Sequential involvement of Lck and SHP-1 with MHC-recognizing receptors on NK cells inhibits FcR-initiated tyrosine kinase activation.
Recognition of major histocompatibility (MHC) class I complexes on target cells by killer cell inhibitory receptors (KIR) blocks natural killer (NK) and T cell cytotoxic function. The inhibitory effect of KIR ligation requires the phosphotyrosine-dependent association of KIR with the cytoplasmic SH2-containing protein tyrosine phosphatase SHP-1. Using a somatic genetic model, we first define a requirement for the Src family protein tyrosine kinase (PTK) Lck in mediating KIR tyrosine phosphorylation. We then investigate how KIR ligation interrupts PTK-dependent NK cell activation signals. Specifically, we show that KIR ligation inhibits the Fc receptor (FcR)-induced tyrosine phosphorylation of the FcR-associated zeta signaling chain, the PTK ZAP-70, and phospholipase C gamma. Overexpression of catalytically inactive SHP-1 (acting as a dominant negative) restores the tyrosine phosphorylation of these signaling events and reverses KIR-mediated inhibition of NK cell cytotoxic function. These results suggest sequential roles for Lck and SHP-1 in the inhibition of PTK following MHC recognition by NK cells.
Binstadt
B A
BA
Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Brumbaugh
K M
KM
Dick
C J
CJ
Scharenberg
A M
AM
Williams
B L
BL
Colonna
M
M
Lanier
L L
LL
Kinet
J P
JP
Abraham
R T
RT
Leibson
P J
PJ
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D019204:GTP-Binding Proteins / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D008285:Major Histocompatibility Complex; D051379:Mice; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011961:Receptors, Fc / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011961:Receptors, Fc; D011971:Receptors, Immunologic; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D019204:GTP-Binding Proteins; C490245:GEM protein, human; C088119:Gem protein, mouse; D020559:Monomeric GTP-Binding Proteins