Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration

Abstract

Cell migration is a dynamic process that requires temporal and spatial regulation of integrin activation and focal adhesion assembly-disassembly1. Talin, an actin and β integrin tail-binding protein, is essential for integrin activation and focal adhesion formation2,3. Calpain-mediated cleavage of talin plays a key role in focal adhesion turnover3; however, the talin head (TH) domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions, and maintains cell edge protrusions2,4,5, suggesting that additional steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that TH binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration6,7, more tightly than full length talin and that this interaction leads to TH ubiquitination and degradation. TH was a substrate for Cdk5, a regulator of cell migration and cancer metastasis8–11. Cdk5 phosphorylated TH at Ser425, inhibiting its binding to Smurf1, thus preventing TH ubiquitination and degradation. Expression of talS425A, which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitination, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, TH produced by calpain cleavage of talin, is degraded via Smurf1-mediated ubiquitination; moreover, phosphorylation by Cdk5 regulates Smurf1 binding to TH and, in this way, controls TH turnover and adhesion stability and, ultimately, cell migration.