Overview of insulin-like growth factor pathway upstream of IGF1R The hypothalamus regulates the release of growth hormone (GH) by either stimulating the pituitary gland with growth hormone-releasing hormone (GHRH) or inhibiting it with somatostatin (SST). Circulating IGFs are mainly produced by the liver after stimulation by GH. The insulin-like growth factor 1 receptor (IGF1-R) binds either insulin-like growth factor 1 (IGF1) or insulin-like growth factor 2 (IGF2). Most of circulating IGF1 is bound in a ternary complex with insulin-like growth factor binding protein 3 (IGFBP3) and the acid-labile subunit (ALS). In the ternary complex, IGF1 cannot cross the endothelial cell barrier; its half-life in circulation is prolonged and its ability to activate IGFR1 is reduced. The binding of IGFs to IGF1R stimulates the receptor’s tyrosine kinase activity, which activates downstream signaling pathways, including the PI3K-AKT-TOR and RAF-MAPK systems. These downstream networks stimulate angiogenesis and cell proliferation and survival, and inhibit apoptosis. The insulin-like growth factor 2 receptor (IGF2R) binds only IGF-2 and does not activate intracellular signaling pathways. The insulin receptor (IR) can bind either insulin (INS) or IGF-I. Other abbreviations: GHRHR, growth hormone releasing hormone receptor; SSTR, somatostatin receptor; GHR, growth hormone receptor; POU1F1, pituitary-specific positive transcription factor 1. Text color scheme: The signifies genes analyzed.
