Protein phosphatase 1 associates with the integrin αIIb subunit and regulates signaling

Abstract

Regulation of integrin activation occurs by specific interactions among cytoplasmic proteins and integrin α and β cytoplasmic tails. We report that the catalytic subunit of protein phosphatase 1 (PP1c) constitutively associates with the prototypic integrin αIIbβ3 in platelets and in cell lines overexpressing the integrin. PP1c binds directly to the cytoplasmic domain of integrin αIIb subunit containing a conserved PP1c binding motif 989KVGF992. Anchored PP1c is inactive, while thrombin-induced platelet aggregation or fibrinogen- αIIbβ3 engagement caused PP1c dissociation and concomitant activation as revealed by dephosphorylation of PP1c substrate, myosin light chain. Inhibition of ligand binding to activated αIIbβ3 blocks PP1c dissociation and represses PP1c activation. These studies reveal a previously unrecognized role for integrins whereby the a subunit cytoplasmic tail localizes the machinery for initiating and temporally maintaining the regulatory signaling activity of a phosphatase.