Insulin Receptor Tyrosine Kinase and MAPK/ERK Signaling: Molecular Mechanisms and Clinical Implications

Abstract

Insulin is a peptide hormone that coordinates glucose availability with anabolic, growth, vascular, and survival responses through the insulin receptor (IR), a preformed receptor tyrosine kinase. Insulin binding reorganizes the extracellular receptor and brings the intracellular kinase domains into an active configuration, producing trans-autophosphorylation and phosphorylation of adaptor proteins. These phosphotyrosine-dependent docking events divide insulin signaling into interconnected metabolic and mitogenic branches. The mitogenic branch is initiated mainly through SHC and GRB2/SOS, activates Ras, and proceeds through the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. Activated ERK1/2 phosphorylates cytoplasmic, cytoskeletal, and nuclear proteins, including transcriptional regulators such as Elk-1, c-Myc, c-Fos, HIF-1alpha, PDX1, and BETA2, thereby influencing proliferation, differentiation, migration, survival, metabolism, and gene expression. Signal duration is limited by receptor trafficking, protein tyrosine and serine/threonine phosphatases, and inhibitory feedback. Dysregulation contributes to insulin resistance, type 2 diabetes, endothelial dysfunction, reproductive and hepatic metabolic disorders, diabetic complications, chronic inflammation, and context-dependent tumor-promoting signaling. Future work should define tissue-specific signaling thresholds and exploit receptor conformational bias to preserve metabolic efficacy while minimizing excessive mitogenic signaling