TI - Two distinct roles of mitogen -activated protein kinases in platelets and a novel Rac1-MAPK -dependent integrin outside-in retractile signaling pathway . AB - Mitogen-activated protein kinases ( MAPK ) , p38 , and extracellular stimuli-responsive kinase ( ERK ) , are acutely but transiently activated in platelets by platelet agonists , and the agonist -induced platelet MAPK activation is inhibited by ligand binding to the integrin alpha (IIb) beta(3) . Here we show that , although the activation of MAPK , as indicated by MAPK phosphorylation , is initially inhibited after ligand binding to integrin alpha ( IIb ) beta(3) , integrin outside-insignaling results in a late but sustained activation of MAPKs in platelets . Furthermore , we show that the early agonist -induced MAPK activation and the late integrin-mediated MAPK activation play distinct roles in different stages of platelet activation . Agonist -induced MAPK activation primarily plays an important role in stimulating secretion of platelet granules , while integrin-mediated MAPK activation is important in facilitating clot retraction . The stimulatory role of MAPK in clot retraction is mediated by stimulating myosin light chain ( MLC ) phosphorylation . Importantly , integrin -dependent MAPK activation , MAPK -dependent MLC phosphorylation , and clot retraction are inhibited by a Rac1 inhibitor and in Rac1 knockout platelets , indicating that integrin-induced activation of MAPK and MLC and subsequent clot retraction is Rac1 -dependent . Thus , our results reveal 2 different activation mechanisms of MAPKs that are involved in distinct aspects of platelet function and a novel Rac1-MAPK -dependent cell retractile signaling pathway .