The RAS and RHO family comprise two major branches of the RAS superfamily of
small GTPases. These
proteins function as regulated molecular switches and control cytoplasmic signaling networks that regulate a diversity of cellular processes, including cell proliferation and cell migration. In the early 1980s, mutationally activated RAS genes encoding KRAS, HRAS and NRAS were discovered in human
cancer and now comprise the most frequently mutated oncogene family in
cancer. Only recently, exome sequencing studies identified
cancer-associated alterations in two RHO family
GTPases, RAC1 and RHOA. RAS and RHO
proteins share significant identity in their amino acid sequences,
protein structure and biochemistry.
Cancer-associated RAS
mutant proteins harbor missense mutations that are found primarily at one of three mutational hotspots (G12, G13 and Q61) and have been identified as gain-of-function oncogenic alterations. Although these residues are conserved in RHO family
proteins, the gain-of-function mutations found in RAC1 are found primarily at a distinct hotspot. Unexpectedly, the
cancer-associated mutations found with RHOA are located at different hotspots than those found with RAS. Furthermore, since the RHOA mutations suggested a loss-of-function phenotype, it has been unclear whether RHOA functions as an oncogene or
tumor suppressor in
cancer development. Finally, whereas RAS mutations are found in a broad spectrum of
cancer types, RHOA and RAC1 mutations occur in a highly restricted range of
cancer types. In this review, we focus on RHOA missense mutations found in
cancer and their role in driving
tumorigenesis, with comparisons to
cancer-associated mutations in RAC1 and
RAS GTPases.