LRP12 is an endogenous transmembrane inactivator of α 4 integrins

Dynamic regulation of integrin activation and inactivation is critical for precisely controlled cell adhesion and migration in physiological and pathological processes. The molecular basis for integrin activation has been intensively studied; however, the understanding of integrin inactivation is still limited. Here, we identify LRP12 as an endogenous transmembrane inhibitor for a4 integrin activation. The LRP12 cytoplasmic domain directly binds to the integrin a4 cytoplasmic tail and inhibits talin binding to the b subunit, thus keeping in-tegrin inactive. In migrating cells, LRP12-a4 interaction induces nascent adhesion (NA) turnover at the lead-ing-edge protrusion. Knockdown of LRP12 leads to increased NAs and enhanced cell migration. Consis-tently, LRP12-deficient T cells show an enhanced homing capability in mice and lead to aggravated chronic colitis in a T cell-transfer colitis model. Altogether, LRP12 is a transmembrane inactivator for integrins that inhibits a4 integrin activation and controls cell migration by maintaining balanced NA dynamics.

Automated summary

Dynamic regulation of integrin activation and inactivation is crucial for cell adhesion and migration. LRP12 is identified as a transmembrane inhibitor for a4 integrin activation, maintaining the balance of nascent adhesion turnover and controlling cell migration. Knockdown of LRP12 leads to increased nascent adhesions and enhanced cell migration.