Growth hormone (GH), derived largely from the anterior pituitary, regulates postnatal growth and metabolism in vertebrates in an endocrine fashion. Recent studies also suggest roles for autocrine-derived GH and for an intact GH axis in formation and behavior of cancers in animals. GH receptor (GHR) is a cell surface glycoprotein cytokine receptor superfamily member that binds GH in its extracellular domain (ECD) and activates signaling via its intracellular domain's (ICD) interaction with the JAK2 tyrosine kinase. Our recent studies of mechanisms regulating GHR availability and activation reveal exciting insights, including: 1) JAK2 association influences GHR surface presentation, stability, and trafficking;2) reducing prolactin receptor (PRLR) levels in human T47D breast cancer cells augments GHR abundance and GH sensitivity;3) novel, conformationally-sensitive anti-GHR ECD antibodies may be useful GH antagonists. We hypothesize: 1) JAK2 expression levels and PRLR expression levels strongly influence GH responsiveness;2) GH-induced GHR conformational changes that underlie GH signaling are potential targets for therapeutic intervention.
Our specific aims are: 1. Determine mechanisms by which JAK2 and PRLR regulate GHR processing, cel surface stability, and downregulation. We will study how GHR predimerization impacts JAK2's modulation of GHR trafficking and the role of GHR ICD tyrosine residues on GH-independent and GH-dependent GHR trafficking. Effects of PRLR expression on GHR availability, GHR-JAK2 association, and GH actions in breast cancer cells will be examined. 2. Determine in vivo efficacy of conformation-specific inhibitory anti-GHR ECD monoclonal antibodies. We will characterize inhibitory properties of two anti-GHR antibodies and Fab fragments in signaling studies, also assessing impact of PRLR expression. We will determine in vivo efficacy of these reagents to antagonize GH signaling and cancer explant growth. These studies probe important determinants of GH sensitivity. Completion will reveal mechanisms regulating cell surface GHR availability and fate and therapeutically relevant tools to modulate GH sensitivity.

Public Health Relevance

Growth hormone is a key regulator of growth and metabolism and recent work suggests that antagonism of growth hormone action may be of therapeutic potential in certain cancers. These studies of the growth hormone receptor investigate the determinants of growth hormone sensitivity at the cellular level. The knowledge gained and the development of inhibitory anti-GH receptor monoclonal antibodies as potential therapeutics may have broad relevance in our understanding of normal physiology and in treatment of cancer.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Malozowski, Saul N
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Zhao, Yueshui; Xiao, Xiaoqiu; Frank, Stuart J et al. (2014) Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-?, and IL-1?. Am J Physiol Endocrinol Metab 307:E186-98
Xu, Jie; Sun, Dongmei; Jiang, Jing et al. (2013) The role of prolactin receptor in GH signaling in breast cancer cells. Mol Endocrinol 27:266-79
Nylund, Cade M; D'Mello, Sharon; Kim, Mi-Ok et al. (2011) Granulocyte macrophage-colony-stimulating factor autoantibodies and increased intestinal permeability in Crohn disease. J Pediatr Gastroenterol Nutr 52:542-8
Jiang, Jing; Wan, Yu; Wang, Xiangdong et al. (2011) Inhibitory GH receptor extracellular domain monoclonal antibodies: three-dimensional epitope mapping. Endocrinology 152:4777-88
Denson, Lee A; Kim, Mi-Ok; Bezold, Ramona et al. (2010) A randomized controlled trial of growth hormone in active pediatric Crohn disease. J Pediatr Gastroenterol Nutr 51:130-9
Houghton, A McGarry; Rzymkiewicz, Danuta M; Ji, Hongbin et al. (2010) Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med 16:219-23
Pasternak, Brad A; D'Mello, Sharon; Jurickova, Ingrid I et al. (2010) Lipopolysaccharide exposure is linked to activation of the acute phase response and growth failure in pediatric Crohn's disease and murine colitis. Inflamm Bowel Dis 16:856-69
Wang, Xiangdong; Yang, Ning; Deng, Luqin et al. (2009) Interruption of growth hormone signaling via SHC and ERK in 3T3-F442A preadipocytes upon knockdown of insulin receptor substrate-1. Mol Endocrinol 23:486-96
Aalbers, Anna M; Chin, Daisy; Pratt, Katherine L et al. (2009) Extreme elevation of serum growth hormone-binding protein concentrations resulting from a novel heterozygous splice site mutation of the growth hormone receptor gene. Horm Res 71:276-84
Han, X; Ren, X; Jurickova, I et al. (2009) Regulation of intestinal barrier function by signal transducer and activator of transcription 5b. Gut 58:49-58

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