Growth hormone (GH) regulates growth and metabolism by binding GH receptor (GHR), a cytokine receptor superfamily member, in target tissues. This activates the GHR-associated cytoplasmic tyrosine kinase, JAK2, and several signaling systems including STAT5. An important GH-induced outcome in some cell types is STAT5-mediated expression of the insulin-like growth factor (IGF)-1 gene and IGF-1 secretion. For six decades, our appreciation of GH physiology has been influenced by the somatomedin hypothesis, which held that GH-induced hepatically-derived circulating endocrine IGF-1 (aka somatomedin-C) mediates GH's somatogenic actions. Indeed, IGF-1 acts via the type 1 IGF-1 receptor (IGF-1R) to transmit tyrosine-kinase-mediated anabolic signals. However, our novel findings suggest IGF-1R also functions in relevant cell types (preadipocytes, islet ?-cells, osteoblasts, prostate cancer cells) as a proximal GHR-interacting element to augment GH sensitivity, even absent IGF-1 binding. Specifically, we find GH acutely promotes IGF-1R association with GHR and that IGF-1R deletion reduces acute GH signaling and consequent IGF-1 gene expression. IGF-1R reconstitution in IGF-1R-deleted cells rescues GH responsiveness in a fashion that depends on IGF-1R extracellular domain (ECD) elements. Further, a recombinantly-produced soluble IGF-1R ECD fragment containing these elements binds GHR in response to GH and blunts GH-induced signaling and gene expression in a dominant-negative fashion. Supporting our findings, recent reports indicate overlap in the metabolic phenotypes of mice with islet ?-cell-specific deletion of either GHR or IGF-1R, suggesting GHR-IGF-1R interaction is physiologically relevant in cell types that coexpress the receptors, unlike liver that is heavily endowed with GHR, but nearly devoid of IGF-1R. We hypothesize: 1) IGF-1R, by virtue of specific interaction with GHR, augments GH-induced somatogenic and metabolic signaling in a physiologically-relevant fashion. 2) Modulation of GHR-IGF-1R interaction could be a therapeutically-relevant target to promote or inhibit GH actions, particularly in non-hepatic tissues that express IGF-1R and when IGF-1R is aberrantly expressed in liver.
Specific aims : 1) Define elements in IGF-1R that allow transmembrane-anchored IGF-1R to augment GH signaling; 2) Uncover specific modulators of GH action based on dominant-negative effects of soluble IGF-1R on GH signaling; 3) Examine functional effects of IGF-1R on GHR action in liver and pancreatic ?-cells in in vivo systems. Proposed studies address a fundamentally novel hypothesis about how GH-induced GHR action is influenced by physical and functional coupling of GHR with IGF-1R and IGF-1R-associated molecules. Our discoveries will enrich the linear GH?GHR?IGF-1?IGF-1R pathway (somatomedin hypothesis), suggesting parallel GHR/IGF-1R-mediated effects, especially in extrahepatic GH action. Relationships of this work with aspects of metabolic regulation and other areas, including growth disorders and cancer biology, could be many and our results may suggest novel strategies to modulate GH action.

Public Health Relevance

Growth hormone is a key regulator of growth and metabolism that is known to exert some of its actions by promoting production and actions of insulin-like growth factor-1. These studies examine new mechanistic hypotheses about how growth hormone mediates some of its activities by causing the growth hormone receptor to physically and functionally interact with the insulin-like growth factor-1 receptor. The knowledge gained will have broad relevance in our understanding of normal physiology and of the pathophysiology of metabolic diseases.

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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Liu, Ying; Jiang, Jing; Lepik, Bradford et al. (2017) Subdomain 2, Not the Transmembrane Domain, Determines the Dimerization Partner of Growth Hormone Receptor and Prolactin Receptor. Endocrinology 158:3235-3248
Hjortebjerg, Rikke; Berryman, Darlene E; Comisford, Ross et al. (2017) Insulin, IGF-1, and GH Receptors Are Altered in an Adipose Tissue Depot-Specific Manner in Male Mice With Modified GH Action. Endocrinology 158:1406-1418
McGinnis, Graham R; Tang, Yawen; Brewer, Rachel A et al. (2017) Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart. J Mol Cell Cardiol 110:80-95