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Department of Medicine, Division of Endocrinology and Metabolism (J.J., S.J.F.), and Department of Cell Biology (R.G., Y.Z., S.J.F.), University of Alabama, and Veterans Affairs Medical Center (S.J.F.), Birmingham, Alabama 35294; Center for Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Medical School (C.A.B., G.B.), Chicago, Illinois 60611; and Immunex Corp. (R.A.B.), Seattle, Washington 98101
Address all correspondence and requests for reprints to: Dr. Stuart J. Frank, University of Alabama, 1530 3rd Avenue South, BDB 731, Birmingham, Alabama 35294-0012. E-mail: frank{at}endo.dom.uab.edu
GH signals by interacting with GH receptor (GHR). A substantial fraction of circulating GH complexes with GH-binding protein (GHBP), which corresponds to the GHR extracellular domain. GHBP is generated by 1) alternative splicing of a common GHR precursor messenger RNA to encode secreted GHBP (the source of the vast majority of GHBP in rodents); and 2) proteolysis of the cell-associated GHR with shedding of GHBP (a mechanism operative in rabbits and humans). We previously observed that phorbol ester (PMA)-induced activation of protein kinase C (PKC) causes metalloprotease-mediated GHR proteolysis and GHBP shedding in human IM-9 lymphocytes. We now demonstrate that PMA-induced hydroxamate (IC3)-inhibitable GHR proteolysis and GHBP shedding were also detected in murine 3T3-F442A and 3T3-L1 preadipocytes and in Chinese hamster ovary (CHO) cells stably expressing rabbit GHR (rbGHR), although the degree of GHBP shedding was much smaller for murine GHR than for rabbit or human GHRs. PMA-induced GHR proteolysis in 3T3-F442A, 3T3-L1, and CHO-rbGHR cells was significantly reduced by pretreatment with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 inhibitors, suggesting involvement of the mitogen-activated protein kinase pathway in regulating this PKC-dependent effect. In contrast, GHR proteolysis promoted by N-ethylmaleimide, although inhibited by IC3, was unaffected by inhibition of either PKC or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1. Thus, different pathways leading to metalloprotease-mediated receptor proteolysis are accessed by PMA vs. N-ethylmaleimide. To determine whether other, possibly more physiologically relevant, stimuli induce GHR proteolysis, we tested effects of platelet-derived growth factor (PDGF) and serum. Treatment of serum-deprived cells with PDGF (in 3T3-F442A cells) or serum (in 3T3-F442A and CHO-rbGHR cells) promoted GHR proteolysis, which was inhibited by IC3. Interestingly, PMA-, PDGF-, and serum-induced GHR proteolysis was associated with substantial decreases in GH-induced activation of Janus kinase-2, which were also prevented by IC3. These findings suggest that inducible metalloprotease-mediated GHR proteolysis constitutes an important mechanism of receptor down-regulation and modulation of GH signaling.
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  X. Wang, J. Jiang, J. Warram, G. Baumann, Y. Gan, R. K. Menon, L. A. Denson, K. R. Zinn, and S. J. Frank Endotoxin-Induced Proteolytic Reduction in Hepatic Growth Hormone (GH) Receptor: A Novel Mechanism for GH Insensitivity Mol. Endocrinol., June 1, 2008; 22(6): 1427 - 1437. [Abstract] [Full Text] [PDF]
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 K. Loesch, L. Deng, X. Wang, K. He, J. Jiang, and S. J. Frank Endoplasmic Reticulum-Associated Degradation of Growth Hormone Receptor in Janus Kinase 2-Deficient Cells Endocrinology, December 1, 2007; 148(12): 5955 - 5965. [Abstract] [Full Text] [PDF]
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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]
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L. Deng, K. He, X. Wang, N. Yang, C. Thangavel, J. Jiang, S. Y. Fuchs, and S. J. Frank Determinants of Growth Hormone Receptor Down-Regulation Mol. Endocrinol., July 1, 2007; 21(7): 1537 - 1551. [Abstract] [Full Text] [PDF]
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K. Loesch, L. Deng, J. W. Cowan, X. Wang, K. He, J. Jiang, R. A. Black, and S. J. Frank Janus Kinase 2 Influences Growth Hormone Receptor Metalloproteolysis Endocrinology, June 1, 2006; 147(6): 2839 - 2849. [Abstract] [Full Text] [PDF]
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K. He, K. Loesch, J. W. Cowan, X. Li, L. Deng, X. Wang, J. Jiang, and S. J. Frank Janus Kinase 2 Enhances the Stability of the Mature Growth Hormone Receptor Endocrinology, November 1, 2005; 146(11): 4755 - 4765. [Abstract] [Full Text] [PDF]
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 J. W. Cowan, X. Wang, R. Guan, K. He, J. Jiang, G. Baumann, R. A. Black, M. S. Wolfe, and S. J. Frank Growth Hormone Receptor Is a Target for Presenilin-dependent {gamma}-Secretase Cleavage J. Biol. Chem., May 13, 2005; 280(19): 19331 - 19342. [Abstract] [Full Text] [PDF]
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J. Jiang, X. Wang, K. He, X. Li, C. Chen, P. P. Sayeski, M. J. Waters, and S. J. Frank A Conformationally Sensitive GHR [Growth Hormone (GH) Receptor] Antibody: Impact on GH Signaling and GHR Proteolysis Mol. Endocrinol., December 1, 2004; 18(12): 2981 - 2996. [Abstract] [Full Text] [PDF]
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Y. Huang, S.-O. Kim, N. Yang, J. Jiang, and S. J. Frank Physical and Functional Interaction of Growth Hormone and Insulin-Like Growth Factor-I Signaling Elements Mol. Endocrinol., June 1, 2004; 18(6): 1471 - 1485. [Abstract] [Full Text] [PDF]
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N. Yang, Y. Huang, J. Jiang, and S. J. Frank Caveolar and Lipid Raft Localization of the Growth Hormone Receptor and Its Signaling Elements: IMPACT ON GROWTH HORMONE SIGNALING J. Biol. Chem., May 14, 2004; 279(20): 20898 - 20905. [Abstract] [Full Text] [PDF]
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X. Wang, K. He, M. Gerhart, J. Jiang, R. J. Paxton, R. K. Menon, R. A. Black, G. Baumann, and S. J. Frank Reduced Proteolysis of Rabbit Growth Hormone (GH) Receptor Substituted with Mouse GH Receptor Cleavage Site Mol. Endocrinol., October 1, 2003; 17(10): 1931 - 1943. [Abstract] [Full Text] [PDF]
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Y. Huang, S.-O. Kim, J. Jiang, and S. J. Frank Growth Hormone-induced Phosphorylation of Epidermal Growth Factor (EGF) Receptor in 3T3-F442A Cells: MODULATION OF EGF-INDUCED TRAFFICKING AND SIGNALING J. Biol. Chem., May 23, 2003; 278(21): 18902 - 18913. [Abstract] [Full Text] [PDF]
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X. Wang, K. He, M. Gerhart, Y. Huang, J. Jiang, R. J. Paxton, S. Yang, C. Lu, R. K. Menon, R. A. Black, et al. Metalloprotease-mediated GH Receptor Proteolysis and GHBP Shedding. DETERMINATION OF EXTRACELLULAR DOMAIN STEM REGION CLEAVAGE SITE J. Biol. Chem., December 20, 2002; 277(52): 50510 - 50519. [Abstract] [Full Text] [PDF]
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P. van Kerkhof, M. Smeets, and G. J. Strous The Ubiquitin-Proteasome Pathway Regulates the Availability of the GH Receptor Endocrinology, April 1, 2002; 143(4): 1243 - 1252. [Abstract] [Full Text] [PDF]
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V. Beauloye, B. Willems, V. de Coninck, S. J. Frank, M. Edery, and J.-P. Thissen Impairment of Liver GH Receptor Signaling by Fasting Endocrinology, March 1, 2002; 143(3): 792 - 800. [Abstract] [Full Text] [PDF]
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Y. Zhang, R. Guan, J. Jiang, J. J. Kopchick, R. A. Black, G. Baumann, and S. J. Frank Growth Hormone (GH)-induced Dimerization Inhibits Phorbol Ester-stimulated GH Receptor Proteolysis J. Biol. Chem., June 29, 2001; 276(27): 24565 - 24573. [Abstract] [Full Text] [PDF]
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 S. Y. Shvartsman, M. P. Hagan, A. Yacoub, P. Dent, H. S. Wiley, and D. A. Lauffenburger Autocrine loops with positive feedback enable context-dependent cell signaling Am J Physiol Cell Physiol, March 1, 2002; 282(3): C545 - C559. [Abstract] [Full Text] [PDF]
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