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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

Oncogene volume 27, pages 2934–2940 (2008)Cite this article

Abstract

The Raf–mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3K)–AKT pathways are two downstream effectors of the small GTPase Ras. Although both pathways are positively regulated by Ras, the Raf–MAPK and PI3K–AKT pathways have been shown to control opposing functions within the cell, suggesting a need for cross-talk regulation. The PI3K–AKT pathway can inhibit the Raf–MAPK pathway directly during processes such as muscle differentiation. Here we describe the ability of the Raf–MAPK pathway to negatively regulate the PI3K–AKT pathway during cellular arrest. Constitutive activation of Raf or methyl ethyl ketone 1 (MEK1) leads to inhibition of AKT and cellular arrest. Furthermore, we show that activation of Raf–MEK1 signaling causes negative feedback inhibition of Ras through the ephrin receptor EphA2. EphA2-mediated negative feedback inhibition is required for Raf-induced AKT inhibition and cell cycle arrest, therefore establishing the inhibition of the Ras–PI3K–AKT pathway as a necessary event for the Raf–MEK1-regulated cellular arrest.

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Acknowledgements

We thank Dr Hartmut Land for cell lines and reagents, and Dr Daksha Patel and Dr Simon McDade for review of this manuscript. This work was supported by grants from NIH RO1 AI 30798 and RO1 DE015935 to DJ McCance.

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Author notes

  1. C W Menges

    Present address: 5Current address: Professor Department of Human Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA,

Authors and Affiliations

  1. Departments of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    C W Menges

  2. The Center for Cancer Research and Cell Biology, Queens University, Belfast, UK

    C W Menges & D J McCance

  3. Departments of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    D J McCance

  4. The James P Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

    D J McCance

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  1. C W Menges
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Correspondence to D J McCance.

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Menges, C., McCance, D. Constitutive activation of the Raf–MAPK pathway causes negative feedback inhibition of Ras–PI3K–AKT and cellular arrest through the EphA2 receptor. Oncogene 27, 2934–2940 (2008). https://doi.org/10.1038/sj.onc.1210957

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