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Lnk regulates integrin αIIbβ3 outside-in signaling in mouse platelets, leading to stabilization of thrombus development in vivo

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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
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)

Submitter: 小田 淳

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