Fast-cycling Rho GTPases

Abstract

The Rho GTPases were discovered more than 30 years ago, and they were for a long time considered to follow simple cycling between GDP-bound and GTP-bound conformations, as for the Ras subfamily of small GTPases. The Rho GTPases consist of 20 members, but at least 10 of these do not follow this classical GTPase cycle. Thus, based on their kinetic properties, these Rho GTPases can instead be classified as atypical. Some of these atypical Rho GTPases do not hydrolyze GTP, and some have significantly increased intrinsic GDP/GTP exchange activity. This review focuses on this latter category of atypical Rho GTPases, the so-called 'fast-cycling' Rho GTPases. The different members of these fast-cycling atypical Rho GTPases are described in more detail here, along with their potential regulatory mechanisms. Finally, some insights are provided into the involvement of the atypical Rho GTPases in human pathologies.

Keywords: Atypical Rho GTPases; RhoD; RhoU; actin; cell migration; stress fibers.

Figure 1.

(A) The atypical Rho GTPases. (B) The amino-acid sequence over codons 12, 59, and 61 of the atypical Rho GTPases. (C) Phylogenetic tree representation of all of the human Rho GTPases. The dark grey area marks the GTPase deficient Rho GTPases and light grey are marks the fast-cycling Rho GTPases.

Figure 2.

Multiple alignments of the N-termini of the human Rho GTPases, produced using the ClustalW algorithm. *, identical amino-acid residues; :, conserved amino-acid residues. ¤, position of the amino-acid residue equivalent to codon 12 of Rac1; gray shading, APPVPPRR motif of the minimal SH3-domain-binding motif in RhoU.

Figure 3.

Schematic representation of RhoD and RhoF functions. (A) RhoF can trigger formation of filopodia by I-BAR-containing proteins, such as IRTKS, or Diaphanous-related formins (mDia1-3). (B) RhoD binds the Golgi complex component WHAMM, defining a role in Golgi homeostasis. (C) RhoD and its effector Rabankyrin-5 have roles in internalization and trafficking of receptor tyrosine kinanses (RTK), such as the PDGF-β receptor. (D) Under normal conditions, the RhoD:PAK6 complex inhibits ROCK activation by RhoC. (E) Under Vaccinia infection, the virus-derived protein F11 sequesters RhoD, which leads to dissociation of the RhoD:PAK6 complex. Under these conditions, RhoC can induce cell contraction and membrane blebbing in a ROCK-dependent and Myosin II-dependent manner.