IRS-2, originally described as 4PS, acts as a signaling intermediate downstream of the Insulin, IGF-1, IL-4, IL-9 and IL-13 receptors. In IRS-2-deficient mice, reduction in total PI 3-kinase activity by 30% and abolition of downstream activation of protein kinase C (PKC) ζ leads to the development of type 2 diabetes. Additionally, reconstitution with retroviral IRS-2 restores IRS-2/PI 3-kinase/PKC ζ signalling as well as glucose uptake. IRS-2 translocates to the nuclei of mouse embryo fibroblasts expressing the Insulin-like growth factor 1 receptor. Various mutations in the IGF-IR can result in an abrogation of or decrease in the translocation of IRS proteins to the nucleoli. IRS-2 is responsible for mitogen-activated protein kinase (MAPK) and protein kinase B (PKB) activation by Insulin and is the major adapter molecule linking the Insulin receptor to this step.
