Mutationally activated Rho GTPases in cancer

Small GTPases. Jul-Sep 2013;4(3):159-63. doi: 10.4161/sgtp.26530. Epub 2013 Oct 2.

Abstract

The Rho family of GTPases (members of the Ras superfamily) are best known for their roles in regulating cytoskeletal dynamics. It is also well established that misregulation of Rho proteins contributes to tumorigenesis and metastasis. Unlike Ras proteins, which are frequently mutated in cancer (around 30%), Rho proteins themselves are generally not found to be mutated in cancer. Rather, misregulation of Rho activity in cancer was thought to occur by overexpression of these proteins or by misregulation of molecules that control Rho activity, such as activation or overexpression of GEFs and inactivation or loss of GAPs or GDIs. Recent studies, enabled by next-generation tumor exome sequencing, report activating point mutations in Rho GTPases as driver mutations in melanoma, as well as breast, and head and neck cancers. The Rac1(P29L) mutation identified in these tumor studies was previously identified by our lab as an activating Rac mutation in C. elegans neuronal development, highlighting the conserved nature of this mutation. Furthermore, this finding supports the relevance of studying Rho GTPases in model organisms such as C. elegans to study the mechanisms that underlie carcinogenesis. This review will describe the recent findings that report activating Rho mutations in various cancer types, moving Rho GTPases from molecules misregulated in cancer to mutagenic targets that drive tumorigenesis.

Keywords: C. elegans; Rho GTPases; cancer.

Publication types

  • Review

MeSH terms

  • Animals
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Mutation
  • Neoplasms / enzymology*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors / genetics
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors / metabolism

Substances

  • Guanine Nucleotide Exchange Factors
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors
  • rac1 GTP-Binding Protein
  • rho GTP-Binding Proteins