Title: | Lnk regulates integrin αIIbβ3 outside-in signaling in mouse platelets, leading to stabilization of thrombus development in vivo |
Authors: | Takizawa, Hitoshi Browse this author |
Nishimura, Satoshi Browse this author |
Takayama, Naoya Browse this author |
Oda, Atsushi Browse this author →KAKEN DB |
Nishikii, Hidekazu Browse this author |
Morita, Yohei Browse this author |
Kakinuma, Sei Browse this author |
Yamazaki, Satoshi Browse this author |
Okamura, Satoshi Browse this author |
Tamura, Noriko Browse this author |
Goto, Shinya Browse this author |
Sawaguchi, Akira Browse this author |
Manabe, Ichiro Browse this author |
Takatsu, Kiyoshi Browse this author |
Nakauchi, Hiromitsu Browse this author |
Takaki, Satoshi Browse this author |
Eto, Koji Browse this author |
Issue Date: | 4-Jan-2010 |
Publisher: | American Society for Clinical Investigation |
Journal Title: | Journal of Clinical Investigation |
Volume: | 120 |
Issue: | 1 |
Start Page: | 179 |
End Page: | 190 |
Publisher DOI: | 10.1172/JCI39503 |
Abstract: | 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 αIIbβ3-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 β3 integrin subunit, and reduced binding of Fyn to integrin αIIbβ3. These results provide new insight into the mechanism of αIIbβ3-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. |
Type: | article |
URI: | http://hdl.handle.net/2115/48286 |
Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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