The RHO Family GTPases: Mechanisms of Regulation and Signaling

Cells. 2021 Jul 20;10(7):1831. doi: 10.3390/cells10071831.

Abstract

Much progress has been made toward deciphering RHO GTPase functions, and many studies have convincingly demonstrated that altered signal transduction through RHO GTPases is a recurring theme in the progression of human malignancies. It seems that 20 canonical RHO GTPases are likely regulated by three GDIs, 85 GEFs, and 66 GAPs, and eventually interact with >70 downstream effectors. A recurring theme is the challenge in understanding the molecular determinants of the specificity of these four classes of interacting proteins that, irrespective of their functions, bind to common sites on the surface of RHO GTPases. Identified and structurally verified hotspots as functional determinants specific to RHO GTPase regulation by GDIs, GEFs, and GAPs as well as signaling through effectors are presented, and challenges and future perspectives are discussed.

Keywords: CDC42; RAC1; RHO signaling; RHOA; RHOGAP; RHOGDI; RHOGEF; effectors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / metabolism
  • Cardiovascular Diseases / pathology
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism
  • Cognition Disorders / pathology
  • Communicable Diseases / genetics
  • Communicable Diseases / metabolism
  • Communicable Diseases / pathology
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism
  • Gene Expression Regulation
  • Humans
  • Multigene Family
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Rho Guanine Nucleotide Exchange Factors / genetics*
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • Signal Transduction
  • cdc42 GTP-Binding Protein / genetics*
  • cdc42 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / genetics*
  • rac1 GTP-Binding Protein / metabolism
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / genetics*
  • rho Guanine Nucleotide Dissociation Inhibitor alpha / metabolism
  • rhoA GTP-Binding Protein / genetics*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • ARHGDIA protein, human
  • GTPase-Activating Proteins
  • Protein Isoforms
  • RAC1 protein, human
  • Rho Guanine Nucleotide Exchange Factors
  • rho GTPase-activating protein
  • rho Guanine Nucleotide Dissociation Inhibitor alpha
  • RHOA protein, human
  • CDC42 protein, human
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein