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 intracellular cholesterol shuttle, and as a regulator of diverse signaling molecules. Of the 12 residues conserved across all caveolin isoforms from all species examined to date, only Ser(80) and Ser(168) could serve as phosphorylation sites. We show here that mimicking chronic phosphorylation of Ser(80) by mutation to Glu (i.e. Cav-1(S80E)), blocks phosphate incorporation. However, Cav-1(S168E) is phosphorylated to the same extent as wild-type caveolin-1. Cav-1(S80E) targets to the endoplasmic reticulum membrane, remains oligomeric, and maintains normal membrane topology. In contrast, Cav-1(S80A), which cannot be phosphorylated, targets to caveolae membranes. Some exocrine cells secrete caveolin-1 in a regulated manner. Cav-1(S80A) is not secreted by AR42J pancreatic adenocarcinoma cells even in the presence of dexamethasone, an agent that induces the secretory phenotype. Conversely, Cav-1(S80E) is secreted to a greater extent than wild-type caveolin-1 following dexamethasone treatment. We conclude that caveolin-1 phosphorylation on invariant serine residue 80 is required for endoplasmic reticulum retention and entry into the regulated secretory pathway.
Schlegel
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A
Department of Molecular Pharmacology, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Arvan
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P
Lisanti
M P
MP
D000595:Amino Acid Sequence; D000818:Animals; D051242:Caveolin 1; D022461:Caveolins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000378:metabolism*
C495540:CAV1 protein, human; D051242:Caveolin 1; D022461:Caveolins; D012694:Serine