Immunoreceptor tyrosine-based inhibitory motif of the IL-4 receptor associates with SH2-containing phosphatases and regulates IL-4-induced proliferation.
Immunoreceptor tyrosine-based inhibitory motifs (ITIM) have been implicated in the negative modulation of immunoreceptor signaling pathways. The IL-4R alpha-chain (IL-4Ralpha) contains a putative ITIM in the carboxyl terminal. To determine the role of ITIM in the IL-4 signaling pathway, we ablated the ITIM of IL-4Ralpha by deletion and site-directed mutagenesis ... and stably expressed the wild-type (WT) and mutant hIL-4Ralpha in 32D/insulin receptor substrate-2 (IRS-2) cells. Strikingly, 32D/IRS-2 cells expressing mutant human (h)IL-4Ralpha were hyperproliferative in response to IL-4 compared with cells expressing WT hIL-4Ralpha. Enhanced tyrosine phosphorylation of Stat6, but not IRS-2, induced by hIL-4 was observed in cells expressing mutant Y713F. Using peptides corresponding to the ITIM of hIL-4Ralpha, we demonstrate that tyrosine-phosphorylated peptides, but not their nonphosphorylated counterparts, coprecipitate SH2-containing tyrosine phosphatase-1, SH2-containing tyrosine phosphatase-2, and SH2-containing inositol 5'-phosphatase. The in vivo association of SH2-containing inositol 5'-phosphatase with IL-4Ralpha was verified by coimmunoprecipitation with anti-IL-4Ralpha Abs. These results demonstrate a functional role for ITIM in the regulation of IL-4-induced proliferation.
Mesh Terms:
Amino Acid Motifs, Amino Acid Sequence, Cell Line, Cytoplasm, Enzyme Activation, Humans, Insulin Receptor Substrate Proteins, Interleukin-4, Intracellular Signaling Peptides and Proteins, Janus Kinase 1, Lymphocyte Activation, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphoproteins, Phosphoric Monoester Hydrolases, Phosphorylation, Protein Phosphatase 1, Protein Phosphatase 2, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Receptors, Immunologic, Receptors, Interleukin-4, SH2 Domain-Containing Protein Tyrosine Phosphatases, STAT6 Transcription Factor, Sequence Deletion, Signal Transduction, Trans-Activators, Tyrosine, src Homology Domains
Amino Acid Motifs, Amino Acid Sequence, Cell Line, Cytoplasm, Enzyme Activation, Humans, Insulin Receptor Substrate Proteins, Interleukin-4, Intracellular Signaling Peptides and Proteins, Janus Kinase 1, Lymphocyte Activation, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphoproteins, Phosphoric Monoester Hydrolases, Phosphorylation, Protein Phosphatase 1, Protein Phosphatase 2, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Receptors, Immunologic, Receptors, Interleukin-4, SH2 Domain-Containing Protein Tyrosine Phosphatases, STAT6 Transcription Factor, Sequence Deletion, Signal Transduction, Trans-Activators, Tyrosine, src Homology Domains
J. Immunol.
Date: Dec. 01, 2001
PubMed ID: 11714803
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