Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling.
In this report, we demonstrate that insulin receptor substrate-2 (IRS-2) is tyrosyl-phosphorylated following stimulation of 3T3-F442A fibroblasts with growth hormone (GH), leukemia inhibitory factor and interferon-gamma. In response to GH and leukemia inhibitory factor, IRS-2 is immediately phosphorylated, with maximal phosphorylation detected at 15 min; the signal is substantially diminished by 60 min. In response to interferon-gamma, tyrosine phosphorylation of IRS-2 was prolonged, with substantial signal still detected at 60 min. Characterization of the mechanism of signaling utilized by GH indicated that tyrosine residues in GH receptor are not necessary for tyrosyl phosphorylation of IRS-2; however, the regions of GH receptor necessary for IRS-2 tyrosyl phosphorylation are the same as those required for JAK2 association and tyrosyl phosphorylation. The role of IRS-2 as a signaling molecule for GH is further demonstrated by the finding that GH stimulates association of IRS-2 with the 85-kDa regulatory subunit of phosphatidylinositol 3'-kinase and with the protein-tyrosine phosphatase SHP2. These results are consistent with the possibility that IRS-2 is a downstream signaling partner of multiple members of the cytokine family of receptors that activate JAK kinases.
Argetsinger
L S
LS
Department of Physiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0622, USA. cartersu@umich.edu
Norstedt
G
G
Billestrup
N
N
White
M F
MF
Carter-Su
C
C
D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006131:Growth Inhibitors / Q000378:metabolism*; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007371:Interferon-gamma / Q000378:metabolism*; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D006131:Growth Inhibitors; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D010750:Phosphoproteins; D019382:Human Growth Hormone; D014443:Tyrosine; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor)