Janus kinase 2-dependent activation of p38 mitogen-activated protein kinase by growth hormone. Resultant transcriptional activation of ATF-2 and CHOP, cytoskeletal re-organization and mitogenesis.
We demonstrate here that p38 mitogen-activated protein (MAP) kinase is activated in response to cellular stimulation by human GH (hGH) in Chinese hamster ovary cells stably transfected with GH receptor cDNA. This activation requires the proline-rich box 1 region of the GH receptor required for JAK2 association and is prevented by pretreatment of cells with the JAK2-specific inhibitor AG490. ATF-2 is both phosphorylated and transcriptionally activated by hGH, and its transcriptional activation also requires the proline-rich box 1 region of the GH receptor. Expression of wild type JAK2 can further enhance hGH-induced ATF-2-, CHOP-, and Elk-1-mediated transcriptional activation, whereas pretreatment with AG490 is inhibitory. Use of either specific pharmacological inhibitors or transient transfection of cells with p38alpha MAP kinase cDNA or a dominant negative variant demonstrated that hGH-stimulated transcriptional activation of ATF-2 and CHOP, but not Elk-1, is regulated by p38 MAP kinase. Both the p38 MAP kinase and p44/42 MAP kinase are critical for hGH-stimulated mitogenesis, whereas only p38 MAP kinase is required for hGH-induced actin cytoskeletal re-organization. p38 MAP kinase is therefore an important regulator in coordinating the pleiotropic effects of GH.
Zhu
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Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Drive, Singapore 117609, Republic of Singapore.
Lobie
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D051698:Activating Transcription Factor 2; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D006224:Cricetinae; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003599:Cytoskeleton / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019382:Human Growth Hormone / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D022762:CCAAT-Enhancer-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; C497251:Ddit3 protein, rat; C494112:ELK1 protein, human; C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D019382:Human Growth Hormone; D051742:Transcription Factor CHOP; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases