title: Regulation of Ras localization and cell transformation by evolutionarily conserved palmitoyltransferases.
abstract: Ras can act on the plasma membrane (PM) to mediate extracellular signaling and tumorigenesis. To identify key components controlling Ras PM localization, we performed an unbiased screen to seek Schizosaccharomyces pombe mutants with reduced PM Ras. Five mutants were found with mutations affecting the same gene, S. pombe erf2 (sp-erf2), encoding sp-Erf2, a palmitoyltransferase, with various activities. sp-Erf2 localizes to the trans-Golgi compartment, a process which is mediated by its third transmembrane domain and the Erf4 cofactor. In fission yeast, the human ortholog zDHHC9 rescues the phenotypes of sp-erf2 null cells. In contrast, expressing zDHHC14, another sp-Erf2-like human protein, did not rescue Ras1 mislocalization in these cells. Importantly, ZDHHC9 is widely overexpressed in cancers. Overexpressing ZDHHC9 promotes, while repressing it diminishes, Ras PM localization and transformation of mammalian cells. These data strongly demonstrate that sp-Erf2/zDHHC9 palmitoylates Ras proteins in a highly selective manner in the trans-Golgi compartment to facilitate PM targeting via the trans-Golgi network, a role that is most certainly critical for Ras-driven tumorigenesis.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Evelin
authors.initials: E
authors.lastname: Young
authors.forename: Ze-Yi
authors.initials: ZY
authors.lastname: Zheng
authors.forename: Angela D
authors.initials: AD
authors.lastname: Wilkins
authors.forename: Hee-Tae
authors.initials: HT
authors.lastname: Jeong
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Olivier
authors.initials: O
authors.lastname: Lichtarge
authors.forename: Eric C
authors.initials: EC
authors.lastname: Chang
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D017124:Conserved Sequence / Q000235:genetics; D019143:Evolution, Molecular; D005816:Genetic Complementation Test; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D041681:NIH 3T3 Cells; D010169:Palmitic Acids / Q000378:metabolism; D012568:Schizosaccharomyces / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D010169:Palmitic Acids; D029702:Schizosaccharomyces pombe Proteins; D049452:Green Fluorescent Proteins; D000217:Acyltransferases; C587068:Erf2 protein, S pombe; C504825:ZDHHC9 protein, human; C492657:Ras1 protein, S pombe; D018631:ras Proteins