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Molecular and Cellular Biology, September 2003, p. 6291-6299, Vol. 23, No. 17
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.17.6291-6299.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Vav1 Dephosphorylation by the Tyrosine Phosphatase SHP-1 as a Mechanism for Inhibition of Cellular Cytotoxicity

Christopher C. Stebbins,1 Carsten Watzl,1,{dagger} Daniel D. Billadeau,2 Paul J. Leibson,2 Deborah N. Burshtyn,3 and Eric O. Long1*

Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852,1 Department of Immunology, Mayo Clinic Foundation, Rochester, Minnesota 55905,2 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada3

Received 18 September 2002/ Returned for modification 11 November 2002/ Accepted 29 May 2003

Here, we present data suggesting a novel mechanism for regulation of natural killer (NK) cell cytotoxicity through inhibitory receptors. Interaction of activation receptors with their ligands on target cells induces cytotoxicity by NK cells. This activation is under negative control by inhibitory receptors that recruit tyrosine phosphatase SHP-1 upon binding major histocompatibility class I on target cells. How SHP-1 blocks the activation pathway is not known. To identify SHP-1 substrates, an HLA-C-specific inhibitory receptor fused to a substrate-trapping mutant of SHP-1 was expressed in NK cells. Phosphorylated Vav1, a regulator of actin cytoskeleton, was the only protein detectably associated with the catalytic site of SHP-1 during NK cell contact with target cells expressing HLA-C. Vav1 trapping was independent of actin polymerization, suggesting that inhibition of cellular cytotoxicity occurs through an early dephosphorylation of Vav1 by SHP-1, which blocks actin-dependent activation signals. Such a mechanism explains how inhibitory receptors can block activating signals induced by different receptors.

* Corresponding author. Mailing address: LIG-NIAID-NIH, Twinbrook II, 12441 Parklawn Dr., Rockville, MD 20852-1727. Phone: (301) 496-8266. Fax: (301) 402-0259. E-mail: elong{at}nih.gov.

{dagger} Present address: Institute for Immunology, University Heidelberg, INF 305, 69120 Heidelberg, Germany.

Molecular and Cellular Biology, September 2003, p. 6291-6299, Vol. 23, No. 17
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.17.6291-6299.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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