34 The insulin and IGF system is a complex network of ligands, receptors, and signaling pathways. INSULIN RECEPTOR SIGNALING The hormone insulin is secreted mainly by the β-cells from the islets of Langerhans in the

pancreas in response to elevation in glucose levels. The main insulin target tissues are liver, skeletal muscle, and adipose tissue. In these tissues insulin has a metabolic effect, whereas high levels of the insulin receptor (IR) in the brain and lower levels in pancreas, monocytes, granulocytes, erythrocytes, endothelial Inhibitors,research,lifescience,medical cells, and fibroblasts35 suggest that insulin has other roles as well. Insulin binds to the extracellular portion of the transmembrane tyrosine kinase IR. Structurally, IR has two extracellular α-subunits Inhibitors,research,lifescience,medical and two transmembrane β-subunits that are joined to each other by disulfide bonds (Figure 1). In addition, alternative splicing yields two IR isoforms: isoform A (IR-A) lacking exon 11, and isoform B (IR-B) including exon 11. Upon insulin binding, autophosphorylation of the β-subunit leads to phosphorylation of intracellular proteins Inhibitors,research,lifescience,medical such as insulin receptor substrates (IRS-1 to 4) and other adaptor proteins. Phosphorylation of IRS-1 activates the phosphatidylinositol 3-kinase (PI3K) cascade which turns on the protein kinase B (Akt) pathway. IR

activation also activates the mitogen-activated protein kinase (MAPK) pathway. Figure 1 The insulin receptor Inhibitors,research,lifescience,medical (IR) with its two subtypes IR-A and IR-B, the insulin growth factor 1 receptor (IGF-1R) and the hybrid

GDC-0449 in vitro receptors (IGF-1R/IR-A and IGF-1R/IR-B). Structurally, IR and the IGF-1R have two extracellular α-subunits and two transmembrane … IGF-1 RECEPTOR SIGNALING Circulating IGF-1 is produced mainly in the liver and Inhibitors,research,lifescience,medical responds to growth hormone (GH) stimulation. IGF-1 is also expressed by almost all tissues.36 IGFs mainly regulate growth processes and have mitogenic effects. The circulating ligands IGF-1 and IGF-2 are bound to IGF-binding proteins (IGFBPs). There are six IGFBPs, named IGFBP-1 to IGFBP-6; they bind IGF-1 and IGF-2 but not insulin and protect them from Oxymatrine degradation. Like insulin, IGF ligands (IGF-1 and IGF-2) bind to a tyrosine kinase receptor, the IGF-1 receptor (IGF-1R). The IGF-1R is similar in structure to the insulin receptor, with two extracellular α-subunits and two transmembrane β-subunits (Figure 1). Binding of IGF-1 or IGF-2 to the IGF-1R leads to receptor autophosphorylation, which results in IRS phosphorylation that then leads to activation of the PI3K cascade. IGF ligand binding can also activate the mitogen-activated protein kinase (MAPK) pathway (Figure 2). In addition, IGF-2 can also bind IGF-2 receptor (IGF-2R) which leads to endocytosis of the ligand–receptor complex, and therefore IGF-2R functions as a clearance receptor for IGF-2.