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.