Reactome | RHO GTPase Effectors

RHO GTPase Effectors

Stable Identifier

R-HSA-195258

DOI

10.3180/REACT_355444.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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RHO GTPases regulate cell behaviour by activating a number of downstream effectors that regulate cytoskeletal organization, intracellular trafficking and transcription (reviewed by Sahai and Marshall 2002).

One of the best studied RHO GTPase effectors are protein kinases ROCK1 and ROCK2, which are activated by binding RHOA, RHOB or RHOC. ROCK1 and ROCK2 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) (Amano et al. 1996, Ishizaki et al. 1996, Leung et al. 1996, Ohashi et al. 2000, Sumi et al. 2001, Riento and Ridley 2003, Watanabe et al. 2007).

PAK1, PAK2 and PAK3, members of the p21-activated kinase family, are activated by binding to RHO GTPases RAC1 and CDC42 and subsequent autophosphorylation and are involved in cytoskeleton regulation (Manser et al. 1994, Manser et al. 1995, Zhang et al. 1998, Edwards et al. 1999, Lei et al. 2000, Parrini et al. 2002; reviewed by Daniels and Bokoch 1999, Szczepanowska 2009).

RHOA, RHOB, RHOC and RAC1 activate protein kinase C related kinases (PKNs) PKN1, PKN2 and PKN3 (Maesaki et al. 1999, Zong et al. 1999, Owen et al. 2003, Modha et al. 2008, Hutchinson et al. 2011, Hutchinson et al. 2013), bringing them in proximity to the PIP3-activated PDPK1 (PDK1) and thus enabling PDPK1-mediated phosphorylation of PKN1, PKN2 and PKN3 (Flynn et al. 2000, Torbett et al. 2003). PKNs play important roles in cytoskeleton organization (Hamaguchi et al. 2000), regulation of cell cycle (Misaki et al. 2001), receptor trafficking (Metzger et al. 2003) and apoptosis (Takahashi et al. 1998). PKN1 is also involved in the ligand-dependent transcriptional activation by the androgen receptor (Metzger et al. 2003, Metzger et al. 2005, Metzger et al. 2008).

Citron kinase (CIT) binds RHO GTPases RHOA, RHOB, RHOC and RAC1 (Madaule et al. 1995), but the mechanism of CIT activation by GTP-bound RHO GTPases has not been elucidated. CIT and RHOA are implicated to act together in Golgi apparatus organization through regulation of the actin cytoskeleton (Camera et al. 2003). CIT is also involved in the regulation of cytokinesis through its interaction with KIF14 (Gruneberg et al. 2006, Bassi et al. 2013, Watanabe et al. 2013).

RHOA, RHOG, RAC1 and CDC42 bind kinectin (KTN1), a kinesin anchor protein involved in kinesin-mediated vesicle motility (Vignal et al. 2001, Hotta et al. 1996). The effect of RHOG activity on cellular morphology, exhibited in the formation of microtubule-dependent cellular protrusions, depends both on RHOG interaction with KTN1, as well as on the kinesin activity (Vignal et al. 2001). RHOG and KTN1 also cooperate in microtubule-dependent lysosomal transport (Vignal et al. 2001).

IQGAP proteins IQGAP1, IQGAP2 and IQGAP3, bind RAC1 and CDC42 and stabilize them in their GTP-bound state (Kuroda et al. 1996, Swart-Mataraza et al. 2002, Wang et al. 2007). IQGAPs bind F-actin filaments and 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). Binding of IQGAPs to F-actin is inhibited by calmodulin (Bashour et al. 1997, Pelikan-Conchaudron et al. 2011). IQGAP1 is involved in the regulation of adherens junctions through its interaction with E-cadherin (CDH1) and catenins (CTTNB1 and CTTNA1) (Kuroda et al. 1998, Hage et al. 2009). IQGAP1 contributes to cell polarity and lamellipodia formation through its interaction with microtubules (Fukata et al. 2002, Suzuki and Takahashi 2008).

RHOQ (TC10) regulates the trafficking of CFTR (cystic fibrosis transmembrane conductance regulator) by binding to the Golgi-associated protein GOPC (also known as PIST, FIG and CAL). In the absence of RHOQ, GOPC bound to CFTR directs CFTR for lysosomal degradation, while GTP-bound RHOQ directs GOPC:CFTR complex to the plasma membrane, thereby rescuing CFTR (Neudauer et al. 2001, Cheng et al. 2005).

RAC1 and CDC42 activate WASP and WAVE proteins, members of the Wiskott-Aldrich Syndrome protein family. WASPs and WAVEs simultaneously interact with G-actin and the actin-related ARP2/3 complex, acting as nucleation promoting factors in actin polymerization (reviewed by Lane et al. 2014).

RHOA, RHOB, RHOC, RAC1 and CDC42 activate a subset of formin family members. Once activated, formins bind G-actin and the actin-bound profilins and accelerate actin polymerization, while some formins also interact with microtubules. Formin-mediated cytoskeletal reorganization plays important roles in cell motility, organelle trafficking and mitosis (reviewed by Kuhn and Geyer 2014).

Rhotekin (RTKN) and rhophilins (RHPN1 and RHPN2) are effectors of RHOA, RHOB and RHOC and have not been studied in detail. They 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). Similar to formins (Miralles et al. 2003), cytoskeletal changes triggered by RTKN activation may lead to stimulation of SRF-mediated transcription (Reynaud et al. 2000).

RHO GTPases RAC1 and RAC2 are needed for activation of 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-). Superoxide serves as a secondary messenger and also directly contributes to the microbicidal activity of neutrophils (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).

Literature References

PubMed ID	Title	Journal	Year
8702756	Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase) Amano, M, Ito, M, Kimura, K, Fukata, Y, Chihara, K, Nakano, T, Matsuura, Y, Kaibuchi, K	J Biol Chem	1996
12778124	Rocks: multifunctional kinases in cell behaviour Riento, K, Ridley, AJ	Nat Rev Mol Cell Biol	2003
18066052	Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation Metzger, E, Yin, N, Wissmann, M, Kunowska, N, Fischer, K, Friedrichs, N, Patnaik, D, Higgins, JM, Potier, N, Scheidtmann, KH, Buettner, R, Schüle, R	Nat. Cell Biol.	2008
9199170	IQGAP1, a Rac- and Cdc42-binding protein, directly binds and cross-links microfilaments Bashour, AM, Fullerton, AT, Hart, MJ, Bloom, GS	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 Reynaud, C, Fabre, S, Jalinot, P	J. Biol. Chem.	2000
24914801	Formins as effector proteins of Rho GTPases Kühn, S, Geyer, M	Small GTPases	2014
17151359	Regulation of myosin II dynamics by phosphorylation and dephosphorylation of its light chain in epithelial cells Watanabe, T, Hosoya, H, Yonemura, S	Mol Biol Cell	2007
8756646	The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases Brill, S, Li, S, Lyman, CW, Church, DM, Wasmuth, JJ, Weissbach, L, Bernards, A, Snijders, AJ	Mol. Cell. Biol.	1996
8543060	A novel partner for the GTP-bound forms of rho and rac Madaule, P, Furuyashiki, T, Reid, T, Ishizaki, T, Watanabe, G, Morii, N, Narumiya, S	FEBS Lett.	1995
9368021	Regulation of cross-linking of actin filament by IQGAP1, a target for Cdc42 Fukata, M, Kuroda, S, Fujii, K, Nakamura, T, Shoji, I, Matsuura, Y, Okawa, K, Iwamatsu, A, Kikuchi, A, Kaibuchi, K	J. Biol. Chem.	1997
10072071	Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense Roberts, AW, Kim, C, Zhen, L, Lowe, JB, Kapur, R, Petryniak, B, Spaetti, A, Pollock, JD, Borneo, JB, Bradford, GB, Atkinson, SJ, Dinauer, MC, Williams, DA	Immunity	1999
23716662	Citron kinase controls a molecular network required for midbody formation in cytokinesis Bassi, ZI, Audusseau, M, Riparbelli, MG, Callaini, G, D'Avino, PP	Proc. Natl. Acad. Sci. U.S.A.	2013
8571126	Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho Watanabe, G, Saito, Y, Madaule, P, Ishizaki, T, Fujisawa, K, Morii, N, Mukai, H, Ono, Y, Kakizuka, A, Narumiya, S	Science	1996
15546864	Regulation of cystic fibrosis transmembrane regulator trafficking and protein expression by a Rho family small GTPase TC10 Cheng, J, Wang, H, Guggino, WB	J. Biol. Chem.	2005
24128008	Differential binding of RhoA, RhoB, and RhoC to protein kinase C-related kinase (PRK) isoforms PRK1, PRK2, and PRK3: PRKs have the highest affinity for RhoB Hutchinson, CL, Lowe, PN, McLaughlin, SH, Mott, HR, Owen, D	Biochemistry	2013
16079795	LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription Metzger, E, Wissmann, M, Yin, N, Müller, JM, Schneider, R, Peters, AH, Günther, T, Buettner, R, Schüle, R	Nature	2005
12732141	Actin dynamics control SRF activity by regulation of its coactivator MAL Miralles, F, Posern, G, Zaromytidou, AI, Treisman, R	Cell	2003
24969695	Structure and role of WASP and WAVE in Rho GTPase signalling in cancer Lane, J, Martin, T, Weeks, HP, Jiang, WG	Cancer Genomics Proteomics	2014
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
1660188	Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2 Knaus, UG, Heyworth, PG, Evans, T, Curnutte, JT, Bokoch, GM	Science	1991
8798539	Identification of IQGAP as a putative target for the small GTPases, Cdc42 and Rac1 Kuroda, S, Fukata, M, Kobayashi, K, Nakafuku, M, Nomura, N, Iwamatsu, A, Kaibuchi, K	J. Biol. Chem.	1996
18237546	Regulation of lamellipodia formation and cell invasion by CLIP-170 in invasive human breast cancer cells Suzuki, K, Takahashi, K	Biochem. Biophys. Res. Commun.	2008
12110184	Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170 Fukata, M, Watanabe, T, Noritake, J, Nakagawa, M, Yamaga, M, Kuroda, S, Matsuura, Y, Iwamatsu, A, Perez, F, Kaibuchi, K	Cell	2002
10975528	Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch Lei, M, Lu, W, Meng, W, Parrini, MC, Eck, MJ, Mayer, BJ, Harrison, SC	Cell	2000
11948177	IQGAP1 is a component of Cdc42 signaling to the cytoskeleton Swart-Mataraza, JM, Li, Z, Sacks, DB	J. Biol. Chem.	2002
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 Sudo, K, Ito, H, Iwamoto, I, Morishita, R, Asano, T, Nagata, K	Neurosci. Res.	2006
8816443	The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton Leung, T, Chen, XQ, Manser, E, Lim, L	Mol. Cell. Biol.	1996
21730051	The IQGAP1 protein is a calmodulin-regulated barbed end capper of actin filaments: possible implications in its function in cell migration Pelikan-Conchaudron, A, Le Clainche, C, Didry, D, Carlier, MF	J. Biol. Chem.	2011
9535855	Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA Zhang, B, Chernoff, J, Zheng, Y	J. Biol. Chem.	1998
11018042	Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase Sumi, T, Matsumoto, K, Nakamura, T	J Biol Chem	2001
14595335	Citron-N is a neuronal Rho-associated protein involved in Golgi organization through actin cytoskeleton regulation Camera, P, da Silva, JS, Griffiths, G, Giuffrida, MG, Ferrara, L, Schubert, V, Imarisio, S, Silengo, L, Dotti, CG, Di Cunto, F	Nat. Cell Biol.	2003
8617235	The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase Ishizaki, T, Maekawa, M, Fujisawa, K, Okawa, K, Iwamatsu, A, Fujita, A, Watanabe, N, Saito, Y, Kakizuka, A, Morii, N, Narumiya, S	EMBO J	1996
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 Mircescu, H, Steuve, S, Savonet, V, Degraef, C, Mellor, H, Dumont, JE, Maenhaut, C, Pirson, I	Eur. J. Biochem.	2002
10753910	Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase Flynn, P, Mellor, H, Casamassima, A, Parker, PJ	J. Biol. Chem.	2000
10470034	p21-activated protein kinase: a crucial component of morphological signaling? Daniels, RH, Bokoch, GM	Trends Biochem Sci	1999
16762923	Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1 Miyano, K, Ueno, N, Takeya, R, Sumimoto, H	J. Biol. Chem.	2006
23444367	Citron kinase mediates transition from constriction to abscission through its coiled-coil domain Watanabe, S, De Zan, T, Ishizaki, T, Narumiya, S	J. Cell. Sci.	2013
19513348	Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements Szczepanowska, J	Acta Biochim Pol	2009
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 Jyoti, A, Singh, AK, Dubey, M, Kumar, S, Saluja, R, Keshari, RS, Verma, A, Chandra, T, Kumar, A, Bajpai, VK, Barthwal, MK, Dikshit, M	Antioxid. Redox Signal.	2014
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10619026	The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1 Maesaki, R, Ihara, K, Shimizu, T, Kuroda, S, Kaibuchi, K, Hakoshima, T	Mol. Cell	1999
12221077	The RhoA-binding protein, rhophilin-2, regulates actin cytoskeleton organization Peck, JW, Oberst, M, Bouker, KB, Bowden, E, Burbelo, PD	J. Biol. Chem.	2002
10559936	Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics Edwards, DC, Sanders, LC, Bokoch, GM, Gill, GN	Nat Cell Biol	1999
11162552	PIST: a novel PDZ/coiled-coil domain binding partner for the rho-family GTPase TC10 Neudauer, CL, Joberty, G, Macara, IG	Biochem. Biophys. Res. Commun.	2001
21351730	Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1 Hutchinson, CL, Lowe, PN, McLaughlin, SH, Mott, HR, Owen, D	Biochemistry	2011
9751706	Proteolytic activation of PKN by caspase-3 or related protease during apoptosis Takahashi, M, Mukai, H, Toshimori, M, Miyamoto, M, Ono, Y	Proc. Natl. Acad. Sci. U.S.A.	1998
8107774	A brain serine/threonine protein kinase activated by Cdc42 and Rac1 Manser, E, Leung, T, Salihuddin, H, Zhao, ZS, Lim, L	Nature	1994
18006505	The Rac1 polybasic region is required for interaction with its effector PRK1 Modha, R, Campbell, LJ, Nietlispach, D, Buhecha, HR, Owen, D, Mott, HR	J. Biol. Chem.	2008
10591629	Ropporin, a sperm-specific binding protein of rhophilin, that is localized in the fibrous sheath of sperm flagella Fujita, A, Nakamura, K, Kato, T, Watanabe, N, Ishizaki, T, Kimura, K, Mizoguchi, A, Narumiya, S	J. Cell. Sci.	2000
10924361	Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N Hamaguchi, T, Ito, M, Feng, J, Seko, T, Koyama, M, Machida, H, Takase, K, Amano, M, Kaibuchi, K, Hartshorne, DJ, Nakano, T	Biochem. Biophys. Res. Commun.	2000
12635176	RHO-GTPases and cancer Sahai, E, Marshall, CJ	Nat. Rev. Cancer	2002
12514133	A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer Metzger, E, Müller, JM, Ferrari, S, Buettner, R, Schüle, R	EMBO J.	2003
9988689	Loop 6 of RhoA confers specificity for effector binding, stress fiber formation, and cellular transformation Zong, H, Raman, N, Mickelson-Young, LA, Atkinson, SJ, Quilliam, LA	J. Biol. Chem.	1999
9694656	Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin- mediated cell-cell adhesion Kuroda, S, Fukata, M, Nakagawa, M, Fujii, K, Nakamura, T, Ookubo, T, Izawa, I, Nagase, T, Nomura, N, Tani, H, Shoji, I, Matsuura, Y, Yonehara, S, Kaibuchi, K	Science	1998
19737400	Rac1 activation inhibits E-cadherin-mediated adherens junctions via binding to IQGAP1 in pancreatic carcinoma cells Hage, B, Meinel, K, Baum, I, Giehl, K, Menke, A	Cell Commun. Signal	2009
12783890	Hyperosmotic-induced protein kinase N 1 activation in a vesicular compartment is dependent upon Rac1 and 3-phosphoinositide-dependent kinase 1 Torbett, NE, Casamassima, A, Parker, PJ	J. Biol. Chem.	2003
16507994	Involvement of Rac1 in activation of multicomponent Nox1- and Nox3-based NADPH oxidases Ueyama, T, Geiszt, M, Leto, TL	Mol. Cell. Biol.	2006
14514689	Molecular dissection of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PRK1) Owen, D, Lowe, PN, Nietlispach, D, Brosnan, CE, Chirgadze, DY, Parker, PJ, Blundell, TL, Mott, HR	J. Biol. Chem.	2003
17244649	IQGAP3, a novel effector of Rac1 and Cdc42, regulates neurite outgrowth Wang, S, Watanabe, T, Noritake, J, Fukata, M, Yoshimura, T, Itoh, N, Harada, T, Nakagawa, M, Matsuura, Y, Arimura, N, Kaibuchi, K	J. Cell. Sci.	2007
11804587	Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1 Parrini, MC, Lei, M, Harrison, SC, Mayer, BJ	Mol Cell	2002
8769096	Interaction of the Rho family small G proteins with kinectin, an anchoring protein of kinesin motor Hotta, K, Tanaka, K, Mino, A, Kohno, H, Takai, Y	Biochem. Biophys. Res. Commun.	1996
11689693	Kinectin is a key effector of RhoG microtubule-dependent cellular activity Vignal, E, Blangy, A, Martin, M, Gauthier-Rouvière, C, Fort, P	Mol. Cell. Biol.	2001
16636067	Nox1-dependent reactive oxygen generation is regulated by Rac1 Cheng, G, Diebold, BA, Hughes, Y, Lambeth, JD	J. Biol. Chem.	2006
7559638	Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family Manser, E, Chong, C, Zhao, ZS, Leung, T, Michael, G, Hall, C, Lim, L	J. Biol. Chem.	1995
10652353	Rho-associated kinase ROCK activates LIM-kinase 1 by phosphorylation at threonine 508 within the activation loop Ohashi, K, Nagata, K, Maekawa, M, Ishizaki, T, Narumiya, S, Mizuno, K	J Biol Chem	2000