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

Int J Dev Neurosci. 2014 Jun;35:35-41. doi: 10.1016/j.ijdevneu.2014.03.006. Epub 2014 Mar 21.

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.

Keywords: AKT; Autism spectrum disorders; Rett syndrome; mTOR.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Brain / metabolism*
  • Child Development Disorders, Pervasive / metabolism*
  • Humans
  • Insulin-Like Growth Factor I / metabolism*
  • Oncogene Protein v-akt / metabolism*
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism*
  • Tissue Distribution

Substances

  • Insulin-Like Growth Factor I
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinase
  • Oncogene Protein v-akt