Molecular Endocrinology, Vol 8, 539-544, Copyright © 1994 by Endocrine Society

ARTICLES

Insulin-like growth factor-1 activation of extracellular signal-related kinase-1 and -2 in growth hormone-secreting cells

J Webster, D Prager and S Melmed
Department of Medicine, Cedars-Sinai Medical Center-UCLA School of Medicine 90048.

Intracellular pathways mediating feedback regulation by insulin-like growth factor-1 (IGF-1) of pituitary GH gene expression remain incompletely understood. Extracellular signal-related kinases (ERKs), a family of serine/threonine kinases, are activated by tyrosine kinase- associated growth factor receptors. To further define the IGF-1 postreceptor events occurring in GH-secreting cells, we investigated the activity of ERKs in response to IGF-1 in GC cells following stable transfection with either wild type human IGF-1 receptor cDNA (WT cells) or a mutant cDNA encoding a truncated, kinase-defective IGF-1 receptor with a dominant negative effect on endogenous receptor function (952STOP cells). Zymography of immunoprecipitated ERKs in myelin basic protein (MBP)-containing polyacrylamide gels demonstrated dose- dependent induction of ERK-1 and -2 activity by IGF-1 in GC cells with maximal activity occurring at 6 min. IGF-1-induced ERK activity in WT- transfected cells was up to 80-fold basal and 4-fold that observed in GC cells. 952STOP cells expressing the tyrosine kinase-deficient receptor were refractory to IGF-1 action, demonstrating minimal ERK induction. In contrast, 12-O-tetradecanoylphorbol 13-acetate stimulated ERK activity to the same degree in all three cell types regardless of their IGF-I receptor status. Forskolin (50 microM), isobutylmethylxanthine (0.5 mM), and forskolin/isobutylmethylxanthine in combination attenuated IGF-1-induced ERK activity in WT cells by 54, 55, and 75% respectively. The rapid, dose-dependent, and IGF-1 receptor- dependent activation of ERKs and the attenuation of this effect by cAMP suggest an interrelated role for both molecules in IGF-1 signal transduction in GH-secreting cells.

This article has been cited by other articles:

				T. D. Stein and J. A. Johnson Lack of Neurodegeneration in Transgenic Mice Overexpressing Mutant Amyloid Precursor Protein Is Associated with Increased Levels of Transthyretin and the Activation of Cell Survival Pathways J. Neurosci., September 1, 2002; 22(17): 7380 - 7388. [Abstract] [Full Text] [PDF]

				B. Borud, T. Hoang, M. Bakke, A. L. Jacob, J. Lund, and G. Mellgren The Nuclear Receptor Coactivators p300/CBP/Cointegrator-Associated Protein (p/CIP) and Transcription Intermediary Factor 2 (TIF2) Differentially Regulate PKA-Stimulated Transcriptional Activity of Steroidogenic Factor 1 Mol. Endocrinol., April 1, 2002; 16(4): 757 - 773. [Abstract] [Full Text] [PDF]

				D. M. Klotz, S. C. Hewitt, P. Ciana, M. Raviscioni, J. K. Lindzey, J. Foley, A. Maggi, R. P. DiAugustine, and K. S. Korach Requirement of Estrogen Receptor-alpha in Insulin-like Growth Factor-1 (IGF-1)-induced Uterine Responses and in Vivo Evidence for IGF-1/Estrogen Receptor Cross-talk J. Biol. Chem., March 1, 2002; 277(10): 8531 - 8537. [Abstract] [Full Text] [PDF]

				B. G. Rowan, N. Garrison, N. L. Weigel, and B. W. O'Malley 8-Bromo-Cyclic AMP Induces Phosphorylation of Two Sites in SRC-1 That Facilitate Ligand-Independent Activation of the Chicken Progesterone Receptor and Are Critical for Functional Cooperation between SRC-1 and CREB Binding Protein Mol. Cell. Biol., December 1, 2000; 20(23): 8720 - 8730. [Abstract] [Full Text]

				C. M. Boney, P. A. Gruppuso, R. A. Faris, and A. R. Frackelton Jr. The Critical Role of Shc in Insulin-Like Growth Factor-I-Mediated Mitogenesis and Differentiation in 3T3-L1 Preadipocytes Mol. Endocrinol., June 1, 2000; 14(6): 805 - 813. [Abstract] [Full Text]

				T. Takahashi, K. Fukuda, J. Pan, H. Kodama, M. Sano, S. Makino, T. Kato, T. Manabe, and S. Ogawa Characterization of Insulin-Like Growth Factor-1-Induced Activation of the JAK/STAT Pathway in Rat Cardiomyocytes Circ. Res., November 12, 1999; 85(10): 884 - 891. [Abstract] [Full Text] [PDF]

				A. Niiori-Onishi, Y. Iwasaki, N. Mutsuga, Y. Oiso, K. Inoue, and H. Saito Molecular Mechanisms of the Negative Effect of Insulin-Like Growth Factor-I on Growth Hormone Gene Expression in MtT/S Somatotroph Cells Endocrinology, January 1, 1999; 140(1): 344 - 349. [Abstract] [Full Text]

				C. M. Boney, R. M. Smith, and P. A. Gruppuso Modulation of Insulin-Like Growth Factor I Mitogenic Signaling in 3T3-L1 Preadipocyte Differentiation Endocrinology, April 1, 1998; 139(4): 1638 - 1644. [Abstract] [Full Text] [PDF]

				A. I. Castillo and A. Aranda Differential Regulation of Pituitary-Specific Gene Expression by Insulin-Like Growth Factor 1 in Rat Pituitary GH4C1 and GH3 Cells Endocrinology, December 1, 1997; 138(12): 5442 - 5451. [Abstract] [Full Text] [PDF]

				T. C. Haddad and C. A. Conover Insulin and Interleukin-4 Induce Desensitization to the Mitogenic Effects of Insulin-like Growth Factor-I. PIVOTAL ROLE FOR INSULIN RECEPTOR SUBSTRATE-2 J. Biol. Chem., August 1, 1997; 272(31): 19525 - 19531. [Abstract] [Full Text] [PDF]

				W. L. Lowe Jr., R. Fu, and M. Banko Growth Factor-Induced Transcription via the Serum Response Element Is Inhibited by Cyclic Adenosine 3',5'-Monophosphate in MCF-7 Breast Cancer Cells Endocrinology, June 1, 1997; 138(6): 2219 - 2226. [Abstract] [Full Text] [PDF]

				A. G. Scrimgeour, V. A. Blakesley, B. S. Stannard, and D. LeRoith Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase Pathways Are Not Sufficient for Insulin-Like Growth Factor I-Induced Mitogenesis and Tumorigenesis Endocrinology, June 1, 1997; 138(6): 2552 - 2558. [Abstract] [Full Text] [PDF]

				D. Ray and S. Melmed Pituitary Cytokine and Growth Factor Expression and Action Endocr. Rev., April 1, 1997; 18(2): 206 - 228. [Abstract] [Full Text]