Growth hormone (GH) initiates biological actions by interacting with GH receptor (GHR), which activates the cytoplasmic tyrosine kinase, JAK2, and signaling molecules including signal transducer and activator of transcription (STAT)-5. GH-induced STAT5 activity enhances transcription of GH-responsive genes, including insulin-like growth factor (IGF)-1. IGF-1 interacts with cell surface IGF-1 receptor (IGF-1R), a disulfide-linked heterotetramer, causing activation of its tyrosine kinase, autophosphorylation, and intracellular signals. The somatomedin hypothesis of GH action holds that GH-induced IGF-1 mediates many of GH's somatogenic actions. Our proposal addresses the idea that, in addition to the """"""""linear"""""""" GH? GHR ?IGF-1 ?GF-1R pathway, IGF-1R also subserves GH signaling in several novel ways. Our preliminary data in osteoblasts, preadipocytes, and human cancer cells indicate that: 1) deletion of IGF-1R diminishes acute GH signaling and reconstitution with kinase-deficient IGF-1R undoes this defect;2) cotreatment with IGF-1 plus GH enhances GH responsiveness;and 3) GH promotes association of IGF-1R with the GHR-JAK2 complex. Collectively, these data suggest novel molecular mechanisms by which GH and IGF-1 collaborate. Exploring these mechanisms is of fundamental significance, especially as GH and IGF-1 signaling pathways serve both independent and overlapping growth functions in vivo and disruption of the GH-IGF-1 axis reduces incidence and aggressiveness of experimental cancers. We hypothesize: 1) GH action is facilitated by IGF-1R's presence in GH target cells such that, even without IGF-1, IGF-1R acts a proximal element in GH signaling;further, IGF-1 augments GH signaling, likely by decreasing the threshold for GH-induced GHR triggering. 2) These effects of IGF-1R and IGF-1 on GH signaling relate to the GH-induced formation of a GHR/JAK2/IGF-1R complex.
Our specific aims are to: 1.Define IGF-1R determinants that allow enhanced GH signaling. 2. Investigate determinants of GH-induced GHR/JAK2/IGF-1R complex formation. 3. Define molecular determinants and mechanisms of IGF-1 enhancement of GH signaling. 4. Examine consequences of GHR-IGF-1R collaboration in in vivo systems. These studies pursue a novel hypothesis about how GHR and IGF-1R interact. Completion of the aims will allow new insights into how GH uses the IGF-1R to enable GH actions and how GH and IGF-1 collaborate to optimize GH effects. These insights have potential relevance to the endocrinology of growth and the behavior of human cancers.

Public Health Relevance

Growth hormone is a key regulator of growth and metabolism that is known to promote 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 and how insulin-like growth factor-1 contributes to GH action. The knowledge gained will have broad relevance in our understanding of normal physiology and potentially in hormonal contributions to cancer pathophysiology.

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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Silva, Corinne M
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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