Constitutively active Ras negatively regulates Erk MAP kinase through induction of MAP kinase phosphatase 3 (MKP3) in NIH3T3 cells
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초록
The Ras/Raf/MEK/Erk signaling pathway is important forregulation 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 cellsdespite active activation of Ras. However, little is known aboutthe modulation of Erk1/2 activity by active Ras. Here, we showthat overexpression of active H-Ras (H-RasG12R) in NIH3T3fibroblasts impaired FGF2-induced Erk1/2 phosphorylation, ascompared to wild-type cells. Northern blot analysis revealedthat prolonged expression of active Ras increased MAP kinasephosphatase 3 (MKP3) mRNA expression, a negative regulatorof Erk MAPK. Inhibition of the phosphatidylinositol 3-kinase(PI3K)/Akt pathway abrogated active Ras-induced up-regulationof MKP3 expression, leading to the rescue of Erk1/2 phosphorylation. Our results demonstrated that the Ras/Raf/MEK/Erksignaling cascade is negatively regulated by the PI3K/Aktdependenttranscriptional activation of the MKP3 gene.
Abstract
The Ras/Raf/MEK/Erk signaling pathway is important forregulation 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 cellsdespite active activation of Ras. However, little is known aboutthe modulation of Erk1/2 activity by active Ras. Here, we showthat overexpression of active H-Ras (H-RasG12R) in NIH3T3fibroblasts impaired FGF2-induced Erk1/2 phosphorylation, ascompared to wild-type cells. Northern blot analysis revealedthat prolonged expression of active Ras increased MAP kinasephosphatase 3 (MKP3) mRNA expression, a negative regulatorof Erk MAPK. Inhibition of the phosphatidylinositol 3-kinase(PI3K)/Akt pathway abrogated active Ras-induced up-regulationof MKP3 expression, leading to the rescue of Erk1/2 phosphorylation. Our results demonstrated that the Ras/Raf/MEK/Erksignaling cascade is negatively regulated by the PI3K/Aktdependenttranscriptional activation of the MKP3 gene.
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