Differential tyrosine phosphorylation of JAK1, JAK2, and STAT1 by growth hormone and interferon-gamma in IM-9 cells.
Both the growth hormone (GH) and interferon gamma (IFN gamma) receptors are members of the cytokine receptor family that activate tyrosine phosphorylation despite the lack of a tyrosine kinase domain. Recently, the Janus kinase (JAK) family of tyrosine kinases have been shown to play an integral role in intracellular signaling by the cytokine receptors. We demonstrate that, in the human IM-9 lymphocyte, both JAK1 and JAK2 are tyrosine-phosphorylated in response to IFN gamma, whereas only JAK2 is tyrosine-phosphorylated in response to GH. Furthermore, dimerization of the GH receptor appears to be necessary for GH stimulated tyrosine phosphorylation of JAK2. We provide two lines of evidence that the JAK2 kinases can be regulated independently by GH and IFN gamma in IM-9 cells: 1) desensitization of JAK2 to GH stimulation does not affect the IFN gamma stimulated tyrosine phosphorylation of JAK2; and 2) JAK2 tyrosine phosphorylation by GH and IFN gamma is additive to that seen with either hormone alone. Furthermore, we demonstrate that although IFN gamma activates the tyrosine phosphorylation of the p91 signal transducer and activator of transcription (STAT1) in IM-9 cells, GH does not. GH does activate the tyrosine phosphorylation of a 93-kDa protein that appears to be distinct from STAT1.
Silva
C M
CM
Division of Endocrinology and Metabolism, University of Virginia Health Sciences Center, Charlottesville 22908.
Lu
H
H
Weber
M J
MJ
Thorner
M O
MO
D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon / Q000378:metabolism; D011986:Receptors, Somatotropin / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D000096743:Interferon gamma Receptor
D004268:DNA-Binding Proteins; D013006:Growth Hormone; D007371:Interferon-gamma; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D017471:Receptors, Interferon; D011986:Receptors, Somatotropin; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human; C507904:JAK1 protein, human; C507924:JAK2 protein, human