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 cell.
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 approximately 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.
Immunology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, Tampa, FL 33612, USA.
Joseph A
JA
Wahle
Kim H T
KH
Paraiso
Robert D
RD
Kendig
Harshani R
HR
Lawrence
Liwei
L
Chen
Jerry
J
Wu
William G
WG
Kerr
D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000072181:Inositol Polyphosphate 5-Phosphatases; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport; D011971:Receptors, Immunologic / Q000032:analysis / Q000378:metabolism*; D000071176:Signaling Lymphocytic Activation Molecule Family; D014638:Vanadates / Q000494:pharmacology; D018909:src Homology Domains
D015703:Antigens, CD; C490007:Cd244a protein, mouse; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D014638:Vanadates; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases