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Molecular and Cellular Biology, September 2006, p. 6936-6949, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.01040-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Evidence for the Requirement of ITAM Domains but Not SLP-76/Gads Interaction for Integrin Signaling in Hematopoietic Cells

Farhad Abtahian,1 Natalie Bezman,1 Regina Clemens,1 Eric Sebzda,2 Lan Cheng,2 Sanford J. Shattil,3 Mark L. Kahn,2 and Gary A. Koretzky1,4,5*

Signal Transduction Program, Leonard and Madlyn Abramson Family Cancer Research Institute,1 Division of Cardiology and Department of Medicine,2 Department of Pathology and Laboratory Medicine,4 Division of Rheumatology and Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,5 Hematology-Oncology Division, Department of Medicine, University of California, San Diego, La Jolla, California3

Received 9 June 2006/ Accepted 18 June 2006

Syk tyrosine kinase and Src homology 2 (SH2) domain-containing leukocyte-specific phosphoprotein of 76 kDa (SLP-76) are signaling mediators activated downstream of immunoreceptor tyrosine-based activation motif (ITAM)-containing immunoreceptors and integrins. While the signaling cascades descending from integrins are similar to immunoreceptors, the mechanism of Syk activation and SLP-76 recruitment remains unclear. We used an in vivo structure-function approach to study the requirements for the domains of Syk and SLP-76 in immunoreceptor and integrin signaling. We found that both SH2 domains and the kinase domain of Syk are required for immunoreceptor-dependent signaling and cellular response via integrins. While the Gads-binding domain of SLP-76 is needed for immunoreceptor signaling, it appears dispensable for integrin signaling. Syk and SLP-76 also are required for initiating and/or maintaining separation between the blood and lymphatic vasculature. Therefore, we correlated the signaling requirement of the various domains of Syk and SLP-76 to their requirement in regulating vascular separation. Our data suggest ITAMs are required in Syk-dependent integrin signaling, demonstrate the separation of the structural features of SLP-76 to selectively support immunoreceptor versus integrin signaling, and provide evidence that the essential domains of SLP-76 for ITAM signals are those which most efficiently support separation between lymphatic and blood vessels.

* Corresponding author. Mailing address: University of Pennsylvania, 421 Curie Blvd., 416 BRBII/III, Philadelphia, PA 19104. Phone: (215) 746-5522. Fax: (215) 746-5525. E-mail: koretzky{at}mail.med.upenn.edu.

Molecular and Cellular Biology, September 2006, p. 6936-6949, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.01040-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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