INSR (Insulin receptor, CD22) is a receptor tyrosine kinase that is pivotal to the regulation of glucose homeostasis and mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including insulin receptor substrates (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Phosphorylation of IRS proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Pathogenic variants in INSR are associated with severe syndromic insulin resistance including the diseases Donohue syndrome and Rabson-Mendenhall syndrome and for increased risk of gestational diabetes. In immunohistochemistry, INSR has cytoplasmic positivity in all tissues throughout the body. References: The UniProt Consortium. Nucleic Acids Res. 47: D506-515 (2019); Nucleic Acids Res. 2016 Jan 4;44(D1):D733-45, PMID:26553804; Ben harouch S, Klar A, Falik Zaccai TC. INSR-Related Severe Syndromic Insulin Resistance. GeneReviews. Seattle (WA): University of Washington, Seattle. 2018. URL: https://www.ncbi.nlm.nih.gov/books/NBK476444/;