title: Where no Ras has gone before: VPS35 steers N-Ras through the cytosol.
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.
authors.affiliation: a Perlmutter Cancer Center, New York University School of Medicine , New York , NY , USA.
authors.forename: Mo
authors.initials: M
authors.lastname: Zhou
authors.affiliation: a Perlmutter Cancer Center, New York University School of Medicine , New York , NY , USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Philips
mesh_terms: D003600:Cytosol / Q000378:metabolism*; D006801:Humans; D017368:Protein Prenylation; D021381:Protein Transport; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; D018631:ras Proteins
keywords: N-Ras; Ras; VPS35; cytosolic protein; oncogene; prenylation; trafficking