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.