Human GH Receptor-IGF-1 Receptor Interaction: Implications for GH Signaling

Abstract

GH signaling yields multiple anabolic and metabolic effects. GH binds the transmembrane GH receptor (GHR) to activate the intracellular GHR-associated tyrosine kinase, Janus kinase 2 (JAK2), and downstream signals, including signal transducer and activator of transcription 5 (STAT5) activation and IGF-1 gene expression. Some GH effects are partly mediated by GH-induced IGF-1 via IGF-1 receptor (IGF-1R), a tyrosine kinase receptor. We previously demonstrated in non-human cells that GH causes formation of a GHR-JAK2-IGF-1R complex and that presence of IGF-1R (even without IGF-1 binding) augments proximal GH signaling. In this study, we use human LNCaP prostate cancer cells as a model system to further study the IGF-1R's role in GH signaling. GH promoted JAK2 and GHR tyrosine phosphorylation and STAT5 activation in LNCaP cells. By coimmunoprecipitation and a new split luciferase complementation assay, we find that GH augments GHR/IGF-1R complex formation, which is inhibited by a Fab of an antagonistic anti-GHR monoclonal antibody. Short hairpin RNA-mediated IGF-1R silencing in LNCaP cells reduced GH-induced GHR, JAK2, and STAT5 phosphorylation. Similarly, a soluble IGF-1R extracellular domain fragment (sol IGF-1R) interacts with GHR in response to GH and blunts GH signaling. Sol IGF-1R also markedly inhibits GH-induced IGF-1 gene expression in both LNCaP cells and mouse primary osteoblast cells. On the basis of these and other findings, we propose a model in which IGF-1R augments GH signaling by allowing a putative IGF-1R-associated molecule that regulates GH signaling to access the activated GHR/JAK2 complex and envision sol IGF-1R as a dominant-negative inhibitor of this IGF-1R-mediated augmentation. Physiological implications of this new model are discussed.

Excess growth hormone suppresses DNA damage repair in epithelial cells

“…We previously found that in vitro GH treatment and overexpression did not affect IGF-1 or IGF-1R in colon cells (24). However, we cannot exclude that our observed in vivo effects of GH on DDR in colon may also be mediated by IGF-1 signaling, especially as IGF-1R also interacts with the GHR and may augment GH signaling (79). p53 activates IGF-1 binding protein 3 (IGFBP3), which suppresses IGF-1 function (80), and transcriptionally activates IGF-1R (81,82).…”

Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium

“…These findings support that a genetic risk score in the growth pathway are associated with high grade PCA. IGF genes have been previously linked with PCA ( Cheng et al , 2006 ; Johansson et al , 2007 ; Cao et al , 2014 ; Gan et al , 2014 ; Qian et al , 2014 ; Takeuchi et al , 2014 ; Travis et al , 2016 ). GHSR genes are also previously reported to associate with prostate cancer risk ( Dressen, 2007 ).…”

Hormone signaling pathways as treatment targets in renal cell cancer (Review)

“…Both GH and IGF-I have been shown to act as oncogenes by inducing mitogenic and anti-apoptotic effects in a variety of tumors and cancer-derived cell lines via endocrine and/or autocrine/paracrine mechanisms. It should be noted that the expression of IGF-IR is increased by the activation of oncogenes such as SV40 T antigen and c-MYB, but decreased by the activation of tumor suppressor genes such as p53 and wT1 (48). Oncogenic transformation seems to be responsible for the local expression of IGF-IR and GHR in tumor tissues including RCC.…”