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J. Biol. Chem., Vol. 281, Issue 30, 20949-20957, July 28, 2006

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Fer and Fps/Fes Participate in a Lyn-dependent Pathway from FcRI to Platelet-Endothelial Cell Adhesion Molecule 1 to Limit Mast Cell Activation^*

Christian M. Udell¹, Lionel A. Samayawardhena, Yuko Kawakami, Toshiaki Kawakami, and Andrew W. B. Craig²

From the Department of Biochemistry, Queen's University, Kingston, Ontario K7L 3N6, Canada and the Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121

Mast cells express the high affinity IgE receptor FcRI, which upon aggregation by multivalent antigens elicits signals that cause rapid changes within the mast cell and in the surrounding tissue. We previously showed that FcRI aggregation caused a rapid increase in phosphorylation of both Fer and Fps/Fes kinases in bone marrow-derived mast cells. In this study, we report that FcRI aggregation leads to increased Fer/Fps kinase activities and that Fer phosphorylation downstream of FcRI is independent of Syk, Fyn, and Gab2 but requires Lyn. Activated Fer/Fps readily phosphorylate the C terminus of platelet-endothelial cell adhesion molecule 1 (Pecam-1) on immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and a non-ITIM residue (Tyr⁷⁰⁰) in vitro and in transfected cells. Mast cells devoid of Fer/Fps kinase activities display a reduction in FcRI aggregation-induced tyrosine phosphorylation of Pecam-1, with no defects in recruitment of Shp1/Shp2 phosphatases observed. Lyn-deficient mast cells display a dramatic reduction in Pecam-1 phosphorylation at Tyr⁶⁸⁵ and a complete loss of Shp2 recruitment, suggesting a role as an initiator kinase for Pecam-1. Consistent with previous studies of Pecam-1-deficient mast cells, we observe an exaggerated degranulation response in mast cells lacking Fer/Fps kinases at low antigen dosages. Thus, Lyn and Fer/Fps kinases cooperate to phosphorylate Pecam-1 and activate Shp1/Shp2 phosphatases that function in part to limit mast cell activation.

Received for publication, May 3, 2006

^* This work was supported in part by National Cancer Institute of Canada Grant 14312 (to A. W. B. C.) and by funds from the Terry Fox Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a scholarship from Ontario Graduate Scholarship fund.

² Supported by a New Investigator Award from Canadian Institutes of Health Research. To whom correspondence should be addressed. Tel.: 613-533-2496; Fax: 613-533-2497; E-mail: ac15{at}post.queensu.ca.

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