TY - JOUR
T1 - A Mitogen-activated Protein Kinase-dependent Signaling Pathway in the Activation of Platelet Integrin αIIbβ3
AU - Li, Zhenyu
AU - Xi, Xiaodong
AU - Du, Xiaoping
PY - 2001/11/9
Y1 - 2001/11/9
N2 - We have recently shown that the platelet integrin αII/β 3 is activated by von Willebrand factor (vWF) binding to its platelet receptor, glycoprotein Ib-IX (GPIb-IX), via the protein kinase G (PKG) signaling pathway. Here we show that GPIb-IX-mediated activation of integrin αIIbβ3 is inhibited by dominant negative mutants of Raf-1 and MEK1 in a reconstituted integrin activation model in Chinese hamster ovary (CHO) cells and that the integrin-dependent platelet aggregation induced by either vWF or low dose thrombin is inhibited by MEK inhibitors PD98059 and U0126. Thus, mitogen-activated protein kinase (MAPK) pathway is important in GPIb-IX-dependent activation of platelet integrin αIIbβ3. Furthermore, vWF binding to GPIb-IX induces phosphorylation of Thr-202/ Tyr-204 of extracellular signal-regulated kinase 2 (ERK2). GPIb-IX-induced ERK2 phosphorylation is inhibited by PKG inhibitors and enhanced by overexpression of recombinant PKG. PKG activators also induce ERK phosphorylation, indicating that activation of MAPK pathway is downstream from PKG. Thus, our data delineate a novel integrin activation pathway in which ligand binding to GPIb-IX activates PKG that stimulates MAPK pathway, leading to integrin activation.
AB - We have recently shown that the platelet integrin αII/β 3 is activated by von Willebrand factor (vWF) binding to its platelet receptor, glycoprotein Ib-IX (GPIb-IX), via the protein kinase G (PKG) signaling pathway. Here we show that GPIb-IX-mediated activation of integrin αIIbβ3 is inhibited by dominant negative mutants of Raf-1 and MEK1 in a reconstituted integrin activation model in Chinese hamster ovary (CHO) cells and that the integrin-dependent platelet aggregation induced by either vWF or low dose thrombin is inhibited by MEK inhibitors PD98059 and U0126. Thus, mitogen-activated protein kinase (MAPK) pathway is important in GPIb-IX-dependent activation of platelet integrin αIIbβ3. Furthermore, vWF binding to GPIb-IX induces phosphorylation of Thr-202/ Tyr-204 of extracellular signal-regulated kinase 2 (ERK2). GPIb-IX-induced ERK2 phosphorylation is inhibited by PKG inhibitors and enhanced by overexpression of recombinant PKG. PKG activators also induce ERK phosphorylation, indicating that activation of MAPK pathway is downstream from PKG. Thus, our data delineate a novel integrin activation pathway in which ligand binding to GPIb-IX activates PKG that stimulates MAPK pathway, leading to integrin activation.
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U2 - 10.1074/jbc.M106129200
DO - 10.1074/jbc.M106129200
M3 - Article
C2 - 11522789
AN - SCOPUS:0035834714
SN - 0021-9258
VL - 276
SP - 42226
EP - 42232
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 45
ER -