Differential tyrosine phosphorylation of inhibitory versus activating Ly-49 receptor proteins and their recruitment of SHP-1 phosphatase.
Killer cell inhibitory receptors represent a family of p58/70-Ig-like proteins expressed on the surface of human NK cells. Engagement of class I MHC by killer cell inhibitory receptors turns off the lytic machinery of NK cells. This receptor/ligand interaction results in phosphorylation of intracellular tyrosine residues of p58/70 proteins. Murine NK cells express surface receptors of an unrelated family of type II lectin-like proteins, Ly-49, that have similar functions. Ly-49A, -C, and -G2 represent murine inhibitory receptors. However, Ly-49D functions as an activation receptor on the surface of NK cells. This dichotomy of function between Ly-49 family members suggested different signaling events upon receptor/ligand interaction. Here we demonstrate that: 1) in transfected Cos7 and murine NK cells, Ly-49A, -C, and -G2 are phosphorylated following pervanadate stimulation, whereas Ly-49D is not; 2) mAb-induced receptor ligation mediates tyrosine phosphorylation of Ly-49A and -G2, but not Ly-49D; 3) SHP-1 coprecipitates with Ly-49A and -G2 following receptor phosphorylation; and 4) tyrosine phosphorylation of Ly-49 inhibitory receptors depends on tyrosine residues restricted to the immunoreceptor tyrosine-based inhibitory motif. Our data further support the involvement of immunoreceptor tyrosine-based inhibitory motifs as crucial sequences regulating receptor-mediated inhibitory functions in NK cells.
Mason
L H
LH
Division of Basic Sciences, Science Applications International Corporation Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702, USA.
Gosselin
P
P
Anderson
S K
SK
Fogler
W E
WE
Ortaldo
J R
JR
McVicar
D W
DW
D000818:Animals; D000950:Antigens, Ly / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D014443:Tyrosine
D000950:Antigens, Ly; D047908:Intracellular Signaling Peptides and Proteins; D014443:Tyrosine; 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