Caveolin-1 binding to endoplasmic reticulum membranes and entry into the regulated secretory pathway are regulated by serine phosphorylation - Protein sorting at the level of the endoplasmic reticulum

Caveolin-1 serves as the main coat protein of caveolae membranes, as an int racellular cholesterol shuttle, and as a regulator of diverse signaling mol ecules. Of the 12 residues conserved across all caveolin isoforms from all species examined to date, only Ser(80) and Ser(168) could serve as phosphor ylation sites. me show here that mimicking chronic phosphorylation of Ser(8 0) by mutation to Glu tie. Cav-1(S80E), blocks phosphate incorporation. How ever, Cav-1(S168E) is phosphorylated to the same extent as wild-type caveol in-1. Cav-1(S80E) targets to the endoplasmic reticulum membrane, remains ol igomeric, and maintains normal membrane topology. In contrast, Cav-1(S80A), which cannot be phosphorylated, targets to caveolae membranes. Some exocri ne cells secrete caveolin-1 in a regulated manner. Cav-1(S80A) is not secre ted by AR42J pancreatic adenocarcinoma cells even in the presence of dexame thasone, an agent that induces the secretory phenotype. Conversely, Cav-1(S 80E) is secreted to a greater extent than wildtype caveolin-1 following dex amethasone treatment. We conclude that caveolin-1 phosphorylation on invari ant serine residue 80 is required for endoplasmic reticulum retention and e ntry into the regulated secretory pathway.