RGT, a synthetic peptide corresponding to the integrin β3 cytoplasmic C-terminal sequence, selectively inhibits outside-in signaling in human platelets by disrupting the interaction of integrin αIIbβ3 with Src kinase
| Autor: | Hongchen Liu, Xiaoyu Su, Xiao-dong Xi, Jingsong Yan, Xiaoping Du, Jian-Qing Mi, Panagiotis Flevaris, Xuefeng Wang, Yuanjing Lu, Sai-Juan Chen, Zheng Ruan, Nelly Kieffer |
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| Rok vydání: | 2008 |
| Předmět: |
Immunology
Integrin Clot Retraction Platelet Glycoprotein GPIIb-IIIa Complex Biochemistry CD49c Collagen receptor Platelet Adhesiveness Humans Phosphorylation Dose-Response Relationship Drug biology Integrin beta3 Fibrinogen binding Cell Biology Hematology Molecular biology Peptide Fragments Cell biology src-Family Kinases Integrin alpha M biology.protein Integrin beta 6 Protein Binding Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Blood. 112:592-602 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Mutational analysis has established that the cytoplasmic tail of the integrin β3 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 platelet 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 β3 and dose-dependently inhibited the purified recombinant β3 cytoplasmic domain binding to Src-SH3. In addition, phosphorylation of the β3 cytoplasmic tyrosines, Y747 and Y759, 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 β3 and selective blockade of integrin αIIbβ3 outside-in signaling by myr-RGT suggest a potential new antithrombotic strategy. |
| Databáze: | OpenAIRE |
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