorylation in the presence of caveolin-1.