Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jan;10(1):20-25.
doi: 10.1080/21541248.2016.1263380. Epub 2017 Jan 27.

Where no Ras has gone before: VPS35 steers N-Ras through the cytosol

Mo Zhou  1 , Mark R Philips  1
Affiliations

Where no Ras has gone before: VPS35 steers N-Ras through the cytosol

Mo Zhou et al. Small GTPases. 2019 Jan.

Abstract

Ras is the best-studied member of the superfamily of small GTPases because of its role in cancer. Ras proteins transmit signals for proliferation, differentiation and survival. Three RAS genes encode 4 isoforms. All Ras isoforms have long been considered membrane bound, a localization required for function. Our recent study revealed that N-Ras differs from all other isoforms in being largely cytosolic even following modification with a prenyl lipid. Endogenous, cytosolic N-Ras chromatographed in both high and low molecular weight pools, a pattern that required prenylation, suggesting prenyl-dependent interaction with other proteins. VPS35, a coat protein of the retromer, was shown to interact with prenylated N-Ras in the cytosol. Silencing VPS35 results in partial N-Ras mislocalization on vesicular and tubulovesicular structures, reduced GTP-loading of Ras proteins, and inhibited proliferation and MAPK signaling in an oncogenic N-Ras-driven tumor cell line. Our data revealed a novel regulator of N-Ras trafficking and signaling.

Keywords: N-Ras; Ras; VPS35; cytosolic protein; oncogene; prenylation; trafficking.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Model of N-Ras trafficking. Nascent N-Ras is palmitoylated on the cytoplasmic face of the Golgi and then is transferred by vesicular transport to the plasma membrane. N-Ras later gains access to the cytoplasmic face of endosomes either through endocytosis (not shown) or depalmitoylation that allows trafficking through the cytosol, perhaps associated with chaperones. N-Ras is then extracted from Rab7 positive endosomes by association with VPS35 thereby contributing to a relatively large cytosolic pool that can be delivered to the Golgi for repalmitoylation and another cycle of targeting to the plasma membrane. Independent of this process, VPS35/26/29 form the retromer on Rab7 positive endosomes that delivers cargo such as CIMPR (cation-independent mannose 6-phosphate receptor) back to the trans-Golgi network.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Wright LP, Philips MR. Thematic review series: lipid posttranslational modifications. CAAX modification and membrane targeting of Ras. J Lipid Res 2006; 47:883-91; PMID:16543601; http://dx.doi.org/10.1194/jlr.R600004-JLR200 - DOI - PubMed
    1. Hancock JF, Magee AI, Childs JE, Marshall CJ. All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 1989; 57:1167-77; PMID:2661017; http://dx.doi.org/10.1016/0092-8674(89)90054-8 - DOI - PubMed
    1. Schafer WR, Trueblood CE, Yang C, Mayer MP, Rosenberg S, Poulter CD, Kim SH, Rine J. Enzymatic coupling of cholesterol intermediates to a mating pheromone precursor and to the ras protein. Science 1990; 249:1133-9; PMID:2204115; http://dx.doi.org/10.1126/science.2204115 - DOI - PubMed
    1. Boyartchuk VL, Ashby MN, Rine J. Modulation of Ras and a-Factor Function by Carboxyl-Terminal Proteolysis. Science 1997; 275:1796-800; PMID:9065405; http://dx.doi.org/10.1126/science.275.5307.1796 - DOI - PubMed
    1. Otto JC, Kim E, Young SG, Casey PJ. Cloning and characterization of a mammalian prenyl protein-specific protease. J Biol Chem 1999; 274:8379-82; PMID:10085068; http://dx.doi.org/10.1074/jbc.274.13.8379 - DOI - PubMed

Publication types

LinkOut - more resources