CrkII participation in the cellular effects of growth hormone and insulin-like growth factor-1. Phosphatidylinositol-3 kinase dependent and independent effects.
We have examined the role of CrkII in the cellular response to both human growth hormone (hGH) and human insulin-like growth factor-1 (hIGF-1). We have demonstrated that overexpression of the adaptor molecule enhances both basal phosphatidylinositol 3-kinase (PI 3-kinase) activity and also dramatically enhances the ability of both hormones to stimulate PI 3-kinase activity in the cell. Many of the effects of CrkII overexpression on hGH- and hIGF-1-stimulated cellular function can then be attributed to CrkII enhancement of PI 3-kinase stimulation by these hormones. Thus, CrkII-enhanced PI 3-kinase activity is used to enhance actin filament reorganization in response to both hGH and hIGF-1, to enhance stress activated protein kinase (SAPK) activity in response to hGH, and to diminish STAT5-mediated transcription in response to hGH. It is apparent, however, that CrkII also regulates cellular function independent of its ability to stimulate PI 3-kinase activity. This is evidenced by the ability of CrkII, in a PI 3-kinase-independent manner, to diminish the activation of p44/42 mitogen-activated protein kinase in response to both hGH and hIGF-1 and to inhibit the activation of SAPK by hIGF-1. Therefore, despite the common use of CrkII to activate PI 3-kinase, CrkII also allows hGH or hIGF-1 to selectively switch the activation of SAPK. Thus, common utilization of CrkII by hGH and hIGF-1 allows the execution of common cellular effects of these hormones, concomitant with the retention of hormonal specificity.
Goh
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Institute of Molecular and Cell Biology, 30 Medical Dr., Singapore 117609, Republic of Singapore.
Zhu
T
T
Yakar
S
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LeRoith
D
D
Lobie
P E
PE
D016475:3T3 Cells; D000818:Animals; D019382:Human Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D018909:src Homology Domains
D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases