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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.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01248-13.
ACKNOWLEDGMENTS
We thank Wayne P. Wahls (University of Arkansas for Medical Sciences), Sara Mole (University College London), and Snezhana Oliferenko (Temasek Lifesciences Lab) for kindly providing reagents and Charles M. Perou and Cheng Fan (University of North Carolina) for help in analyzing microarray data.
We also sincerely thank our funding sources. A Graduate Research Fellowship from the National Science Foundation supported E.Y. Z.-Y.Z. was supported by a postdoctoral fellowship from the Susan G. Komen for the Cure Foundation (PDF0707860). The Jiangsu Health International Exchange Program sponsored M.L. E.C.C. is supported by grants from the NIH (CA90464, CA107187, GM81627, P30-CA58183, and CA125123), the Nancy Owens Memorial Foundation, and the Mary Kay Ash Foundation. O.L. is supported by grants from the NIH (R01-GM066099, R01-GM079656) and NSF (ABI-1062455).