Intracellular tyrosine residues of the human growth hormone receptor are not required for the signaling of proliferation or Jak-STAT activation.
Ligand binding and dimerization of the growth hormone (GH) receptor leads to the rapid tyrosine phosphorylation of the intracellular kinase, Jak2, to the tyrosine phosphorylation and activation of STAT protein(s) and to the tyrosine phosphorylation of the receptor itself. Expression of the human GH receptor in the mouse promyeloid, interleukin-3-dependent cell line, FDC-P1, shows that this receptor can signal ligand-dependent proliferation in these cells as well as induce the tyrosine phosphorylation of Jak2 and the activation of transcription factors. We now examine the requirement for tyrosine phosphorylation of the GH receptor for these three events by expression of a receptor without tyrosine residues in the intracellular domain. Six of the seven intracellular tyrosine residues were removed by a carboxyl-terminal truncation, and the remaining tyrosine was changed to phenylalanine to yield the GH receptor D351Stop/Y314F. When expressed in FDC-P1 cells, this receptor retained its ability to induce the tyrosine phosphorylation of Jak2, to induce the activation of transcription factors, and to signal ligand-dependent cell proliferation. Thus, tyrosine phosphorylation of the GH receptor is not essential for the signaling of these three events at least in this system. This finding contrasts with that for the interferon-gamma receptor system where data indicate that the specific tyrosine phosphorylation of the interferon-gamma receptor leads to an association with the STAT protein, p91, that is the mechanism by which ligand couples the receptor to the signal transduction system.
Wang
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YD
Department of Molecular Biology, Genentech, Inc., South San Francisco, California 94080, USA.
Wong
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K
Wood
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WI
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003545:Cysteine; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D053614:Janus Kinase 2; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009838:Oligodeoxyribonucleotides; D010766:Phosphorylation; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D007377:Interleukin-3; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; D011986:Receptors, Somatotropin; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D019000:Phosphotyrosine; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D003545:Cysteine