Abstract
Caveolin‐1 (Cav1), a major Src kinase substrate phosphorylated on tyrosine‐14 (Y14), contains the highly‐conserved membrane‐proximal caveolin scaffolding domain (CSD; amino acids 82‐101). Here we show, using CSD mutants (F92A/V94A) and membrane‐permeable CSD competing peptides, that Src kinase‐dependent pY14Cav1 regulation of focal adhesion protein stabilization, focal adhesion tension and cancer cell migration is CSD‐dependent. Quantitative proteomic analysis of Cav1‐GST (1‐101 amino acids) pulldowns showed 6‐fold increased binding of vinculin and, to a lesser extent, α‐actinin, talin and filamin, to phosphomimetic Cav1Y14D relative to non‐phosphorylatable Cav1Y14F. Consistently, pY14Cav1 enhanced CSD‐dependent vinculin tension in focal adhesions, dampening force fluctuation and synchronously stabilizing cellular focal adhesions in a high‐tension mode, paralleling effects of actin stabilization. By promoting focal adhesion traction, functional interaction between Cav1 Y14 phosphorylation and the CSD shifts the molecular clutch linking adhesions and the actin cytoskeleton to high gear, and thereby drives cancer cell migration.
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