Two signaling molecules required for caveolin phosphorylation have been identified: Fyn and Abl. The data suggest a novel mechanism for the attenuation of Src-kinase activity by Abl: stable tyrosine phosphorylation of a scaffolding protein (cav-eolin-1) and recruitment of a negative regulator of Src-family kinase activity (Csk). The unexpected complexity of this pathway has important implications for treatment of diseases, including cancer and diabetes.

Three binding partners for phosphocaveolin have been identified: TRAF2, Grb7, and Csk. The identification of Csk as a binding partner for phosphorylated cav-eolin-1 led to a unique model for the function of caveolae in cells. It also demonstrated the utility of a powerful new technique to identify novel phosphotyrosine-directed protein interactions.

A novel feedback mechanism for Src-family kinase regulation has been identified: recruitment and activation of Csk by Src-family kinase substrates such as caveolin-1. Recruitment and activation of Abl in the complex induces sustained activation of Csk and attenuation of Src-family kinase activity, consistent with the counter-regulatory effects of these kinases. This previously undescribed, but simple, mechanism can explain a number of well-studied observations, including transient activation of Src-family kinases in forming focal contacts, and the counter-regulatory effects of Abl and Src-family kinases in cell growth, migration, and actin polymerization.

A novel role for caveolae and caveolin tyrosine phosphorylation in cells was proposed: regulation of cortical actin assembly and/or remodeling. The caveolin-1/Csk/Src family kinase/Abl signaling complex may be involved in transmitting signals to the actin cytoskeleton (i.e., from integrins or oxidative stress) or transmitting signals from the actin cytoskeleton (i.e., from shear or osmotic stress).

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