RGT, a synthetic peptide corresponding to the integrin ß3 cytoplasmic C-terminal sequence, selectively inhibits outside-in signaling in human platelets by disrupting the interaction of integrin αIIbβ3 with Src kinase

Xiaoyu Su, Jianqing Mi, Jinsong Yan, Panagiotis Flevaris, Yuanjing Lu, Hongchen Liu, Zheng Ruan, Xuefeng Wang, Nelly Kieffer, Saijuan Chen, Xiaoping Du, Aodong Xi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Mutational analysis has established that the cytoplasmic tail of the integrin (53 subunit binds c-Src (termed as Src in this study) and is critical for bidirectional integrin signaling. Here we show in washed human platelets that a cell-permeable, myristoylated RGT peptide (myr-RGT) corresponding to the integrin β3 C-terminal sequence dose-dependently inhibited stable platelet adhesion and spreading on immobilized fibrinogen, and fibrin clot retraction as well. Myr-RGT also inhibited the aggregation-dependent plate-let secretion and secretion-dependent second wave of platelet aggregation induced by adenosine diphosphate, ristocetin, or thrombin. Thus, myr-RGT inhibited integrin outside-in signaling. In contrast, myr-RGT had no inhibitory effect on adenosine diphosphate-induced soluble fibrinogen binding to platelets that is dependent on integrin inside-out signaling. Furthermore, the RGT peptide induced dissociation of Src from integrin (Í3 and dose-dependently inhibited the purified recombinant (53 cytoplasmie domain binding to Src-SH3. In addition, phosphorylation of the (53 cytoplasmic tyrosines, Y 747 and Y 759, was inhibited by myr-RGT. These data indicate an important role for β3-Src interaction in outside-in signaling. Thus, in intact human platelets, disruption of the association of Src with (53 and selective blockade of integrin αllbβ3 out-side-in signaling by myr-RGT suggest a potential new antithrombotic strategy.

Original languageEnglish (US)
Pages (from-to)592-602
Number of pages11
JournalBlood
Volume112
Issue number3
DOIs
StatePublished - Aug 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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