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Department of Physiology (J.A.V., C.C.-S.) and Department of Biological Chemistry (E.R.B., K.L.G.), The University of Michigan Medical School, Ann Arbor, Michigan 48109-0622; and the Departments of Physiology and Medicine (S.B.W., J.E.P.), The University of Iowa, Iowa City, Iowa 52242
Address all correspondence and requests for reprints to: Dr. Christin Carter-Su, Department of Physiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0622. E-mail: cartersu{at}umich.edu
We have shown previously that GH stimulates the mitogen-activated protein (MAP) kinases designated ERKs (extracellular signal-regulated kinases) 1 and 2. To examine pathways coupling GH receptor (GHR) to MAP kinase activation, we have determined the effects of GH on SHC-growth factor receptor bound 2-son of Sevenless (SHC-Grb2-SOS) association and activation of Ras, Raf, and MAP-ERK kinase (MEK). GH promoted the rapid, transient association of SHC with the Grb2-SOS complex, which correlated with the time course of Ras, Raf, and MEK activation. Despite the continuous presence of GH, these activation events were transient with Ras, Raf, and MEK returning to near basal activity by 15 or 30 min. The inactivation of Ras, Raf, and MEK directly correlated with the serine/threonine phosphorylation of SOS and dissociation of SOS from Grb2 but not Grb2 from tyrosine-phosphorylated SHC. Phosphorylation was blocked by the MEK inhibitor, PD98059. Based upon the established functions of the MAP kinase pathway, these data indicate that GH stimulation results in the assembly of a SHC-Grb2-SOS complex that serves to activate Ras and thereby engage the Raf-MEK-ERK pathway. Activation of this pathway generates a feedback kinase cascade that phosphorylates SOS resulting in the dissociation of SHC-Grb2 complexes from SOS, thereby causing a more rapid termination of the signaling pathway than would result from SHC dephosphorylation.
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S. Jeay, G. E. Sonenshein, M.-C. Postel-Vinay, and E. Baixeras Growth Hormone Prevents Apoptosis through Activation of Nuclear Factor-{kappa}B in Interleukin-3-Dependent Ba/F3 Cell Line Mol. Endocrinol., May 1, 2000; 14(5): 650 - 661. [Abstract] [Full Text]
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T. Zhu and P. E. Lobie 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 J. Biol. Chem., January 21, 2000; 275(3): 2103 - 2114. [Abstract] [Full Text] [PDF]
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S.-O. Kim, J. C. D. Houtman, J. Jiang, J. M. Ruppert, P. J. Bertics, and S. J. Frank Growth Hormone-induced Alteration in ErbB-2 Phosphorylation Status in 3T3-F442A Fibroblasts J. Biol. Chem., December 10, 1999; 274(50): 36015 - 36024. [Abstract] [Full Text] [PDF]
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C. Benbassat, L. N. N. Shoba, M. Newman, M. L. Adamo, S. J. Frank, and W. L. Lowe Jr. Growth Hormone-Mediated Regulation of Insulin-Like Growth Factor I Promoter Activity in C6 Glioma Cells Endocrinology, July 1, 1999; 140(7): 3073 - 3081. [Abstract] [Full Text]
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C. A. Gebert, S.-H. Park, and D. J. Waxman Down-Regulation of Liver JAK2-STAT5b Signaling by the Female Plasma Pattern of Continuous Growth Hormone Stimulation Mol. Endocrinol., February 1, 1999; 13(2): 213 - 227. [Abstract] [Full Text]
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T. Zhu, E. L. K. Goh, D. LeRoith, and P. E. Lobie Growth Hormone Stimulates the Formation of a Multiprotein Signaling Complex Involving p130Cas and CrkII. RESULTANT ACTIVATION OF c-Jun N-TERMINAL KINASE/STRESS-ACTIVATED PROTEIN KINASE (JNK/SAPK) J. Biol. Chem., December 11, 1998; 273(50): 33864 - 33875. [Abstract] [Full Text] [PDF]
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C. Hodge, J. Liao, M. Stofega, K. Guan, C. Carter-Su, and J. Schwartz Growth Hormone Stimulates Phosphorylation and Activation of Elk-1 and Expression of c-fos, egr-1, and junB through Activation of Extracellular Signal-regulated Kinases 1 and 2 J. Biol. Chem., November 20, 1998; 273(47): 31327 - 31336. [Abstract] [Full Text] [PDF]
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 S. J. MacKenzie, S. J. Yarwood, A. H. Peden, G. B. Bolger, R. G. Vernon, and M. D. Houslay Stimulation of p70S6 kinase via a growth hormone-controlled phosphatidylinositol 3-kinase pathway leads to the activation of a PDE4A cyclic AMP-specific phosphodiesterase in 3T3-F442A preadipocytes PNAS, March 31, 1998; 95(7): 3549 - 3554. [Abstract] [Full Text] [PDF]
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C. M. A. dos Santos, P. van Kerkhof, and G. J. Strous The Signal Transduction of the Growth Hormone Receptor Is Regulated by the Ubiquitin/Proteasome System and Continues After Endocytosis J. Biol. Chem., March 30, 2001; 276(14): 10839 - 10846. [Abstract] [Full Text] [PDF]
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G. Piwien-Pilipuk, D. Van Mater, S. E. Ross, O. A. MacDougald, and J. Schwartz Growth Hormone Regulates Phosphorylation and Function of CCAAT/Enhancer-binding Protein beta by Modulating Akt and Glycogen Synthase Kinase-3 J. Biol. Chem., May 25, 2001; 276(22): 19664 - 19671. [Abstract] [Full Text] [PDF]
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C. M. Alves dos Santos, T. ten Broeke, and G. J. Strous Growth Hormone Receptor Ubiquitination, Endocytosis, and Degradation Are Independent of Signal Transduction via Janus Kinase 2 J. Biol. Chem., August 24, 2001; 276(35): 32635 - 32641. [Abstract] [Full Text] [PDF]
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