期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 120, 期 1, 页码 179-190出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI39503
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health, Labour and Welfar
- Japanese Sharyou Foundation (Tokyo, Japan)
- Uehara Memorial Foundation (Tokyo, Japan)
- Mitsubishi Pharma Research Foundation (Osaka, Japan)
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [21390321] Funding Source: KAKEN
The nature of the in vivo cellular events underlying thrombus formation mediated by platelet activation remains unclear because of the absence of a modality for analysis. Lymphocyte adaptor protein (Lnk; also known as Sh2b3) is an adaptor protein that inhibits thrombopoietin-mediated signaling, and as a result, megakaryocyte and platelet counts are elevated in Lnk(-/-) mice. Here we describe an unanticipated role for Lnk in stabilizing thrombus formation and clarify the activities of Lnk in platelets transduced through integrin alpha IIb beta 3-mediated outside-in signaling. We equalized platelet counts in wild-type and Lnk(-/-) mice by using genetic depletion of Lnk and BM transplantation. Using FeCl3- or laser-induced injury and in vivo imaging that enabled observation of single platelet behavior and the multiple steps in thrombus formation, we determined that Lnk is an essential contributor to the stabilization of developing thrombi within vessels. Lnk(-/-) platelets exhibited a reduced ability to fully spread on fibrinogen and mediate clot retraction, reduced tyrosine phosphorylation of the beta 3 integrin subunit, and reduced binding of Fyn to integrin alpha IIb beta 3. These results provide new insight into the mechanism of alpha IIb beta 3-based outside-in signaling, which appears to be coordinated in platelets by Lnk, Fyn, and integrins. Outside-in signaling modulators could represent new therapeutic targets for the prevention of cardiovascular events.
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