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http://dx.doi.org/10.5483/BMBRep.2014.47.12.017

Constitutively active Ras negatively regulates Erk MAP kinase through induction of MAP kinase phosphatase 3 (MKP3) in NIH3T3 cells  

Park, Young Jae (Laboratory of Immunobiology, School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University)
Lee, Jong Min (Department of Biological Sciences, College of Biological Science and Biotechnology, Konkuk University)
Shin, Soon Young (Department of Biological Sciences, College of Biological Science and Biotechnology, Konkuk University)
Kim, Young Ho (Laboratory of Immunobiology, School of Life Science and Biotechnology, College of Natural Sciences, Kyungpook National University)
Publication Information
BMB Reports / v.47, no.12, 2014 , pp. 685-690 More about this Journal
Abstract
The Ras/Raf/MEK/Erk signaling pathway is important for regulation of cell growth, proliferation, differentiation, survival, and apoptosis in response to a variety of extracellular stimuli. Lack of Erk MAPK activation is observed in several cancer cells despite active activation of Ras. However, little is known about the modulation of Erk1/2 activity by active Ras. Here, we show that overexpression of active H-Ras (H-RasG12R) in NIH3T3 fibroblasts impaired FGF2-induced Erk1/2 phosphorylation, as compared to wild-type cells. Northern blot analysis revealed that prolonged expression of active Ras increased MAP kinase phosphatase 3 (MKP3) mRNA expression, a negative regulator of Erk MAPK. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway abrogated active Ras-induced up-regulation of MKP3 expression, leading to the rescue of Erk1/2 phosphorylation. Our results demonstrated that the Ras/Raf/MEK/Erk signaling cascade is negatively regulated by the PI3K/Aktdependent transcriptional activation of the MKP3 gene.
Keywords
Active H-Ras; Mitogen-activated protein kinase; Mitogen-activated protein kinase phosphatase 3; NIH3T3 fibroblast; Phosphatidylinositol 3-kinase;
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