title: 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.
authors.affiliation: Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: cjeskay@hotmail.com.
authors.forename: Jianling
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Natural Sciences, LaGuardia CC, City University of New York, NY 11101, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Alberts
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, New York 10301, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002659:Child Development Disorders, Pervasive / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D007334:Insulin-Like Growth Factor I; D058539:Phosphatidylinositol 3-Kinase; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases
keywords: AKT; Autism spectrum disorders; Rett syndrome; mTOR