Identification of a JAK2-independent pathway regulating growth hormone (GH)-stimulated p44/42 mitogen-activated protein kinase activity. GH activation of Ral and phospholipase D is Src-dependent.
We have demonstrated here that growth hormone (GH) stimulates the formation of the active GTP-bound form of both RalA and RalB in NIH-3T3 cells. Full activation of RalA and RalB by GH required the combined activity of c-Src and JAK2, both kinases activated by GH independent of the other. Activation of RalA and RalB by growth hormone did not require the activity of JAK2 per se. Ras was also activated by GH and was required for the GH-stimulated formation of GTP-bound RalA and RalB. Activation of RalA by GH subsequently resulted in increased phospholipase D activity and the formation of its metabolite, phosphatidic acid. GH-stimulated RalA-phospholipase D-dependent formation of phosphatidic acid was required for activation of p44/42 MAPK and subsequent Elk-1-mediated transcription stimulated by GH. Thus we report the identification of a JAK2-independent pathway regulating GH-stimulated p44/42 MAPK activity.
Zhu
Tao
T
Institute of Molecular and Cell Biology, Singapore, Republic of Singapore.
Ling
Ling
L
Lobie
Peter E
PE
D016475:3T3 Cells; D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D013006:Growth Hormone / Q000378:metabolism*; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010712:Phosphatidic Acids / Q000378:metabolism; D010739:Phospholipase D / Q000378:metabolism; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism; D019061:src-Family Kinases
D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; C494113:Elk1 protein, mouse; D010712:Phosphatidic Acids; D011518:Proto-Oncogene Proteins; C082190:Ralb protein, rat; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D006160:Guanosine Triphosphate; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D019061:src-Family Kinases; C000631346:CSK protein, human; D020928:Mitogen-Activated Protein Kinases; D010739:Phospholipase D; D020725:ral GTP-Binding Proteins; D018631:ras Proteins