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.
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.
|Liu, Ying; Zhang, Yue; Jiang, Jing et al. (2016) GHR/PRLR Heteromultimer Is Composed of GHR Homodimers and PRLR Homodimers. Mol Endocrinol 30:504-17|
|Chen, Hainan; Kleinberger, Jeffrey W; Takane, Karen K et al. (2015) Augmented Stat5 Signaling Bypasses Multiple Impediments to Lactogen-Mediated Proliferation in Human ?-Cells. Diabetes 64:3784-97|
|Gan, Yujun; Paterson, Andrew J; Zhang, Yue et al. (2014) Functional collaboration of insulin-like growth factor-1 receptor (IGF-1R), but not insulin receptor (IR), with acute GH signaling in mouse calvarial cells. Endocrinology 155:1000-9|
|Liu, Ying; Berry, Philip A; Zhang, Yue et al. (2014) Dynamic analysis of GH receptor conformational changes by split luciferase complementation. Mol Endocrinol 28:1807-19|
|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|
|Gan, Yujun; Buckels, Ashiya; Liu, Ying et al. (2014) Human GH receptor-IGF-1 receptor interaction: implications for GH signaling. Mol Endocrinol 28:1841-54|
|Zhang, Yuchao; Liu, Yuantao; Li, Xia et al. (2013) Effects of insulin and IGF-I on growth hormone- induced STAT5 activation in 3T3-F442A adipocytes. Lipids Health Dis 12:56|
|Gan, Yujun; Zhang, Yue; Buckels, Ashiya et al. (2013) IGF-1R modulation of acute GH-induced STAT5 signaling: role of protein tyrosine phosphatase activity. Mol Endocrinol 27:1969-79|
|Zheng, Ying; Qin, Hongwei; Frank, Stuart J et al. (2011) A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway. Blood 118:156-66|
|Li, Xin; Huang, Yao; Jiang, Jing et al. (2011) Synergy in ERK activation by cytokine receptors and tyrosine kinase growth factor receptors. Cell Signal 23:417-24|
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