Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 5627K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bezman, N. A. Articles by Koretzky, G. A. Search for Related Content PubMed PubMed Citation Articles by Bezman, N. A. Articles by Koretzky, G. A. Related Collections Related In this Issue article Social Bookmarking                      What's this?

¹ Leonard and Madlyn Abramson Family Cancer Research Institute, ² Department of Medicine, Division of Hematology/Oncology, ³ Division of Cardiology, ⁴ Division of Rheumatology, and ⁵ Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

CORRESPONDENCE Gary A. Koretzky: Koretzky{at}mail.med.upenn.edu

Src homology 2 domain–containing leukocyte phosphoprotein of 76 kD (SLP76), an adaptor that plays a critical role in platelet activation in vitro, contains three N-terminal tyrosine residues that are essential for its function. We demonstrate that mice containing complementary tyrosine to phenylalanine mutations in Y145 (Y145F) and Y112 and Y128 (Y112/128F) differentially regulate integrin and collagen receptor signaling. We show that mutation of Y145 leads to severe impairment of glycoprotein VI (GPVI)–mediated responses while preserving outside-in integrin signaling. Platelets from Y112/128F mice, although having mild defects in GPVI signaling, exhibit defective actin reorganization after GPVI or IIbβ3 engagement. The in vivo consequences of these signaling defects correlate with the mild protection from thrombosis seen in Y112/128F mice and the near complete protection observed in Y145F mice. Using genetic complementation, we further demonstrate that all three phosphorylatable tyrosines are required within the same SLP76 molecule to support platelet activation by GPVI.

Abbreviations used: Btk, Bruton's tyrosine kinase; CVX, convulxin; GPVI, glycoprotein VI; IP, immunoprecipitation; ITAM, immunoreceptor tyrosine-based activation motif; Itk, IL-2–inducible T cell kinase; KI, knock-in; LAT, linker for activation of T cells; PLC2, phospholipase C 2; PRP, platelet-rich plasma; PTK, protein tyrosine kinase; SH2, Src homology 2; SLP76, SH2 domain–containing leukocyte phosphoprotein of 76 kD.

© 2008 Bezman et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related In this Issue article

Selective signaling

Hema Bashyam
J. Exp. Med. 2008 205: 1716-1717. [Full Text] [PDF]

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS