Signaling by Rho GTPases

Stable Identifier
Homo sapiens
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The Rho family of small guanine nucleotide binding proteins is one of seven phylogenetic branches of the Ras superfamily (Bernards 2005), which, besides Rho, Miro and RHOBTB3 also includes Ran, Arf, Rab and Ras families (Boureux et al. 2007). Miro GTPases and RHOBTB3 ATPase are sometimes described as Rho family members, but they are phylogenetically distinct (Boureux et al. 2007). Phylogenetically, RHO GTPases can be grouped into four clusters. The first cluster consists of three subfamilies: Rho, RhoD/RhoF and Rnd. The second cluster consists of three subfamilies: Rac, Cdc42 and RhoU/RhoV. The third cluster consists of the RhoH subfamily. The fourth cluster consists of the RhoBTB subfamily. Based on their activation type, RHO GTPases can be divided into classical (typical) and atypical (reviewed by Haga and Ridley 2016, and Kalpachidou et al. 2019). Classical RHO GTPases cycle between active GTP-bound states and inactive GDP-bound states through steps that are tightly controlled by members of three classes of proteins: (1) guanine nucleotide dissociation inhibitors or GDIs, which maintain Rho proteins in an inactive state in the cytoplasm, (2) guanine nucleotide exchange factors or GEFs, which destabilize the interaction between Rho proteins and their bound nucleotide, the net result of which is the exchange of bound GDP for the more abundant GTP, and (3) GTPase activating proteins or GAPs, which stimulate the low intrinsic GTP hydrolysis activity of Rho family members, thus promoting their inactivation. GDIs, GEFs, and GAPs are themselves subject to tight regulation, and the overall level of Rho activity reflects the balance of their activities. Many of the Rho-specific GEFs, GAPs, and GDIs act on multiple Rho GTPases, so that regulation of these control proteins can have complex effects on the functions of multiple Rho GTPases (reviewed by Van Aelst and D'Souza-Schorey 1997, Schmidt and Hall 2002, Jaffe and Hall 2005, Bernards 2005, and Hodge and Ridley 2016). Classical RHO GTPases include four subfamilies: Rho (includes RHOA, RHOB and RHOC), Rac (includes RAC1, RAC2, RAC3 and RHOG), Cdc42 (includes CDC42, RHOJ and RHOQ) and RhoD/RhoF (includes RHOD and RHOF) (reviewed in Haga and Ridley 2016). Atypical RHO GTPases do not possess GTPase activity. They therefore constitutively exist in the active GTP-bound state. Atypical RHO GTPases include three subfamilies: Rnd (includes RND1, RND2 and RND3), RhoBTB (includes RHOBTB1 and RHOBTB2), RhoH (RHOH is the only member) and RhoU/RhoV (includes RHOU and RHOV). Members of the Rho family have been identified in all eukaryotes. Among Rho GTPases, RHOA, RAC1 and CDC42 have been most extensively studied.

RHO GTPases regulate cell behavior by activating a number of downstream effectors that regulate cytoskeletal organization, intracellular trafficking and transcription (reviewed by Sahai and Marshall 2002). They are best known for their ability to induce dynamic rearrangements of the plasma membrane-associated actin cytoskeleton (Aspenstrom et al. 2004; Murphy et al. 1999; Govek et al. 2005). Beyond this function, Rho GTPases also regulate actomyosin contractility and microtubule dynamics. Rho mediated effects on transcription and membrane trafficking are believed to be secondary to these functions. At the more macroscopic level, Rho GTPases have been implicated in many important cell biological processes, including cell growth control, cytokinesis, cell motility, cell-cell and cell-extracellular matrix adhesion, cell transformation and invasion, and development (Govek et al., 2005). One of the best studied RHO GTPase effectors are protein kinases ROCK1 and ROCK2, which phosphorylate many proteins involved in the stabilization of actin filaments and generation of actin-myosin contractile force, such as LIM kinases and myosin regulatory light chains (MRLC) (reviewed in Riento and Ridley 2003). The p21-activated kinase family, which includes PAK1, PAK2 and PAK3, is another well characterized family of RHO GTPase effectors involved in cytoskeleton regulation (reviewed in Daniels and Bokoch 1999, Szczepanowska 2009). Protein kinase C related kinases (PKNs), PKN1, PKN2 and PKN3 play important roles in cytoskeleton organization (Hamaguchi et al. 2000), regulation of cell cycle (Misaki et al. 2001), receptor trafficking (Metzger et al. 2003), apoptosis (Takahashi et al. 1998), and transcription (Metzger et al. 2003, Metzger et al. 2005, Metzger et al. 2008). Citron kinase (CIT) is involved in Golgi apparatus organization through regulation of the actin cytoskeleton (Camera et al. 2003) and in the regulation of cytokinesis (Gruneberg et al. 2006, Bassi et al. 2013, Watanabe et al. 2013). Kinectin (KTN1), a kinesin anchor protein, is a RHO GTPase effector involved in kinesin-mediated vesicle motility (Vignal et al. 2001, Hotta et al. 1996), including microtubule-dependent lysosomal transport (Vignal et al. 2001). IQGAP proteins, IQGAP1, IQGAP2 and IQGAP3, are RHO GTPase effectors that modulate cell shape and motility through regulation of G-actin/F-actin equilibrium (Brill et al. 1996, Fukata et al. 1997, Bashour et al. 1997, Wang et al. 2007, Pelikan-Conchaudron et al. 2011), regulate adherens junctions (Kuroda et al. 1998, Hage et al. 2009), and contribute to cell polarity and lamellipodia formation (Fukata et al. 2002, Suzuki and Takahashi 2008). WASP and WAVE proteins (reviewed by Lane et al. 2014), as well as formins (reviewed by Kuhn and Geyer 2014), are RHO GTPase effectors that regulate actin polymerization and play important roles in cell motility, organelle trafficking and mitosis. Rhotekin (RTKN) and rhophilins (RHPN1 and RHPN2) are RHO GTPase effectors that regulate the organization of the actin cytoskeleton and are implicated in the establishment of cell polarity, cell motility and possibly endosome trafficking (Sudo et al. 2006, Watanabe et al. 1996, Fujita et al. 2000, Peck et al. 2002, Mircescu et al. 2002). Cytoskeletal changes triggered by the activation of formins (Miralles et al. 2003) and RTKN (Reynaud et al. 2000) may lead to stimulation of SRF-mediated transcription. NADPH oxidase complexes 1, 2 and 3 (NOX1, NOX2 and NOX3), membrane associated enzymatic complexes that use NADPH as an electron donor to reduce oxygen and produce superoxide (O2-), are also regulated by RHO GTPases (Knaus et al. 1991, Roberts et al. 1999, Kim and Dinauer 2001, Jyoti et al. 2014, Cheng et al. 2006, Miyano et al. 2006, Ueyama et al. 2006). Every RHO GTPase activates multiple downstream effectors and most effectors are regulated by multiple RHO GTPases, resulting in an elaborate cross-talk.

Literature References
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Marshall, CJ, Sahai, E

Nat. Rev. Cancer 2002
9751706 Proteolytic activation of PKN by caspase-3 or related protease during apoptosis

Miyamoto, M, Toshimori, M, Mukai, H, Takahashi, M, Ono, Y

Proc. Natl. Acad. Sci. U.S.A. 1998
17244649 IQGAP3, a novel effector of Rac1 and Cdc42, regulates neurite outgrowth

Kaibuchi, K, Arimura, N, Fukata, M, Yoshimura, T, Noritake, J, Nakagawa, M, Matsuura, Y, Itoh, N, Watanabe, T, Wang, S, Harada, T

J. Cell. Sci. 2007
23875749 Interaction of inducible nitric oxide synthase with rac2 regulates reactive oxygen and nitrogen species generation in the human neutrophil phagosomes: implication in microbial killing

Chandra, T, Dubey, M, Kumar, S, Keshari, RS, Jyoti, A, Verma, A, Saluja, R, Kumar, A, Singh, AK, Bajpai, VK, Dikshit, M, Barthwal, MK

Antioxid. Redox Signal. 2014
15630019 The role of the Rho GTPases in neuronal development

Newey, SE, Govek, EE, Van Aelst, L

Genes Dev 2005
12618308 GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila

Bernards, A

Biochim Biophys Acta 2003
16757309 Ras superfamily and interacting proteins database

Bernards, A

Methods Enzymol 2005
8798539 Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1

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J. Biol. Chem. 1996
21730051 The IQGAP1 protein is a calmodulin-regulated barbed end capper of actin filaments: possible implications in its function in cell migration

Carlier, MF, Didry, D, Pelikan-Conchaudron, A, Le Clainche, C

J. Biol. Chem. 2011
24969695 Structure and role of WASP and WAVE in Rho GTPase signalling in cancer

Jiang, WG, Martin, T, Weeks, HP, Lane, J

Cancer Genomics Proteomics 2014
16762923 Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1

Takeya, R, Miyano, K, Sumimoto, H, Ueno, N

J. Biol. Chem. 2006
10072071 Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense

Kim, C, Zhen, L, Kapur, R, Dinauer, MC, Petryniak, B, Williams, DA, Roberts, AW, Spaetti, A, Pollock, JD, Lowe, JB, Borneo, JB, Bradford, GB, Atkinson, SJ

Immunity 1999
16507994 Involvement of Rac1 in activation of multicomponent Nox1- and Nox3-based NADPH oxidases

Geiszt, M, Ueyama, T, Leto, TL

Mol. Cell. Biol. 2006
23716662 Citron kinase controls a molecular network required for midbody formation in cytokinesis

Bassi, ZI, D'Avino, PP, Riparbelli, MG, Audusseau, M, Callaini, G

Proc. Natl. Acad. Sci. U.S.A. 2013
16431929 KIF14 and citron kinase act together to promote efficient cytokinesis

Chalamalasetty, RB, Neef, R, Barr, FA, Nigg, EA, Chan, EH, Gruneberg, U, Li, X

J. Cell Biol. 2006
16636067 Nox1-dependent reactive oxygen generation is regulated by Rac1

Lambeth, JD, Diebold, BA, Hughes, Y, Cheng, G

J. Biol. Chem. 2006
24914801 Formins as effector proteins of Rho GTPases

Kühn, S, Geyer, M

Small GTPases 2014
23444367 Citron kinase mediates transition from constriction to abscission through its coiled-coil domain

Narumiya, S, Ishizaki, T, De Zan, T, Watanabe, S

J. Cell. Sci. 2013
14595335 Citron-N is a neuronal Rho-associated protein involved in Golgi organization through actin cytoskeleton regulation

Di Cunto, F, Imarisio, S, Ferrara, L, Camera, P, da Silva, JS, Schubert, V, Griffiths, G, Dotti, CG, Silengo, L, Giuffrida, MG

Nat. Cell Biol. 2003
19737400 Rac1 activation inhibits E-cadherin-mediated adherens junctions via binding to IQGAP1 in pancreatic carcinoma cells

Giehl, K, Baum, I, Menke, A, Hage, B, Meinel, K

Cell Commun. Signal 2009
8769096 Interaction of the Rho family small G proteins with kinectin, an anchoring protein of kinesin motor

Mino, A, Kohno, H, Hotta, K, Takai, Y, Tanaka, K

Biochem. Biophys. Res. Commun. 1996
18066052 Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation

Kunowska, N, Patnaik, D, Schüle, R, Metzger, E, Wissmann, M, Potier, N, Scheidtmann, KH, Higgins, JM, Friedrichs, N, Buettner, R, Fischer, K, Yin, N

Nat. Cell Biol. 2008
10470034 p21-activated protein kinase: a crucial component of morphological signaling?

Bokoch, GM, Daniels, RH

Trends Biochem Sci 1999
10591629 Ropporin, a sperm-specific binding protein of rhophilin, that is localized in the fibrous sheath of sperm flagella

Nakamura, K, Mizoguchi, A, Fujita, A, Kato, T, Narumiya, S, Kimura, K, Ishizaki, T, Watanabe, N

J. Cell. Sci. 2000
16212495 Rho GTPases: biochemistry and biology

Hall, A, Jaffe, AB

Annu Rev Cell Dev Biol 2005
9368021 Regulation of cross-linking of actin filament by IQGAP1, a target for Cdc42

Kikuchi, A, Kaibuchi, K, Fukata, M, Kuroda, S, Nakamura, T, Shoji, I, Fujii, K, Matsuura, Y, Okawa, K, Iwamatsu, A

J. Biol. Chem. 1997
12101119 Guanine nucleotide exchange factors for Rho GTPases: turning on the switch

Hall, A, Schmidt, A

Genes Dev 2002
19513348 Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements

Szczepanowska, J

Acta Biochim Pol 2009
12514133 A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer

Schüle, R, Metzger, E, Müller, JM, Ferrari, S, Buettner, R

EMBO J. 2003
27628050 Rho GTPases: Regulation and roles in cancer cell biology

Ridley, AJ, Haga, RB

Small GTPases 2016
10445846 Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth

Der, CJ, Jillian, SA, Solski, PA, Rush, MG, Perez de la Ossa, P, D'Eustachio, P, Murphy, GA

Oncogene 1999
18237546 Regulation of lamellipodia formation and cell invasion by CLIP-170 in invasive human breast cancer cells

Takahashi, K, Suzuki, K

Biochem. Biophys. Res. Commun. 2008
12110184 Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170

Kaibuchi, K, Kuroda, S, Fukata, M, Noritake, J, Nakagawa, M, Matsuura, Y, Watanabe, T, Yamaga, M, Perez, F, Iwamatsu, A

Cell 2002
9308960 Rho GTPases and signaling networks

D'Souza-Schorey, C, Van Aelst, L

Genes Dev 1997
11689693 Kinectin is a key effector of RhoG microtubule-dependent cellular activity

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Mol. Cell. Biol. 2001
12473120 Identification and characterization of a novel activated RhoB binding protein containing a PDZ domain whose expression is specifically modulated in thyroid cells by cAMP

Steuve, S, Dumont, JE, Mircescu, H, Degraef, C, Pirson, I, Mellor, H, Maenhaut, C, Savonet, V

Eur. J. Biochem. 2002
8756646 The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases

Li, S, Church, DM, Weissbach, L, Wasmuth, JJ, Lyman, CW, Snijders, AJ, Bernards, A, Brill, S

Mol. Cell. Biol. 1996
1660188 Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2

Bokoch, GM, Curnutte, JT, Evans, T, Knaus, UG, Heyworth, PG

Science 1991
11134534 PKN delays mitotic timing by inhibition of Cdc25C: possible involvement of PKN in the regulation of cell division

Misaki, K, Kishimoto, T, Ohsumi, K, Oishi, K, Takahashi, M, Isagawa, T, Mukai, H, Yoshinaga, C, Ono, Y

Proc. Natl. Acad. Sci. U.S.A. 2001
12778124 Rocks: multifunctional kinases in cell behaviour

Ridley, AJ, Riento, K

Nat Rev Mol Cell Biol 2003
12732141 Actin dynamics control SRF activity by regulation of its coactivator MAL

Posern, G, Treisman, R, Miralles, F, Zaromytidou, AI

Cell 2003
27301673 Regulating Rho GTPases and their regulators

Ridley, AJ, Hodge, RG

Nat. Rev. Mol. Cell Biol. 2016
10924361 Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N

Hartshorne, DJ, Kaibuchi, K, Seko, T, Ito, M, Feng, J, Nakano, T, Takase, K, Machida, H, Koyama, M, Hamaguchi, T, Amano, M

Biochem. Biophys. Res. Commun. 2000
9199170 IQGAP1, a Rac- and Cdc42-binding protein, directly binds and cross-links microfilaments

Bloom, GS, Fullerton, AT, Hart, MJ, Bashour, AM

J. Cell Biol. 1997
31208035 Rho GTPases in the Physiology and Pathophysiology of Peripheral Sensory Neurons

Kress, M, Quarta, S, Kalpachidou, T, Spiecker, L

Cells 2019
16979770 Identification of a cell polarity-related protein, Lin-7B, as a binding partner for a Rho effector, Rhotekin, and their possible interaction in neurons

Morishita, R, Ito, H, Nagata, K, Sudo, K, Iwamoto, I, Asano, T

Neurosci. Res. 2006
11145705 Rac2 is an essential regulator of neutrophil nicotinamide adenine dinucleotide phosphate oxidase activation in response to specific signaling pathways

Kim, C, Dinauer, MC

J. Immunol. 2001
16079795 LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription

Peters, AH, Schüle, R, Metzger, E, Müller, JM, Wissmann, M, Schneider, R, Buettner, R, Günther, T, Yin, N

Nature 2005
8571126 Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho

Madaule, P, Kakizuka, A, Mukai, H, Fujisawa, K, Narumiya, S, Watanabe, G, Ishizaki, T, Saito, Y, Morii, N, Ono, Y

Science 1996
12221077 The RhoA-binding protein, rhophilin-2, regulates actin cytoskeleton organization

Bouker, KB, Burbelo, PD, Peck, JW, Oberst, M, Bowden, E

J. Biol. Chem. 2002
14521508 Rho GTPases have diverse effects on the organization of the actin filament system

Aspenstrom, P, Saras, J, Fransson, A

Biochem J 2004
10940294 The PDZ protein TIP-1 interacts with the Rho effector rhotekin and is involved in Rho signaling to the serum response element

Fabre, S, Reynaud, C, Jalinot, P

J. Biol. Chem. 2000
17035353 Evolution of the Rho family of ras-like GTPases in eukaryotes

Fort, P, Faure, S, Vignal, E, Boureux, A

Mol Biol Evol 2007
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