Reactome | Signaling by Rho GTPases

Signaling by Rho GTPases

Stable Identifier

R-HSA-194315

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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

PubMed ID	Title	Journal	Year
12778124	Rocks: multifunctional kinases in cell behaviour Ridley, AJ, Riento, K	Nat Rev Mol Cell Biol	2003
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
27301673	Regulating Rho GTPases and their regulators Ridley, AJ, Hodge, RG	Nat. Rev. Mol. Cell Biol.	2016
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
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
24914801	Formins as effector proteins of Rho GTPases Kühn, S, Geyer, M	Small GTPases	2014
31208035	Rho GTPases in the Physiology and Pathophysiology of Peripheral Sensory Neurons Kress, M, Quarta, S, Kalpachidou, T, Spiecker, L	Cells	2019
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
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
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
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
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
10470034	p21-activated protein kinase: a crucial component of morphological signaling? Bokoch, GM, Daniels, RH	Trends Biochem Sci	1999
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
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19513348	Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements Szczepanowska, J	Acta Biochim Pol	2009
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
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
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
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
9308960	Rho GTPases and signaling networks D'Souza-Schorey, C, Van Aelst, L	Genes Dev	1997
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
12618308	GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila Bernards, A	Biochim Biophys Acta	2003
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
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
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17035353	Evolution of the Rho family of ras-like GTPases in eukaryotes Fort, P, Faure, S, Vignal, E, Boureux, A	Mol Biol Evol	2007
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
12101119	Guanine nucleotide exchange factors for Rho GTPases: turning on the switch Hall, A, Schmidt, A	Genes Dev	2002
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
16212495	Rho GTPases: biochemistry and biology Hall, A, Jaffe, AB	Annu Rev Cell Dev Biol	2005
16507994	Involvement of Rac1 in activation of multicomponent Nox1- and Nox3-based NADPH oxidases Geiszt, M, Ueyama, T, Leto, TL	Mol. Cell. Biol.	2006
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
15630019	The role of the Rho GTPases in neuronal development Newey, SE, Govek, EE, Van Aelst, L	Genes Dev	2005
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
11689693	Kinectin is a key effector of RhoG microtubule-dependent cellular activity Blangy, A, Gauthier-Rouvière, C, Vignal, E, Martin, M, Fort, P	Mol. Cell. Biol.	2001
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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
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8798539	Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1 Kobayashi, K, Kaibuchi, K, Fukata, M, Kuroda, S, Nakafuku, M, Nomura, N, Iwamatsu, A	J. Biol. Chem.	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
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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
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
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