Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK-dependent integrin outside-in retractile signaling pathway

Panagiotis Flevaris, Zhenyu Li, Guoying Zhang, Yi Zheng, Junling Liu, Xiaoping Du*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

Abstract

Mitogen-activated protein kinases (MAPK), p38, and extracellular stimuli- responsive kinase (ERK), are acutely but transiently activated in platelets by plate- let agonists, and the agonist-induced platelet MAPK activation is inhibited by ligand binding to the integrin a llbβ 3. Here we show that, although the activation of MAPK, as indicated by MAPK phosphory- lation, is initially inhibited after ligand binding to integrin a llbβ 3, integrin outside-in signaling results in a late but sustained activation of MAPKs in platelets. Further- more, we show that the early agonist- induced MAPK activation and the late integrin-mediated MAPK activation play distinct roles in different stages of plate- let activation. Agonist-induced MAPK ac- tivation primarily plays an important role in stimulating secretion of platelet gran- ules, while integrin-mediated MAPK acti- vation is important in facilitating clot re- traction. The stimulatory role of MAPK in clot retraction is mediated by stimulating myosin light chain (MLC) phosphoryla- tion. Importantly, integrin-dependent MAPK activation, MAPK-dependent MLC phosphorylation, and clot retraction are in- hibited 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 as- pects of platelet function and a novel Rac1-MAPK-dependent cell retractile sig- naling pathway.

Original languageEnglish (US)
Pages (from-to)893-901
Number of pages9
JournalBlood
Volume113
Issue number4
DOIs
StatePublished - Jan 22 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK-dependent integrin outside-in retractile signaling pathway'. Together they form a unique fingerprint.

Cite this