A novelSOS1mutation in Costello/CFC syndrome affects signaling in both RAS and PI3K pathways
In: Journal of Receptors and Signal Transduction, Jg. 33 (2013-03-26), S. 124-128
Online
unknown
Zugriff:
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.The aim of this study was to investigate how this mutation affects RAS/MAPK as well as PI3K/AKT pathway signal transduction.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.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.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 auto-inhibition and enhance RAS signaling. T158A also affects PI3K/AKT signaling, probably via negative feedback via phospho-p70S6K.The SOS1 T158A mutation altered the phosphorylation of gene products involved in both RAS/MAPK and PI3K/AKT pathways.
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A novelSOS1mutation in Costello/CFC syndrome affects signaling in both RAS and PI3K pathways
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Autor/in / Beteiligte Person: | Mizuguchi, Masashi ; Tumurkhuu, Munkhtuya ; Saitoh, Makiko ; Mizuno, Yoko ; Takita, Junko |
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Zeitschrift: | Journal of Receptors and Signal Transduction, Jg. 33 (2013-03-26), S. 124-128 |
Veröffentlichung: | Informa UK Limited, 2013 |
Medientyp: | unknown |
ISSN: | 1532-4281 (print) ; 1079-9893 (print) |
DOI: | 10.3109/10799893.2013.779279 |
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