Faculty Collaboration Database

RAS and RHO family GTPase mutations in cancer: twin sons of different mothers? Crit Rev Biochem Mol Biol 2020 Aug;55(4):386-407

Date

08/26/2020

Pubmed ID

32838579

DOI

10.1080/10409238.2020.1810622

Scopus ID

2-s2.0-85089736184 (requires institutional sign-in at Scopus site)   33 Citations

Abstract

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.

Author List

Hodge RG, Schaefer A, Howard SV, Der CJ

Author

Antje Schaefer PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Carcinogenesis
Cell Movement
Cell Proliferation
Gain of Function Mutation
Humans
Loss of Function Mutation
Proto-Oncogene Proteins p21(ras)
rac1 GTP-Binding Protein
rhoA GTP-Binding Protein