Dysregulation of the IGF‐I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders

Abstract The IGF‐I/PI3K/AKT/mTOR signaling pathway plays an important role in the regulation of cell growth, proliferation, differentiation, motility, survival, metabolism and protein synthesis. Insulin‐like growth factor‐I (IGF‐I) is synthesized in the liver and fibroblasts, and its biological actions are mediated by the IGF‐I receptor (IGF‐IR). The binding of IGF‐I to IGF‐IR leads to the activation of phosphatidylinositol 3‐kinase (PI3K). Activated PI3K stimulates the production of phosphatidylinositol (4,5)‐bisphosphate [PI(4,5)P2] and phosphatidylinositol (3,4,5)‐trisphosphate [PI(3,4,5)P3]. The PH domain of AKT (protein kinase B, PKB) (v‐AKT murine thymoma viral oncogene homolog) binds to PI(4,5)P2 and PI(3,4,5)P3, followed by phosphorylation of the Thr308 and Ser473 regulatory sites. Tuberous sclerosis complex 1 (TSC1) and TSC2 are upstream regulators of mammalian target of rapamycin (mTOR) and downstream effectors of the PI3K/AKT signaling pathway. The activation of AKT suppresses the TSC1/TSC2 heterodimer, which is an upstream regulator of mTOR. Dysregulated IGF‐I/PI3K/AKT/mTOR signaling has been shown to be associated with autism spectrum disorders (ASDs). In this review, we discuss the emerging evidence for a functional relationship between the IGF‐I/PI3K/AKT/mTOR pathway and ASDs, as well as a possible role of this signaling pathway in the diagnosis and treatment of ASDs.