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A novel SOS1 mutation in Costello/CFC syndrome affects signaling in both RAS and PI3K pathways

Munkhtuya Tumurkhuu1, Makiko Saitoh, Junko Takita

  • 1Department of Developmental Medical Sciences, Institute of International Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Journal of Receptor and Signal Transduction Research
|March 27, 2013
PubMed
Abstract

Insights

A novel Son of Sevenless 1 (SOS1) mutation (T158A) enhances RAS/MAPK signaling and impacts PI3K/AKT pathways. This finding sheds light on Costello, Noonan, and CFC syndromes.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Genetics

Background:

  • RAS/MAPK pathway dysregulation underlies Costello, Noonan, and cardio-facio-cutaneous (CFC) syndromes.
  • The role of PI3K/AKT signaling in these conditions remains largely unexplored.
  • A novel SOS1 (T158A) mutation was identified in a patient with overlapping Costello/CFC phenotypes.

Purpose of the Study:

  • To investigate the impact of the SOS1 (T158A) mutation on both RAS/MAPK and PI3K/AKT signaling pathways.
  • To elucidate the functional consequences of this mutation in cellular signaling.

Main Methods:

  • Wild-type and mutant (T158A) Son of Sevenless 1 (SOS1) were expressed in 293T cells.
  • Cells were stimulated with epidermal growth factor (EGF).
  • Phosphorylation levels of ERK1/2, AKT, p70S6K, and pS6 were quantified.

Main Results:

  • The SOS1 (T158A) mutation accelerated and prolonged ERK1/2 phosphorylation following EGF stimulation.
  • Mutant SOS1 cells exhibited reduced phospho-AKT levels at 60 minutes post-stimulation.
  • Differential phosphorylation patterns of p70S6K were observed between wild-type and mutant SOS1 cells.
  • Elevated phospho-ERK1/2 to total ERK1/2 ratio persisted in mutant cells 18 hours post-EGF, while phospho-AKT levels remained unchanged.

Conclusions:

  • The T158A mutation in the SOS1 histone-like domain may disrupt auto-inhibition, leading to enhanced RAS signaling.
  • The mutation influences PI3K/AKT pathway activity, potentially through negative feedback mechanisms involving phospho-p70S6K.
  • The SOS1 T158A mutation alters gene product phosphorylation in both RAS/MAPK and PI3K/AKT pathways, contributing to disease phenotypes.

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