Trends in Cell Biology
Review
Special issue: Membrane DynamicsRho GTPases and actin dynamics in membrane protrusions and vesicle trafficking
Special issue: Membrane Dynamics
Introduction
Rho GTPases are found in all eukaryotic organisms and regulate cell polarity and motility through their effects on the cytoskeleton, membrane trafficking and cell adhesion 1, 2. In mammals there are 22 Rho GTPases (Table 1), many of which affect cell morphology 1, 3, 4. In yeasts and plants, several Rho GTPases contribute directly to polarized cell growth by affecting the actin cytoskeleton 5, 6, 7.
Most Rho GTPases act on membranes and affect the movement of these membranes by changing the membrane-associated actin cytoskeleton. The best-studied members of the family are RhoA, Rac1 and Cdc42, and in mammalian cells Rac1 and Cdc42 have long been known to induce plasma membrane protrusions known as lamellipodia and filopodia by stimulating actin polymerization. Other Rho GTPases, including RhoG, RhoD, TC10 and Rif (also called RhoF), can also induce actin-based protrusions at the plasma membrane 3, 8, 9. On the other hand, several Rho GTPases, including RhoA, RhoB, RhoD and Cdc42, affect specific steps of vesicle trafficking between different intracellular compartments, for example exocytosis or Golgi-to-endoplasmic reticulum (ER) transport and, as with plasma membrane protrusion, their ability to induce actin polymerization is important for these activities 10, 11.
Here, I discuss the regulation and localization of Rho GTPases, how they induce different types of actin filament organization and how this in turn affects both plasma membrane protrusion and vesicle trafficking.
Section snippets
Regulation and localization of Rho GTPases
Most Rho family proteins can bind to GTP and GDP and have intrinsic GTPase activity. In their GTP-bound conformation they interact with and activate downstream target proteins. Their activity is regulated by guanine nucleotide exchange factors (GEFs), which stimulate release of GDP, allowing GTP to bind. They are down-regulated by GTPase-activated proteins (GAPs), which catalyse GTP hydrolysis, converting the proteins to the GDP-bound inactive conformation. Exceptions are Rnd1, Rnd2, Rnd3 (also
Rho GTPases and actin polymerization
Rho GTPases activate two different kinds of molecules that directly stimulate actin polymerization, WASP/WAVE proteins and Diaphanous-related formins (DRFs; Box 2). Although RhoA, Rac1 and Cdc42 have been most studied for their effects on these proteins, other Rho GTPases interact with DRFs (Table 2). WASP/WAVE proteins induce actin polymerization via the Arp2/3 complex, which stimulates the formation of a new actin filament branching off an existing filament (Box 2) [26]. Cdc42 binds directly
Rho GTPases and plasma membrane dynamics
Rho GTPases are believed to stimulate plasma membrane protrusion by inducing actin filament nucleation and polymerization on or close to membranes. This process has been studied extensively in vitro using beads or membrane vesicles with portions of actin-nucleating proteins attached [26].
Rho GTPases and vesicle trafficking
Several Rho GTPases localize to specific intracellular membrane compartments in addition to or instead of the plasma membrane (Table 1), and for some of these there is good evidence that their principal site of action is likely to be on these compartments.
Rho GTPases and polarized membrane growth in plants
Studies on Rho homologues in plants have provided new insight into the links between the actin cytoskeleton and membrane dynamics. Plants have Rho-related proteins known as ROPs (Rho-of-plants) or RACs, several of which affect membrane trafficking 5, 6. Plants have homologues of mammalian Rho targets including WAVEs, formins, phospholipase D and NADPH oxidase, although it is not clear whether plant formins interact with ROPs [92]. In Arabidopsis, constitutively active AtRAC10 induces
Conclusions and future perspectives
By stimulating actin dynamics, Rho GTPases induce plasma membrane protrusion and regulate vesicle trafficking. The two types of Rho-regulated actin nucleators, WASPs/WAVEs and DRFs, induce a branching actin filament network or parallel filaments, respectively, and thus contribute to different types of membrane protrusion: WAVEs (but probably not WASPs) to lamellipodia and DRFs to filopodia. WASPs and DRFs also seem to have distinct roles in vesicle trafficking: WASPs facilitate membrane
References (108)
Small GTPases in vesicle trafficking
Curr. Opin. Plant Biol.
(2004)- et al.
Cell polarity: ROPing the ends together
Curr. Opin. Plant Biol.
(2005) - et al.
The novel Rho-family GTPase rif regulates coordinated actin-based membrane rearrangements
Curr. Biol.
(2000) Actin dynamics at the Golgi complex in mammalian cells
Curr. Opin. Cell Biol.
(2006)Coupling actin and membrane dynamics during calcium-regulated exocytosis: a role for Rho and ARF GTPases
Biochim. Biophys. Acta
(2004)- et al.
GDIs: central regulatory molecules in Rho GTPase activation
Trends Cell Biol.
(2005) RhoGDI is required for Cdc42-mediated cellular transformation
Curr. Biol.
(2003)- et al.
Protein complexes regulating Arp2/3-mediated actin assembly
Curr. Opin. Cell Biol.
(2006) Molecular details of formin-mediated actin assembly
Curr. Opin. Cell Biol.
(2006)Formin proteins: a domain-based approach
Trends Biochem. Sci.
(2005)
The Rho family GTPase Rif induces filopodia through mDia2
Curr. Biol.
Cofilin phosphatases and regulation of actin dynamics
Curr. Opin. Cell Biol.
Regulation and cellular roles of phosphoinositide 5-kinases
Eur. J. Pharmacol.
Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia
Cell
N-WASP and WAVE2 acting downstream of phosphatidylinositol 3-kinase are required for myogenic cell migration induced by hepatocyte growth factor
J. Biol. Chem.
Cellular motility driven by assembly and disassembly of actin filaments
Cell
Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO
Curr. Biol.
The sensory-motor role of growth cone filopodia
Curr. Opin. Neurobiol.
Disruption of the Diaphanous-related formin Drf1 gene encoding mDia1 reveals a role for Drf3 as an effector for Cdc42
Curr. Biol.
ERM proteins: from cellular architecture to cell signaling
Biol. Cell.
Lymphocyte microvilli are dynamic, actin-dependent structures that do not require Wiskott-Aldrich syndrome protein (WASp) for their morphology
Blood
Membrane trafficking at the ER/Golgi interface: functional implications of RhoA and Rac1
Eur. J. Cell Biol.
Mammalian Cdc42 is a brefeldin A-sensitive component of the Golgi apparatus
J. Biol. Chem.
Characterization of the association of the actin-binding protein, IQGAP, and activated Cdc42 with Golgi membranes
J. Biol. Chem.
IQGAP1 in cellular signaling: bridging the GAP
Trends Cell Biol.
Control of vesicular trafficking by Rho GTPases
Curr. Biol.
Tuba, a novel protein containing bin/amphiphysin/Rvs and Dbl homology domains, links dynamin to regulation of the actin cytoskeleton
J. Biol. Chem.
Regulation of cystic fibrosis transmembrane regulator trafficking and protein expression by a Rho family small GTPase TC10
J. Biol. Chem.
Synaptojanin 2, a novel Rac1 effector that regulates clathrin-mediated endocytosis
Curr. Biol.
ARAP1: a point of convergence for Arf and Rho signaling
Mol. Cell
ARAP3 is a PI3K- and rap-regulated GAP for RhoA
Curr. Biol.
Phospholipase D and membrane traffic. Potential roles in regulated exocytosis, membrane delivery and vesicle budding
Biochim. Biophys. Acta
Regulation of epidermal growth factor receptor traffic by the small GTPase rhoB
Curr. Biol.
RhoB and actin polymerization coordinate Src activation with endosome-mediated delivery to the membrane
Dev. Cell
Diaphanous-related formins bridge Rho GTPase and Src tyrosine kinase signaling
Mol. Cell
DBC2 significantly influences cell-cycle, apoptosis, cytoskeleton and membrane-trafficking pathways
J. Mol. Biol.
Formins: intermediates in signal-transduction cascades that affect cytoskeletal reorganization
Trends Plant Sci.
Regulation of microtubules in cell migration
Trends Cell Biol.
Rho GTPases: biochemistry and biology
Annu. Rev. Cell Dev. Biol.
Comparative and evolutionary analysis of genes encoding small GTPases and their activating proteins in eukaryotic genomes
Physiol. Genomics
Rho GTPases have diverse effects on the organization of the actin filament system
Biochem. J.
Rho-family GTPases: it's not only Rac and Rho (and I like it)
J. Cell Sci.
Mechanisms of polarized growth and organelle segregation in yeast
Annu. Rev. Cell Dev. Biol.
Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth
Oncogene
Function and regulation of Rnd proteins
Nat. Rev. Mol. Cell Biol.
RhoE binds to ROCK I and inhibits downstream signaling
Mol. Cell. Biol.
RhoE function is regulated by ROCK I-mediated phosphorylation
EMBO J.
GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors
Nat. Rev. Mol. Cell Biol.
Intracellular localization of the P21rho proteins
J. Cell Biol.
Multiple sequence elements facilitate Chp Rho GTPase subcellular location, membrane association, and transforming activity
Mol Biol Cell
Cited by (932)
Implication of Rac1 GTPase in molecular and cellular mitochondrial functions
2024, Life Sciences