Recruitment of Tyrosine Phosphatase HCP by the Killer Cell Inhibitory Receptor

Abstract

Cytolysis of target cells by natural killer (NK) cells and by some cytotoxic T cells occurs unless prevented by inhibitory receptors that recognize MHC class I on target cells. Human NK cells express a p58 inhibitory receptor specific for HLA-C. We report association of the tyrosine phosphatase HCP with the p58 receptor in NK cells. HCP association was dependent on tyrosine phosphorylation of p58. Phosphotyrosyl peptides corresponding to the p58 tail bound and activated HCP in vitro. Furthermore, introduction of an inactive mutant HCP into an NK cell line prevented the p58-mediated inhibition of target cell lysis. These data imply that the inhibitory function of p58 is dependent on its tyrosine phosphorylation and on recruitment and activation of HCP.

Association of biliary glycoprotein with protein tyrosine phosphatase SHP-1 in malignant colon epithelial cells

“…Other cell surface receptors bind to SHP-1 in hemopoietic cells (Yi et al, 1993a;Klinmuller et al, 1995;Pani et al, 1995;Burshtyn et al, 1996). Binding of SHP-1 to the ITIM sequence in all these cell surface proteins terminates signalling with profound e ects on cellular proliferation.…”

“…Moreover, in contrast to ITAMs, only one tyrosine of Bgp (Tyr 488 ) was convincingly shown to undergo phosphorylation in cells treated with insulin or with the protein tyrosine phosphatase inhibitor vanadate . Recently, several hematopoietic cell surface receptors, such as the erythropoietin receptor (Klinmuller et al, 1995), the IL-3 receptor, Kit (Yi et al, 1993a,b), FcgRIIB1, the natural killer receptor p58 and B cell antigen receptor (D'Ambrosio et al, 1995;Pani et al, 1995;Burshtyn et al, 1996) have been shown to contain a so-called Immunoreceptor Tyrosine-based Inhibition Motif (ITIM) (D'Ambrosio et al, 1995;Burshtyn et al, 1996). This motif is shorter than that of the ITAMs (Figure 1c) and encompasses a single phosphorylated tyrosine residue followed at position +2 relative to the tyrosine by an obligate leucine.…”

Negative Signaling in Fc Receptor Complexes

“…As expected from studies that established the molecular bases of the affinity of SH2 domains of other molecules for tyrosyl-phosphorylated peptides, the affinity of pITIMs for the SH2 domains of these phosphatases required the conservation of both the Y and the Y+3 residues. Synthetic peptides corresponding to pITIMs of all ITIMbearing molecules were found to bind SHP-1 and SHP-2 in vitro (D'Ambrosio et al, 1995;Burshtyn et al, 1996). The in vitro binding of SHP-1 and SHP-2 to the pITIMs of KIR2DL3 and FcγRIIB depends on the Y-2 residue (Vély et al, 1997).…”

“…This condition is fulfilled in vitro when beads are coated with sufficient amounts of pITIMs or in vivo when two tandem pITIMs are present in the intracytoplasmic domain of inhibitory receptors such as KIR2DL3. The deletion (Bruhns et al, 1999) or the mutation (Burshtyn et al, 1996) of either ITIM indeed abrogated the ability of KIR2DL3 to recruit SHP-1. This is not fulfilled by FcγRIIB when co-aggregated with activating receptors.…”

Reduced Tyk2/SHP-1 interaction and lack of SHP-1 mutation in a kindred of familial hemophagocytic lymphohistiocytosis

“…A number of membrane molecules have been found to associate with SHP-1 via its SH2 domains, including receptors of hematopoietic growth factors and cytokines, [21][22][23][24][25] subunits of the B cell antigen receptors [26][27][28][29] and the inhibitory receptor of natural killer cells. 30 The functional significance of these associations is underscored by the increased signaling from these membrane molecules in motheaten hematopoietic cells which lack functional SHP-1. 24,28,[31][32][33][34] It is believed that the increased signaling due to loss of the negative regulatory SHP-1 leads to hyperproliferation and organ infiltration of hematopoietic cells in these mice.…”