Constitutive activation of the Raf–MAPK pathway causes negative feedback inhibition of Ras–PI3K–AKT and cellular arrest through the EphA2 receptor

Menges, Craig W.; McCance, Dennis J.

doi:10.1038/sj.onc.1210957

Cited by 87 publications

(69 citation statements)

References 28 publications

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“…In addition, EphA2 can signal through PI3K in aggressive melanoma cells. 23 These results coupled with previous data, suggest that the inhibitors of tyrosine kinase activity hinder VM channel formation. The activation of EphA2 by ephrin-A1 then stimulated the activation of PI3K, resulting in the formation of tubular networks in three-dimensional matrices.…”

Section: Discussionsupporting

confidence: 69%

Inhibition of tumor growth and vasculogenic mimicry by curcumin through down-regulation of the EphA2/PI3K/MMP pathway in a murine choroidal melanoma model

Chen¹,

He²,

Zhao³

et al. 2011

Cancer Biology & Therapy

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Section: Discussionsupporting

confidence: 69%

Inhibition of tumor growth and vasculogenic mimicry by curcumin through down-regulation of the EphA2/PI3K/MMP pathway in a murine choroidal melanoma model

Chen¹,

He²,

Zhao³

et al. 2011

Cancer Biology & Therapy

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“…Relationships between c-Ras and PI3K have been studied extensively [42][43][44]. C-Ras and PI3K have been known to interact for many years [45].…”

Section: Discussionmentioning

confidence: 99%

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

et al. 2010

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Oncogenic H-Ras G12V and its variants have been shown to inhibit muscle differentiation. However, the role of proto-oncogenic Ras (c-Ras) in muscle differentiation remains unclear. The active GTP-bound form of Ras has been known to associate with diverse effectors including Raf, phosphatidylinositol 3-kinase (PI3K), Ral-GDS, and other molecules to transmit downstream signals. We hypothesize that c-Ras may stimulate muscle differentiation by selectively activating PI3K, an important mediator for muscle differentiation. In our experiments, inhibition of c-Ras by farnesyltransferase inhibitors and a dominant negative form of H-Ras (Ras S17N) suppressed muscle differentiation. Consistently, individual knockdown of H-Ras, K-Ras, and N-Ras by siRNAs all blocked muscle differentiation. Interestingly, we found that c-Ras preferentially interacts with PI3K rather than its major binding partner c-Raf, during myogenic differentiation, with total c-Ras activity remaining unchanged. PI3K and its downstream myogenic pathway, the Nox2/NF-κB/inducible nitric oxide synthase (iNOS) pathway, were found to be suppressed by inhibition of c-Ras activity during differentiation. Furthermore, expression of a constitutively active form of PI3K completely rescued the differentiation block and reactivated the Nox2/NF-κB/iNOS pathway in c-Ras-inhibited cells. On the basis of our results, we conclude that contrary to oncogenic Ras, proto-oncogenic H-Ras, K-Ras, and N-Ras are directly involved in the promotion of muscle differentiation via PI3K and its downstream signaling pathways. In addition, PI3K pathway activation is associated with a concurrent suppression of the otherwise predominantly activated Raf/ Mek/Erk pathway.

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“…One plausible mechanism would involve a negative regulator of Akt activity that could be up-regulated by MAPK signaling. Interestingly, in the presence of cyclohexamide, an inhibitor of de novo protein synthesis, Raf was unable to inhibit Akt phosphorylation, which suggests that Raf -MAPK signaling requires protein synthesis for the inhibition of AKT (82) . Therefore, to assay if the overexpression of eEF1A2 could act on the regulation of Akt activity, we assayed the phosphoAkt expression levels in Hek293 cell line after treatment of the cells with gemcitabine.…”

Section: Eef1a Substratementioning

confidence: 99%

Raf kinases in signal transduction and interaction with translation machinery

Migliaccio

Sanges

Ruggiero

et al. 2013

BioMolecular Concepts

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Abstract:In recent years, a large amount of evidence has given a central role to translational control in diseases such as cancer, tissue hypertrophy and neurodegeneration. Its deregulation can directly modulate cell cycling, transformation and survival response. The aim of this review is to describe the interaction between Raf activation and the main characters of the translational machinery, such as the elongation factor 1A (eEF1A), which has been recognized in recent years as one of the most interesting putative oncogenes. A particular emphasis is given to an intriguing non-canonical role that eEF1A can play in the relationship between the Ras → Raf-1 → MEK1 → ERK-1/2 and PI3K → Akt signaling pathways. Recently, our group has described a C-Raf kinase-mediated phosphorylation of eEF1A triggered by a survival pathway induced upon interferon alpha (IFN α ) treatment in the human epidermoid cancer cell line (H1355). This phosphorylation seems to be the center of the survival pathway that counteracts the well-known pro-apoptotic function of IFN α . Furthermore, we have identified two new phosphorylation sites on eEF1A (Ser21 and Thr88) that are substrates for Raf kinases in vitro and, likely, in vivo as well. These residues seem to have a significant functional role in the control of cellular processes, such as cell proliferation and survival. In fact, overexpression of eEF1A2 in gemcitabine-treated cancer cells caused the upregulation of phosphoAkt and an increase in cell viability, thereby suggesting that eEF1A2 could exert its oncogenic behavior by participating in the regulation of PI3K pathway.

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Constitutive activation of the Raf–MAPK pathway causes negative feedback inhibition of Ras–PI3K–AKT and cellular arrest through the EphA2 receptor

Cited by 87 publications

References 28 publications

Inhibition of tumor growth and vasculogenic mimicry by curcumin through down-regulation of the EphA2/PI3K/MMP pathway in a murine choroidal melanoma model

Inhibition of tumor growth and vasculogenic mimicry by curcumin through down-regulation of the EphA2/PI3K/MMP pathway in a murine choroidal melanoma model

Proto-oncogenic H-Ras, K-Ras, and N-Ras are involved in muscle differentiation via phosphatidylinositol 3-kinase

Raf kinases in signal transduction and interaction with translation machinery

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