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

Z. Y. Zheng, C. M. Cheng, X. R. Fu, L. Y. Chen, L. Xu, S. Terrillon, S. T. Wong, D. Bar-Sagi, Z. Songyang, E. C. Chang

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4630-4638
Number of pages9
JournalOncogene
Volume31
Issue number43
DOIs
StatePublished - Oct 25 2012

Keywords

  • ESCRT-III
  • signal transduction
  • trafficking
  • tumorigenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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