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CHMP6 and VPS4A mediate the recycling of Ras to the plasma membrane to promote growth factor signaling

Oncogene volume 31, pages 4630–4638 (2012)Cite this article

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Abstract

While Ras is well-known to function on the plasma membrane (PM) to mediate growth factor signaling, increasing evidence suggests that Ras has complex roles in the cytoplasm. To uncover these roles, we screened a cDNA library and isolated H-Ras-binding proteins that also influence Ras functions. Many isolated proteins regulate trafficking involving endosomes; CHMP6/VPS20 and VPS4A, which interact with ESCRT-III (Endosomal Sorting Complex Required for Transport-III), were chosen for further study. We showed that the binding is direct and occurs in endosomes. Furthermore, the binding is most efficient when H-Ras has a functional effector-binding loop, and is GTP-bound and ubiquitylated. CHMP6 and VPS4A also bound to N-Ras but not K-Ras. Repressing CHMP6 and VPS4A blocked Ras-induced transformation, which correlated with inefficient Ras localization to the PM as measured by cell fractionation and photobleaching. Moreover, silencing CHMP6 and VPS4A also blocked epidermal growth factor receptor (EGFR) recycling. These data suggest that Ras interacts with key ESCRT-III components to promote recycling of itself and EGFR back to the PM to create a positive feedback loop to enhance growth factor signaling.

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Acknowledgements

We thank Gary Chamness and Evelin Young for thoughtfully reading the manuscript. We are particularly grateful for the generosity of Wesley Sundquist, Mark Philips and Juan Bonifacino for providing many reagents and for sharing unpublished results that are critical for this study. Z-Y Z is supported by a postdoctoral fellowship from the Susan G Komen for the Cure Foundation (PDF0707860). ST was supported by a fellowship from Human Frontier Science Program (LT00147/2005). STW is supported by a grant from NIH (U54CA149169). ZS is a Leukemia and Lymphoma Society Scholar and is supported by grants from NIH (CA133249 and GM081627). ECC is supported by grants from NIH (CA90464, CA107187, GM81627 and P50-CA58183).

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Author notes

  1. S Terrillon

    Present address: Current address: Department of Molecular & Cellular Pharmacology, Abbott Bioresearch Center, Worcester, MA, USA

Authors and Affiliations

  1. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    Z-Y Zheng, C-M Cheng, X-R Fu & E C Chang

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    C-M Cheng & E C Chang

  3. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA

    L-Y Chen & Z Songyang

  4. Department of Biochemistry, New York University School of Medicine, New York, NY, USA

    L Xu, S Terrillon & D Bar-Sagi

  5. Department of Systems Medicine and Bioengineering, Methodist Hospital Research Institute, Houston, TX, USA

    S T Wong

  6. These authors contribute equally to this work,

    Z-Y Zheng & C-M Cheng

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  1. Z-Y Zheng
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Correspondence to E C Chang.

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Zheng, ZY., Cheng, CM., Fu, XR. et al. CHMP6 and VPS4A mediate the recycling of Ras to the plasma membrane to promote growth factor signaling. Oncogene 31, 4630–4638 (2012). https://doi.org/10.1038/onc.2011.607

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