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

Open Access
Publisher Website
Google Scholar
Abstract
Talins are essential for integrin activation, focal adhesion formation and mesenchymal cell migration. The E3 ubiquitin ligase Smurf1 regulates talin head degradation and Cdk5-mediated phosphorylation of the head prevents Smurf1 action on talin. 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 has a key role in focal adhesion turnover3; however, the talin head domain, one of the two cleavage products, stimulates integrin activation, localizes to focal adhesions and maintains cell edge protrusions2,4,5, suggesting that other steps, downstream of talin proteolysis, are required for focal adhesion disassembly. Here we show that talin head binds Smurf1, an E3 ubiquitin ligase involved in cell polarity and migration6,7, more tightly than full-length talin does and that this interaction leads to talin head ubiquitylation and degradation. We found that talin head is a substrate for Cdk5, a cyclin-dependent protein kinase that is essential for cell migration, synaptic transmission and cancer metastasis8,9,10,11. Cdk5 phosphorylated talin head at Ser 425, inhibiting its binding to Smurf1, thus preventing talin head ubiquitylation and degradation. Expression of the mutant talS425A, which resists Cdk5 phosphorylation thereby increasing its susceptibility to Smurf1-mediated ubiqitylation, resulted in extensive focal adhesion turnover and inhibited cell migration. Thus, talin head produced by calpain-induced cleavage of talin is degraded through Smurf1-mediated ubiquitylation; moreover, phosphorylation by Cdk5 regulates the binding of Smurf1 to talin head, controlling talin head turnover, adhesion stability and ultimately, cell migration.