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Constitutive and Growth Factor-Regulated Phosphorylation of Caveolin-1 Occurs at the Same Site (Tyr-14) in Vivo: Identification of a c-Src/Cav-1/Grb7 Signaling Cassette

Department of Molecular Pharmacology and The Albert Einstein Cancer Center (H.L., D.V., F.G., M.P.L.) Department of Cell Biology and The Albert Einstein Cancer Center (P.I., P.E.S.) Department of Pathology and The Albert Einstein Cancer Center (D.B.B.) Departments of Developmental & Molecular Biology (DMB) and Medicine; and the Albert Einstein Cancer Center (B.B., R.G.P.) Albert Einstein College of Medicine Bronx, New York 10461
Department of Pathology (D.M.L.) Washington University School of Medicine St. Louis, Missouri 63110
BD Transduction Laboratories (M.T.W., R.C.-G.) Lexington, Kentucky 40511

Caveolin-1 was first identified as a phospho-protein in Rous sarcoma virus (RSV)-transformed chicken embryo fibroblasts. Tyrosine 14 is now thought to be the principal site for recognition by c-Src kinase; however, little is known about this phosphorylation event. Here, we generated a monoclonal antibody (mAb) probe that recognizes only tyrosine 14-phosphorylated caveolin-1. Using this approach, we show that caveolin-1 (Y14) is a specific tyrosine kinase substrate that is constitutively phosphorylated in Src- and Abl-transformed cells and transiently phosphorylated in a regulated fashion during growth factor signaling. We also provide evidence that tyrosine-phosphorylated caveolin-1 is localized at the major sites of tyrosine-kinase signaling, i.e. focal adhesions. By analogy with other signaling events, we hypothesized that caveolin-1 could serve as a docking site for pTyr-binding molecules. In support of this hypothesis, we show that phosphorylation of caveolin-1 on tyrosine 14 confers binding to Grb7 (an SH2-domain containing protein) both in vitro and in vivo. Furthermore, we demonstrate that binding of Grb7 to tyrosine 14-phosphorylated caveolin-1 functionally augments anchorage-independent growth and epidermal growth factor (EGF)-stimulated cell migration. We discuss the possible implications of our findings in the context of signal transduction.

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