| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on October 24, 2003
Accepted on March 15, 2004
Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL; Endocrinology Section, Medical Service, Veterans Affairs Medical Center, Birmingham, AL
* To whom correspondence should be addressed. E-mail: sjfrank{at}uab.edu.
Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are critical regulators of growth and metabolism. GH interacts with the GHR, a cytokine superfamily receptor, to activate the cytoplasmic tyrosine kinase, JAK2, and initiate intracellular signaling cascades. IGF-I, produced in part in response to GH, binds to the heterotetrameric IGF-I receptor (IGF-1R), which is an intrinsic tyrosine kinase growth factor receptor that triggers proliferation, anti-apoptosis, and other biological actions. Previous in vitro and overexpression studies have suggested that JAKs may interact with IGF-1R and that IGF-I stimulation may activate JAKs. In this study, we explore interactions between GHR-JAK2 and IGF-1R signaling pathway elements utilizing the GH and IGF-I-responsive 3T3-F442A and 3T3-L1 preadipocyte cell lines, which endogenously express both the GHR and IGF-1R. We find that GH induces formation of a complex that includes GHR, JAK2, and IGF-1R in these preadipocytes. The assembly of this complex in intact cells is rapid, GH concentration-dependent, and can be prevented by a GH antagonist, G120K. However, it is not inhibited by the kinase inhibitor, staurosporine, which markedly inhibits GHR tyrosine phosphorylation. Moreover, complex formation does not appear dependent on GH-induced activation of the ERK or PI3K signaling pathways or on the tyrosine phosphorylation of GHR, JAK2, or IGF-1R. These results suggest that GH-induced formation of the GHR-JAK2-IGF-1R complex is governed instead by GH-dependent conformational change(s) in the GHR and/or JAK2. We further demonstrate that GH and IGF-I can synergize in acute aspects of signaling and that IGF-I enhances GH-induced assembly of conformationally active GHRs. These findings suggest the existence of previously unappreciated relationships between these two hormones.
This article has been cited by other articles:
 |
|
 |
|
  N. Yang, J. F. Langenheim, X. Wang, J. Jiang, W. Y. Chen, and S. J. Frank Activation of Growth Hormone Receptors by Growth Hormone and Growth Hormone Antagonist Dimers: Insights into Receptor Triggering Mol. Endocrinol., April 1, 2008; 22(4): 978 - 988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. DiGirolamo, A. Mukherjee, K. Fulzele, Y. Gan, X. Cao, S. J. Frank, and T. L. Clemens Mode of Growth Hormone Action in Osteoblasts J. Biol. Chem., October 26, 2007; 282(43): 31666 - 31674. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Shen, D. D. Lantvit, Q. Lin, Y. Li, K. Christov, Z. Wang, T. G. Unterman, R. G. Mehta, and S. M. Swanson Advanced Rat Mammary Cancers Are Growth Hormone Dependent Endocrinology, October 1, 2007; 148(10): 4536 - 4544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. H. Elsasser, C.-J. Li, T. J. Caperna, S. Kahl, and W. F. Schmidt Growth Hormone (GH)-Associated Nitration of Janus Kinase-2 at the 1007Y-1008Y Epitope Impedes Phosphorylation at This Site: Mechanism for and Impact of a GH, AKT, and Nitric Oxide Synthase Axis on GH Signal Transduction Endocrinology, August 1, 2007; 148(8): 3792 - 3802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Yang, X. Wang, J. Jiang, and S. J. Frank Role of the Growth Hormone (GH) Receptor Transmembrane Domain in Receptor Predimerization and GH-Induced Activation Mol. Endocrinol., July 1, 2007; 21(7): 1642 - 1655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Frank Growth Hormone, Insulin-Like Growth Factor I, and Growth: Local Knowledge Endocrinology, April 1, 2007; 148(4): 1486 - 1488. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Zhang, Q. Zhang, A. Tengholm, and A. Sjoholm Involvement of JAK2 and Src kinase tyrosine phosphorylation in human growth hormone-stimulated increases in cytosolic free Ca2+ and insulin secretion Am J Physiol Cell Physiol, September 1, 2006; 291(3): C466 - C475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Veldhuis, J. N. Roemmich, E. J. Richmond, and C. Y. Bowers Somatotropic and Gonadotropic Axes Linkages in Infancy, Childhood, and the Puberty-Adult Transition Endocr. Rev., April 1, 2006; 27(2): 101 - 140. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xu, A. B. Keeton, J. L. Franklin, X. Li, D. Y. Venable, S. J. Frank, and J. L. Messina Insulin Enhances Growth Hormone Induction of the MEK/ERK Signaling Pathway J. Biol. Chem., January 13, 2006; 281(2): 982 - 992. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
