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SHP‐1/immunoreceptor tyrosine‐based inhibition motif‐independent inhibitory signalling through murine natural killer cell receptor Ly‐49A in a transfectedB‐cell line
Author(s) -
Motoda K.,
Takata M.,
Kiura K.,
Nakamura I.,
Harada M.
Publication year - 2000
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1046/j.1365-2567.2000.00046.x
Subject(s) - protein tyrosine phosphatase , immunoreceptor tyrosine based activation motif , tyrosine , sh2 domain , proto oncogene tyrosine protein kinase src , biology , tyrosine phosphorylation , phosphorylation , microbiology and biotechnology , biochemistry
Summary Ly‐49A is a member of the Ly‐49 family of mouse natural killer cell receptors that inhibit cytotoxicity upon recognition of their ligands, the major histocompatibility complex (MHC) class I molecules, on the target cell surface. Although Ly‐49A has an immunoreceptor tyrosine‐based inhibition motif (ITIM) in its cytoplasmic tail, relatively little is known about the mechanisms underlying its inhibitory function. We report here that antibody‐mediated co‐ligation of the B‐cell receptor (BCR) with the transfected Ly‐49A molecule results in abrogation of BCR‐induced interleukin‐2 (IL‐2) secretion and mild reduction in activation of Erk1/2 and p38 mitogen‐activated protein (MAP) kinases in the B‐cell line A20. Surprisingly, BCR‐induced calcium mobilization was unaffected by cross‐linking of BCR with Ly‐49A. Furthermore, substitution of the single tyrosine residue in ITIM with phenylalanine, did not result in a complete loss of inhibitory function, as measured by BCR‐induced IL‐2 secretion. Deletion of the N‐terminal 37 amino acid peptide, which includes the ITIM, did abrogate the inhibitory activity. Co‐immunoprecipitation experiments revealed that, upon induction of tyrosine phosphorylation, Ly‐49A recruits tyrosine phosphatase src‐homology 2 (SH2) containing tyrosine phosphatases‐1 (SHP‐1), but not inositol phosphatase src‐homology 2 (SH2) containing inositol phosphatase (SHIP), and that the tyrosine residue in the ITIM is critical for this interaction. These results suggest that transfected Ly‐49A utilizes two different inhibitory mechanisms in B‐cell signalling: ITIM‐dependent and ITIM‐independent.