Growth hormone stimulates the formation of a multiprotein signaling complex involving p130(Cas) and CrkII. Resultant activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK).
We have demonstrated previously that growth hormone (GH) activates focal adhesion kinase (FAK), and this activation results in the tyrosine phosphorylation of two FAK substrates, namely paxillin and tensin. We now show here in Chinese hamster ovary cells stably transfected with rat GH receptor cDNA that human (h)GH induces the formation of a large multiprotein signaling complex centered around another FAK-associated protein, p130(Cas) and the adaptor protein CrkII. hGH stimulates the tyrosine phosphorylation of both p130(Cas) and CrkII, their association, and the association of multiple other tyrosine-phosphorylated proteins to the complex. Both the c-Src and c-Fyn tyrosine kinases are tyrosine phosphorylated and activated by cellular hGH stimulation and form part of the multiprotein signaling complex as does tensin, paxillin, IRS-1, the p85 subunit of phosphatidylinositol 3-kinase, C3G, SHC, Grb-2, and Sos-1. c-Cbl and Nck are also tyrosine-phosphorylated by cellular stimulation with hGH and associate with the p130(Cas)-CrkII complex. c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is activated in response to hGH in accordance with the formation of the abovementioned signaling complex, and hGH stimulated JNK/SAPK activity is increased in CrkII overexpressing NIH3T3 cells compared with vector transfected NIH3T3 cells. The formation of such a large multiprotein signaling complex by GH, with the resultant activation of multiple downstream effector molecules, may be central to many of the pleiotropic effects of GH.
Zhu
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Institute of Molecular and Cell Biology and Defence Medical Research Institute, National University of Singapore, 30 Medical Drive, Singapore 117609, Republic of Singapore.
Goh
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LeRoith
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Lobie
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D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D006224:Cricetinae; D050719:Crk-Associated Substrate Protein; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004789:Enzyme Activation; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases; D051419:Paxillin; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk; D051076:Proto-Oncogene Proteins c-fyn; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D000070876:Tensins; D014443:Tyrosine / Q000378:metabolism
C493841:BCAR1 protein, human; C493842:Bcar1 protein, mouse; C493843:Bcar1 protein, rat; C493872:Crk protein, rat; D050719:Crk-Associated Substrate Protein; D003598:Cytoskeletal Proteins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; D008840:Microfilament Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; C496062:Pxn protein, mouse; C496063:Pxn protein, rat; D011994:Recombinant Proteins; D050717:Retinoblastoma-Like Protein p130; D000070876:Tensins; C000603372:Tns1 protein, rat; D014443:Tyrosine; D013006:Growth Hormone; D011494:Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; C494957:FYN protein, human; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases