Multiple decisive phosphorylation sites for the negative feedback regulation of SOS1 via ERK.
EGF-induced activation of ERK has been extensively studied by both experimental and theoretical approaches. Here, we used a simulation model based mostly on experimentally determined parameters to study the ERK-mediated negative feedback regulation of the Ras guanine nucleotide exchange factor, son of sevenless (SOS). Because SOS1 is phosphorylated at multiple serine residues upon stimulation, we evaluated the role of the multiplicity by building two simulation models, which we termed the decisive and cooperative phosphorylation models. The two models were constrained by the duration of Ras activation and basal phosphorylation level of SOS1. Possible solutions were found only in the decisive model wherein at least three, and probably more than four, phosphorylation sites decisively suppress the SOS activity. Thus, the combination of experimental approaches and the model analysis has suggested an unexpected role of multiple phosphorylations of SOS1 in the negative regulation.
Kamioka
Yuji
Y
From the Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto 606-8501; Innovative Techno-Hub for Integrated Medical Bio-Imaging, Kyoto University, Kyoto 606-8501.
Yasuda
Shuhei
S
Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto 606-8501.
Fujita
Yoshihisa
Y
From the Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto 606-8501.
Aoki
Kazuhiro
K
Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto 606-8501; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
Matsuda
Michiyuki
M
From the Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto 606-8501; Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto 606-8501. Electronic address: matsudam@lif.kyoto-u.ac.jp.
D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation / Q000502:physiology; D020837:SOS1 Protein / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D020837:SOS1 Protein; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins