Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha.
Signal regulatory proteins (SIRPs) are receptor-like transmembrane proteins, the majority of which contain a cytoplasmic proline-rich region and four cytoplasmic tyrosines that, when phosphorylated, bind SH2 domain-containing protein tyrosine phosphatases (SHP). We demonstrated previously that growth hormone (GH) induces tyrosyl phosphorylation of SIRPalpha and association of SIRPalpha with SHP-2. The ... GH-activated tyrosine kinase JAK2 associates with and tyrosyl-phosphorylates SIRPalpha1. Here we show that JAK2-SIRPalpha1 association does not require phosphotyrosines in SIRPalpha1 or JAK2 or the proline-rich region of SIRPalpha1. However, when the C-terminal 30 amino acids of SIRPalpha1 containing the proline-rich region and tyrosine 495 are deleted, tyrosyl phosphorylation of SIRPalpha1 by JAK2 and association of SHP-2 with SIRPalpha1 are reduced. GH-dependent tyrosyl phosphorylation of JAK2 is reduced when wild-type SIRPalpha1 compared with SIRPalpha1 lacking the four cytoplasmic tyrosines (SIRP 4YF) is expressed in cells, suggesting that SIRPalpha1 negatively regulates GHR/JAK2 signaling. Consistent with reduced JAK2 activity, overexpression of wild-type SIRPalpha1 but not SIRP 4YF reduces GH-induced phosphorylation of ERKs 1 and 2, STAT3, and STAT5B. These results suggest that SIRPalpha1 is a negative regulator of GH signaling and that the ability of SIRPalpha1 mutants to negatively regulate GHR-JAK2 signaling correlates with their ability to bind SHP-2.
Mesh Terms:
3T3 Cells, Animals, Antigens, Differentiation, Cell Line, DNA-Binding Proteins, Enzyme Activation, Human Growth Hormone, Humans, Janus Kinase 2, Janus Kinase 3, Membrane Glycoproteins, Mice, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Neural Cell Adhesion Molecule L1, Neural Cell Adhesion Molecules, Phosphorylation, Proline, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Receptors, Immunologic, Receptors, Somatotropin, Recombinant Proteins, STAT3 Transcription Factor, Sequence Deletion, Signal Transduction, Trans-Activators, Transfection, Tyrosine, src Homology Domains
3T3 Cells, Animals, Antigens, Differentiation, Cell Line, DNA-Binding Proteins, Enzyme Activation, Human Growth Hormone, Humans, Janus Kinase 2, Janus Kinase 3, Membrane Glycoproteins, Mice, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Neural Cell Adhesion Molecule L1, Neural Cell Adhesion Molecules, Phosphorylation, Proline, Protein Tyrosine Phosphatases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Receptors, Immunologic, Receptors, Somatotropin, Recombinant Proteins, STAT3 Transcription Factor, Sequence Deletion, Signal Transduction, Trans-Activators, Transfection, Tyrosine, src Homology Domains
J. Biol. Chem.
Date: Sep. 08, 2000
PubMed ID: 10842184
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