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Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
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Regulation of Ras localization and cell transformation by evolutionarily conserved palmitoyltransferases

Evelin Young1, Ze-Yi Zheng, Angela D Wilkins

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.

Molecular and Cellular Biology
|November 20, 2013
PubMed

Insights

The study identifies sp-Erf2 as crucial for Ras protein localization to the plasma membrane in yeast. This enzyme, similar to human ZDHHC9, is vital for Ras-driven cancer development.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Ras proteins are key regulators of cellular signaling and are frequently implicated in tumorigenesis.
  • Proper localization of Ras proteins to the plasma membrane (PM) is essential for their function.
  • The mechanisms controlling Ras PM localization are not fully understood.

Purpose of the Study:

  • To identify novel components that regulate Ras PM localization using a genetic screen in Schizosaccharomyces pombe.
  • To elucidate the role of sp-Erf2 in Ras trafficking and its implications in cancer.

Main Methods:

  • An unbiased genetic screen in S. pombe to identify mutants with reduced PM Ras localization.
  • Characterization of the identified gene, sp-erf2, encoding the palmitoyltransferase sp-Erf2.
  • Functional analysis of human orthologs zDHHC9 and zDHHC14 in rescuing sp-erf2 mutant phenotypes.
  • Assessment of ZDHHC9's role in Ras PM localization and mammalian cell transformation.

Main Results:

  • A screen identified mutations in sp-erf2, encoding a palmitoyltransferase, as critical for Ras PM localization.
  • sp-Erf2 localizes to the trans-Golgi compartment, mediated by its transmembrane domain and Erf4 cofactor.
  • The human ortholog zDHHC9, but not zDHHC14, rescued sp-erf2 mutant phenotypes, indicating functional conservation.
  • ZDHHC9 overexpression enhanced Ras PM localization and cell transformation in mammalian cells, while repression diminished these effects.
  • sp-Erf2/zDHHC9 selectively palmitoylates Ras proteins in the trans-Golgi, facilitating PM targeting via the trans-Golgi network.

Conclusions:

  • sp-Erf2/zDHHC9 is a key regulator of Ras protein palmitoylation and PM targeting.
  • This process, occurring in the trans-Golgi, is critical for Ras-driven tumorigenesis.
  • ZDHHC9 represents a potential therapeutic target in cancers driven by Ras signaling.

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