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Inappropriate Recruitment and Activity by the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP1) Is Responsible for Receptor Dominance in the SHIP-Deficient NK Cell¹

Joseph A. Wahle^*, Kim H. T. Paraiso^*, Robert D. Kendig, Harshani R. Lawrence, Liwei Chen, Jerry Wu^, and William G. Kerr^2,*,

^* Immunology, Drug Discovery, and Molecular Oncology Programs, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, Tampa, FL 33612; and Department of Interdisciplinary Oncology, College of Medicine, University of South Florida, Tampa, FL 33612

We have previously demonstrated that the NKR repertoire is profoundly disrupted by SHIP deficiency. This repertoire disruption is characterized by receptor dominance where inhibitory signals from 2B4 repress killing of complex targets expressing MHC class I and activating ligands. In this study, we examine the molecular basis of receptor dominance in SHIP^–/– NK cells. In this study, we show that in SHIP^–/– NK cells there is a pronounced bias toward the 2B4 long isoform. We have also characterized signaling molecules recruited to 2B4 in SHIP^–/– NK cells. Interestingly, we find that 10- to 16-fold more Src homology region 2 domain-containing phosphatase 1 (SHP1) is recruited to 2B4 in SHIP^–/– NK cells when compared with wild type. Consistent with SHP1 overrecruitment, treatment with sodium orthovanadate or a novel inhibitor with micromolar activity against SHP1 restores the ability of SHIP^–/– NK cells to kill Rae1⁺ RMA and M157⁺ targets. These findings define the molecular basis for hyporesponsiveness by SHIP-deficient NK cells.

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 This work was supported in part by grants from the National Institutes of Health (RO1 HL72523) and academic development funds from Moffitt Cancer Center and the University of South Florida. W.G.K. is the Newman Family Scholar of the Leukemia and Lymphoma Society.

² Address correspondence and reprint requests to Dr. William G. Kerr, Moffitt Cancer Center, Stabile Research Building 2, 12902 Magnolia Avenue, Tampa, FL 33612. E-mail address: william.kerr{at}moffitt.org

³ Abbreviations used in this paper: MHC-I, MHC class I; SHP, Src homology region 2 domain-containing phosphatase; WT, wild type; LAK, lymphokine-activated killer; NaOV, sodium orthovanadate; NMR, nuclear magnetic resonance; IP, immunoprecipitate; PTP, protein tyrosine phosphatase; DiFMUP, 6,8-difluoro-4-methylumbelliferyl phosphate; WCL, whole cell lysate; SLAM, signal lymphocyte activation molecule; SAP, SLAM-associated protein; EAT, Ewing’s sarcoma’s/FLI1-activated transcript; s, singlet; br s, broad singlet; d, doublet; m, multiplet.