Snapshot: Rho Family Gtpases Francisco M

SnapShot: Rho Family GTPases Francisco M. Vega and Anne J. Ridley Randall Division of Cell and Molecular Biophysics, King’s College London, London, UK

Rho Localization/ Major GTPase Cellular Functions Roles in Physiology or Disease Knockout Phenotype Modifications Effectors (Human)

RhoA Plasma membrane ROCK I, ROCK Formation of stress fibers, focal adhesions. Promotes transformation, oncogenesis, Unknown (RHOA) (PM) and cytosol/ II, Citron, Cell migration, microtubule stability, cell-cell invasion, and metastasis. Upregulated in geranylgeranylation mDia1,2 adhesion, vesicle trafficking, cytokinesis, human tumors. Smooth muscle contrac- (GG), phosphorylation phagocytosis. tion. Inhibits neurite outgrowth. (PH), ubiquitination (Ub)

RhoB PM, endosomes and PRK/PKN, Formation of stress fibers, focal adhesions. Inhibits tumor growth, cell migration, and Enhanced carcinogen- (RHOB) other intracellular mDia1,2 Endosomal transport. invasion. Downregulated in tumors. induced skin tumor formation Rho membranes/ GG, farnesylation (F), palmitoylation (P)

RhoC PM and cytosol/GG ROCK I, ROCK Formation of stress fibers, focal adhesions, Promotes transformation, oncogenesis, Dispensable for embryogen- (RHOC) II, citron, cell-cell adhesion. invasion, and metastasis. Upregulated in esis but essential for mDia1, FHOD1 tumors. metastasis

Rac1 PM and cytosol/GG PAK1-3, MLK, Formation of lamellipodia, focal complexes. Promotes transformation, oncogenesis, Embryonic lethality (RAC1) IRSp53 Cell migration, microtubule stability, cell-cell metastasis, cell survival. Upregulated in adhesion, vesicle trafficking. Phagocytosis. tumors; Rac1b splice variant expressed in NADPH oxidase activation. tumors. Myoblast fusion.

Rac2 PM and cytosol/GG PAK1-3 Formation of lamellipodia, focal complexes. Upregulated in tumors. Hematopoietic cell defects (RAC2) NADPH oxidase activation, cell migration. Rac Rac3 PM and endomem- PAK1-3 Formation of lamellipodia, focal complexes. Hyperactive or upregulated in breast Affects nervous system (RAC3) branes/GG cancer. Neurite outgrowth. function

RhoG PM, endosomes, ELMO, Kinectin Formation of lamellipodia, membrane Weak transforming activity. Prevents Ras Mild immunological defect (RHOG) and mitocondria/GG ruffles, focal complexes. Cell migration, transformation of fibroblasts. Neurite (predicted) phagocytosis. NADPH oxidase activation. outgrowth.

Cdc42 PM and Golgi/GG WASP, N- Formation of filopodia. Vesicle trafficking, Weak transforming activity. Upregulated in Early embryonic lethality. (CDC42) (predicted) WASP, PAK1-6, cell polarity, migration, cytokinesis, breast cancer. Epidermal differentiation, mDia2 phagocytosis. neural progenitor defects.

TC10 PM, perinuclear, endo- PAK1-3, WASP Formation of filopodia and lamellipodium- Promotes transformation, anchor- Not available (RHOQ) somes; colocalizes with like structures different from Cdc42. age-independent growth. Adipocyte actin filaments/ differentiation. F, GG, and P (predicted)

TCL PM and endosomes/ PAK1-3, WASP Formation of lamellipodia/filopodia longer Adipocyte differentiation. Not available (RHOJ) F, GG, P (predicted) than Cdc42, stress fibers, dorsal ruffles. Cdc42 Chp/Wrch2 PM and WASP, N- Formation of filopodia. Promotes transformation, upregulated in Not available (RHOV) endomembranes/P WASP, PAK1-3 tumors.

Wrch1 PM and Does not bind Formation of filopodia, stress fibers. Promotes Wnt-driven oncogenic trans- Not available (RHOU) endomembranes/P to WASP, N- formation, cell-cycle progression. Blocks WASP, PAK TNFα-mediated signaling. Upregulated or downregulated in primary tumors. Dif- ferentiation of muscle cells.

Rnd1 PM/F (predicted) Socius Loss of stress fibers, focal adhesions. Implicated in smooth-muscle contractility Not available (RND1) No GTPase activity. and axon guidance.

Rnd2 Endosomes and Rapostlin, No known effect on actin cytoskeleton. Regulates neurite outgrowth. Not available (RND2) cytosol/F (predicted) Pragmin No GTPase activity.

Rnd Rnd3/RhoE PM, Golgi, and cytosol/ ROCKI, Loss of stress fibers and focal adhesions. Inhibits cell-cycle progression, trans- Not available (RND3) F, PH p190RhoGAP, Cell migration, cell-cell adhesion. No formation, smooth muscle contraction. Socius GTPase activity. p53-regulated prosurvival factor. Down- regulated in prostate cancer, upregulated in other tumors. Neurite outgrowth.

RhoD PM and endosomes/ mDia3 Stress fibers, focal adhesion dynamics. Cell Cancer cell invasion. Not available (RHOD) GG, F (predicted) migration, vesicle trafficking, cytokinesis. RhoD

Rif/RhoF PM/GG (predicted) mDia2 Formation of stress fibers, Cdc42- Upregulated in follicular lymphomas. Not available (RHOF) independent filopodia. RhoF

RhoH/TTF ?/GG (predicted) ? Inhibits actin polymerization. No GTPase Inhibits proliferation and migration, en- T cell deficiency; essential (RHOH) activity. hances apoptosis. Mutated in lymphomas. for TCR signaling, thymocyte

RhoH maturation

RhoBTB1 vesicular/? ? No known effect on cytoskeleton. No Upregulated in cancer cell lines. Not available (RHOBTB1) GTPase activity.

RhoBTB2/ vesicular/? ? No known effect on cytoskeleton. Protein Candidate tumor suppressor gene. Not available DBC2 transport. No GTPase activity. RhoBTB (RHOBTB2)

Miro-1 Mitochondria/? ? No known effect on actin cytoskeleton. Induces apoptosis. Not available (RHOT1) Mitochondrial homeostasis, axonal transport.

Miro Miro-2 Mitochondria/? ? No known effect on cytoskeleton. Induces apoptosis. Not available (RHOT2) Mitochondrial homeostasis, axonal transport.

430 Cell 129, June 29, 2007 ©2007 Elsevier Inc. DOI 10.1016/j.cell.2007.06.021 See online version for legend, references, and abbreviations. SnapShot: Rho Family GTPases Francisco M. Vega and Anne J. Ridley Randall Division of Cell and Molecular Biophysics, King’s College London, London, UK

Rho GTPases were first characterized as regulators of actin dynamics. They activate two types of actin nucleators, WASP/WAVE proteins and Diaphanous-related formins, and induce the formation of dynamic actin-containing structures such as lamellipodia, filopodia, and stress fibers. Through these effects, they coordinate cell migration and neurite outgrowth and affect development, immune responses, inflammation, and cancer invasion and metastasis. Their ability to interact with membranes also allows them to target actin polymerization to intracellular membrane compartments and thereby regulate vesicle movement. Subsequent studies have revealed that Rho GTPases affect a variety of other cellular processes, including cell-cell adhesion, microtubule dynamics, and cell cycle progression. Most studies have concentrated on just 3 of the 22 mammalian Rho proteins: RhoA, Rac1, and Cdc42. However, recent research indicates that most other members of the Rho family affect the actin cytoskeleton and that several have more specialized functions.

Abbreviations F, farnesylation; GG, geranylgeranylation; P, palmitoylation; PH, phosphorylation; PM, plasma membrane; Ub, ubiquitination.

References

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