Protein phosphatase 1 associates with the integrin alphaIIb subunit and regulates signaling.
Regulation of integrin activation occurs by specific interactions among cytoplasmic proteins and integrin alpha and beta cytoplasmic tails. We report that the catalytic subunit of protein phosphatase 1 (PP1c) constitutively associates with the prototypic integrin alphaIIbbeta3 in platelets and in cell lines overexpressing the integrin. PP1c binds directly to the cytoplasmic domain of integrin alphaIIb subunit containing a conserved PP1c binding motif 989KVGF992. Anchored PP1c is inactive, while thrombin-induced platelet aggregation or fibrinogen-alphaIIbbeta3 engagement caused PP1c dissociation and concomitant activation as revealed by dephosphorylation of PP1c substrate, myosin light chain. Inhibition of ligand binding to activated alphaIIbbeta3 blocks PP1c dissociation and represses PP1c activation. These studies reveal a previously unrecognized role for integrins whereby the alpha subunit cytoplasmic tail localizes the machinery for initiating and temporally maintaining the regulatory signaling activity of a phosphatase.
Vijayan
K Vinod
KV
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. vvijayan@bcm.tmc.edu
Liu
Yan
Y
Li
Tong-Tong
TT
Bray
Paul F
PF
D000595:Amino Acid Sequence; D001665:Binding Sites; D001792:Blood Platelets / Q000737:chemistry; D017124:Conserved Sequence; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D018994:Myosin Light Chains / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D040201:Platelet Membrane Glycoprotein IIb / Q000737:chemistry / Q000378:metabolism*; D054645:Protein Phosphatase 1; D015398:Signal Transduction; D013917:Thrombin / Q000494:pharmacology
D004791:Enzyme Inhibitors; D018994:Myosin Light Chains; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D040201:Platelet Membrane Glycoprotein IIb; D005340:Fibrinogen; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D013917:Thrombin