The Journal of Experimental Medicine
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Published 5 January 2004. doi:10.1084/jem.20030976
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 1, 99-112
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Fyn and PTP-PEST–mediated Regulation of Wiskott-Aldrich Syndrome Protein (WASp) Tyrosine Phosphorylation Is Required for Coupling T Cell Antigen Receptor Engagement to WASp Effector Function and T Cell Activation

Karen Badoura,b, Jinyi Zhanga,b, Fabio Shia,b, Yan Lenga,b, Michael Collinsa,b and Katherine A. Siminovitcha,b

a Department of Medicine, Department of Immunology, Department of Medical Genetics and Microbiology, and Institute of Medical Science, University of Toronto, Toronto, ON M5G 1X5, Canada
b Samuel Lunenfeld and Toronto General Research Institutes, Mount Sinai Hospital and the University Health Network, Toronto, ON M5G 1X5, Canada

Address correspondence to Katherine A. Siminovitch, Mount Sinai Hospital, 600 University Avenue, Room 656A, Toronto, ON M5G 1X5, Canada. Phone: (416) 586-8723; Fax: (416) 586-8731; email: ksimin{at}mshri.on.ca

Involvement of the Wiskott-Aldrich syndrome protein (WASp) in promoting cell activation requires its release from autoinhibitory structural constraints and has been attributed to WASp association with activated cdc42. Here, however, we show that T cell development and T cell receptor (TCR)-induced proliferation and actin polymerization proceed normally in WASp-/- mice expressing a WASp transgene lacking the cdc42 binding domain. By contrast, mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation. These observations identify key roles for Fyn and PTP-PEST in regulating WASp and imply that inducible WASp tyrosine phosphorylation can occur independently of cdc42 binding, but unlike the cdc42 interaction, is absolutely required for WASp contributions to T cell activation.

Key Words: WASp • lymphocyte activation • tyrosine phosphorylation • actin cytoskeletal arrangement

Abbreviations used in this paper: GBD, GTPase binding domain; GFP, green fluorescent protein; GST, gluthathione S-transferase; PKC, protein kinase C; PSTPIP, proline, serine, threonine phosphatase interacting protein; PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatase; pTyr, phosphotyrosine; VCA, verprolin homology central region-acidic region; WASp, Wiskott-Aldrich syndrome protein.


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