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

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

Author information

1
Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: cjeskay@hotmail.com.
2
Department of Natural Sciences, LaGuardia CC, City University of New York, NY 11101, USA.
3
New York State Institute for Basic Research in Developmental Disabilities, New York 10301, USA.

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

PMID:
24662006
DOI:
10.1016/j.ijdevneu.2014.03.006
[Indexed for MEDLINE]

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