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

Chen, Jianling; Alberts, Ian; Li, Xiaohong

doi:10.1016/j.ijdevneu.2014.03.006

Cited by 161Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersPI3K/AKT/mTOR signaling in cancer

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

Chen, Jianling, Alberts, Ian, Li, Xiaohong·2014·International Journal of Developmental Neuroscience

DOI 10.1016/j.ijdevneu.2014.03.006

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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.

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MIA alters key components of the TSC/mTOR signaling pathway with ultimate activation of the translation initiation factor EIF4E, which is predicted to alter regulation of neural progenitor cell divisions during midgestation.
“Consistently, we found that MIA alters key components of the TSC/mTOR signaling pathway with ultimate activation of the translation initiation factor EIF4E which is predicted to alter the regulation of neural progenitor cell divisions during midgestation [127, 156–158].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [156]
Key to this mechanism is the aberrant regulation of the PI3K-TSC1/2-mTOR signaling pathways, which in turn are responsible for the regulation of ribosomal protein S6 kinase (RPS6K) and EIF4E-binding partners (EIF4EBP1/2), acting to promote translation initiation.
“Key to this mechanism is the aberrant regulation of the PI3K–TSC1/2–mTOR signaling pathways, which in turn are responsible for the regulation of ribosomal protein S6 kinase (RPS6K) and EIF4E-binding partners (EIF4EBP1/2), acting to promote translation initiation.80”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [80]

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Authors: Chen, J., Alberts, I., & Li, X.
Affiliations: Shanghai Jiao Tong University (CN)
LaGuardia Community College (US)
New York State Institute for Basic Research in Developmental Disabilities New York 10301 USA
Corresponding author: Chen, Jianling
ORCID: Chen, Jianling
Alberts, Ian
Li, Xiaohong
Venue: International Journal of Developmental Neuroscience
Publisher: Wiley
Published: 2014-03-21
Volume: 35
Issue: 1
Pages: 35-41
ISSN: 0736-5748 (ISSN-L)
1873-474X
DOI: 10.1016/j.ijdevneu.2014.03.006
OpenAlex: W1975867021
Cited by: 151
References: 71
Citations by year: 2026: 10 · 2025: 7 · 2024: 14 · 2023: 12 · 2022: 10 · 2021: 16 · 2020: 15 · 2019: 9 · 2018: 13 · 2017: 16 · 2016: 14 · 2015: 7 · 2014: 7 · 2013: 1
FWCI: 1.42
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: International Journal of Developmental Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: School of Medicine, Shanghai Jiao Tong University
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: autism spectrum disorder, insulin-like growth factor I, IGF-1 receptor, phosphatidylinositol 3-kinase, Akt phosphorylation, mTOR, tuberous sclerosis complex 1, tuberous sclerosis complex 2, phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 3,4,5-trisphosphate, cell growth and proliferation, ASD diagnosis, ASD treatment
MeSH terms: Animals, Brain, Child Development Disorders, Pervasive, Humans, Insulin-Like Growth Factor I, Tissue Distribution, Signal Transduction, Oncogene Protein v-akt, Phosphatidylinositol 3-Kinase, TOR Serine-Threonine Kinases

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

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