Journal
JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION
Volume 33, Issue 2, Pages 124-128Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/10799893.2013.779279
Keywords
Costello syndrome; noonan syndrome; PI3K/AKT pathway; RAS/MAPK pathway; SOS1
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Funding
- Japan Society for the Promotion of Science [20390293, 22659190]
- Ministry of Health, Labour and Welfare, Japan
- Grants-in-Aid for Scientific Research [23390269, 24659491, 20390293, 24659490, 22659190] Funding Source: KAKEN
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Context: Pathological upregulation of the RAS/MAPK pathway causes Costello, Noonan and cardio-facio-cutaneous (CFC) syndrome; however, little is known about PI3K/AKT signal transduction in these syndromes. Previously, we found a novel mutation of the SOS1 gene (T158A) in a patient with Costello/CFC overlapping phenotype. Objective: The aim of this study was to investigate how this mutation affects RAS/MAPK as well as PI3K/AKT pathway signal transduction. Materials and methods: Wild-type and mutant (T158A) Son of Sevenless 1 (SOS1) were transfected into 293T cells. The levels of phospho- and total ERK1/2, AKT, p70S6K and pS6 were examined under epidermal growth factor (EGF) stimulation. Results: After EGF stimulation, the ratio of phospho- ERK1/2 to total ERK1/2 was highest at 5 min in mutant (T158A) SOS1 cells, and at 15 min in wild-type SOS1 cells. Phospho-AKT was less abundant at 60 min in mutant than in wild-type SOS1 cells. Phosphorylation at various sites in p70S6K differed between wild-type and mutant cells. Eighteen hours after activation by EGF, the ratio of phospho- ERK1/2 to total ERK1/2 remained significantly higher in mutant than in wild-type SOS1 cells, but that of phospho- AKT to total AKT was unchanged. Discussion: T158A is located in the histone-like domain, which may have a role in auto-inhibition of RAS exchanger activity of SOS1. T158A may disrupt autoinhibition and enhance RAS signaling. T158A also affects PI3K/AKT signaling, probably via negative feedback via phospho- p70S6K. Conclusion: The SOS1 T158A mutation altered the phosphorylation of gene products involved in both RAS/MAPK and PI3K/AKT pathways.
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