RHO GTPase Effectors

Kühn S, Geyer M. Formins as effector proteins of Rho GTPases. Small GTPases. 2014;5():e29513. PMID: 24914801; PMCID: PMC4111664.; Lane J, Martin T, Weeks HP, Jiang WG. Structure and role of WASP and WAVE in Rho GTPase signalling in cancer. Cancer Genomics Proteomics. 2014 May;11(3):155–65. PMID: 24969695.; Jyoti A, Singh AK, Dubey M, Kumar S, Saluja R, Keshari RS, Verma A, Chandra T, Kumar A, Bajpai VK, Barthwal MK, Dikshit M. Interaction of inducible nitric oxide synthase with rac2 regulates reactive oxygen and nitrogen species generation in the human neutrophil phagosomes: implication in microbial killing. Antioxid Redox Signal. 2014 Jan 20;20(3):417–31. doi: 10.1089/ars.2012.4970. PMID: 23875749.; Hutchinson CL, Lowe PN, McLaughlin SH, Mott HR, Owen D. 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. Biochemistry. 2013 Nov 12;52(45):7999–8011. doi: 10.1021/bi401216w. PMID: 24128008.; Bassi ZI, Audusseau M, Riparbelli MG, Callaini G, D'Avino PP. Citron kinase controls a molecular network required for midbody formation in cytokinesis. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9782–7. PMID: 23716662; PMCID: PMC3683733.; Watanabe S, De Zan T, Ishizaki T, Narumiya S. Citron kinase mediates transition from constriction to abscission through its coiled-coil domain. J Cell Sci. 2013 Apr 15;126(Pt 8):1773–84. doi: 10.1242/jcs.116608. PMID: 23444367.; Pelikan-Conchaudron A, Le Clainche C, Didry D, Carlier MF. The IQGAP1 protein is a calmodulin-regulated barbed end capper of actin filaments: possible implications in its function in cell migration. J Biol Chem. 2011 Oct 07;286(40):35119–28. PMID: 21730051; PMCID: PMC3186398.; Hutchinson CL, Lowe PN, McLaughlin SH, Mott HR, Owen D. Mutational analysis reveals a single binding interface between RhoA and its effector, PRK1. Biochemistry. 2011 Apr 12;50(14):2860–9. doi: 10.1021/bi200039u. PMID: 21351730.; Hage B, Meinel K, Baum I, Giehl K, Menke A. Rac1 activation inhibits E-cadherin-mediated adherens junctions via binding to IQGAP1 in pancreatic carcinoma cells. Cell Communication and Signaling. 2009 Sep 08;7(1):23. doi: 10.1186/1478-811x-7-23.; Szczepanowska J. Involvement of Rac/Cdc42/PAK pathway in cytoskeletal rearrangements. Acta Biochim Pol. 2009 Jun 10;56(2). doi: 10.18388/abp.2009_2453.; Suzuki K, Takahashi K. Regulation of lamellipodia formation and cell invasion by CLIP-170 in invasive human breast cancer cells. Biochemical and Biophysical Research Communications. 2008 Apr;368(2):199–204. doi: 10.1016/j.bbrc.2008.01.069.; Modha R, Campbell LJ, Nietlispach D, Buhecha HR, Owen D, Mott HR. The Rac1 Polybasic Region Is Required for Interaction with Its Effector PRK1. Journal of Biological Chemistry. 2008 Jan;283(3):1492–500. doi: 10.1074/jbc.m706760200.; Metzger E, Yin N, Wissmann M, Kunowska N, Fischer K, Friedrichs N, Patnaik D, Higgins JM, Potier N, Scheidtmann KH, Buettner R, Schüle R. Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation. Nat Cell Biol. 2008 Jan;10(1):53–60. PMID: 18066052; PMCID: PMC2878724.; Wang S, Watanabe T, Noritake J, Fukata M, Yoshimura T, Itoh N, Harada T, Nakagawa M, Matsuura Y, Arimura N, Kaibuchi K. IQGAP3, a novel effector of Rac1 and Cdc42, regulates neurite outgrowth. J Cell Sci. 2007 Feb 15;120(Pt 4):567–77. doi: 10.1242/jcs.03356. PMID: 17244649.; Watanabe T, Hosoya H, Yonemura S. Regulation of myosin II dynamics by phosphorylation and dephosphorylation of its light chain in epithelial cells. Mol Biol Cell. 2007 Feb;18(2):605–16. PMID: 17151359; PMCID: PMC1783795.; Sudo K, Ito H, Iwamoto I, Morishita R, Asano T, Nagata K. Identification of a cell polarity-related protein, Lin-7B, as a binding partner for a Rho effector, Rhotekin, and their possible interaction in neurons. Neurosci Res. 2006 Dec;56(4):347–55. doi: 10.1016/j.neures.2006.08.003. PMID: 16979770.; Miyano K, Ueno N, Takeya R, Sumimoto H. Direct Involvement of the Small GTPase Rac in Activation of the Superoxide-producing NADPH Oxidase Nox1. Journal of Biological Chemistry. 2006 Aug;281(31):21857–68. doi: 10.1074/jbc.m513665200.; Cheng G, Diebold BA, Hughes Y, Lambeth JD. Nox1-dependent Reactive Oxygen Generation Is Regulated by Rac1. Journal of Biological Chemistry. 2006 Jun;281(26):17718–26. doi: 10.1074/jbc.m512751200.; Ueyama T, Geiszt M, Leto TL. Involvement of Rac1 in Activation of Multicomponent Nox1- and Nox3-Based NADPH Oxidases. Molecular and Cellular Biology. 2006 Mar 01;26(6):2160–74. doi: 10.1128/mcb.26.6.2160-2174.2006.; Gruneberg U, Neef R, Li X, Chan EH, Chalamalasetty RB, Nigg EA, Barr FA. KIF14 and citron kinase act together to promote efficient cytokinesis. J Cell Biol. 2006 Jan 30;172(3):363–72. PMID: 16431929; PMCID: PMC2063646.; Metzger E, Wissmann M, Yin N, Müller JM, Schneider R, Peters AH, Günther T, Buettner R, Schüle R. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature. 2005 Sep 15;437(7057):436–9. doi: 10.1038/nature04020. PMID: 16079795.; Cheng J, Wang H, Guggino WB. Regulation of Cystic Fibrosis Transmembrane Regulator Trafficking and Protein Expression by a Rho Family Small GTPase TC10. Journal of Biological Chemistry. 2005 Feb;280(5):3731–9. doi: 10.1074/jbc.m410026200.; Owen D, Lowe PN, Nietlispach D, Brosnan CE, Chirgadze DY, Parker PJ, Blundell TL, Mott HR. Molecular Dissection of the Interaction between the Small G Proteins Rac1 and RhoA and Protein Kinase C-related Kinase 1 (PRK1). Journal of Biological Chemistry. 2003 Dec;278(50):50578–87. doi: 10.1074/jbc.m304313200.; Camera P, da Silva JS, Griffiths G, Giuffrida MG, Ferrara L, Schubert V, Imarisio S, Silengo L, Dotti CG, Di Cunto F. Citron-N is a neuronal Rho-associated protein involved in Golgi organization through actin cytoskeleton regulation. Nat Cell Biol. 2003 Dec;5(12):1071–8. doi: 10.1038/ncb1064. PMID: 14595335.; Torbett NE, Casamassima A, Parker PJ. Hyperosmotic-induced Protein Kinase N 1 Activation in a Vesicular Compartment Is Dependent upon Rac1 and 3-Phosphoinositide-dependent Kinase 1. Journal of Biological Chemistry. 2003 Aug;278(34):32344–51. doi: 10.1074/jbc.m303532200.; Riento K, Ridley AJ. ROCKs: multifunctional kinases in cell behaviour. Nature Reviews Molecular Cell Biology. 2003 Jun 01;4(6):446–56. doi: 10.1038/nrm1128.; Miralles F, Posern G, Zaromytidou AI, Treisman R. Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell. 2003 May 02;113(3):329–42. doi: 10.1016/s0092-8674(03)00278-2. PMID: 12732141.; Metzger E, Müller JM, Ferrari S, Buettner R, Schüle R. A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer. EMBO J. 2003 Jan 15;22(2):270–80. PMID: 12514133; PMCID: PMC140098.; Mircescu H, Steuve S, Savonet V, Degraef C, Mellor H, Dumont JE, Maenhaut C, Pirson I. Identification and characterization of a novel activated RhoB binding protein containing a PDZ domain whose expression is specifically modulated in thyroid cells by cAMP. European Journal of Biochemistry. 2002 Dec;269(24):6241–9. doi: 10.1046/j.1432-1033.2002.03343.x.; Peck JW, Oberst M, Bouker KB, Bowden E, Burbelo PD. The RhoA-binding protein, Rhophilin-2, Regulates Actin Cytoskeleton Organization. Journal of Biological Chemistry. 2002 Nov;277(46):43924–32. doi: 10.1074/jbc.m203569200.; Swart-Mataraza JM, Li Z, Sacks DB. IQGAP1 Is a Component of Cdc42 Signaling to the Cytoskeleton. Journal of Biological Chemistry. 2002 Jul;277(27):24753–63. doi: 10.1074/jbc.m111165200.; Fukata M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, Kuroda S, Matsuura Y, Iwamatsu A, Perez F, Kaibuchi K. Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell. 2002 Jun 28;109(7):873–85. doi: 10.1016/s0092-8674(02)00800-0. PMID: 12110184.; Sahai E, Marshall CJ. RHO-GTPases and cancer. Nat Rev Cancer. 2002 Feb;2(2):133–42. doi: 10.1038/nrc725. PMID: 12635176.; Parrini MC, Lei M, Harrison SC, Mayer BJ. Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1. Mol Cell. 2002 Jan;9(1):73–83. doi: 10.1016/s1097-2765(01)00428-2. PMID: 11804587.; Vignal E, Blangy A, Martin M, Gauthier-Rouvie`re C, Fort P. Kinectin Is a Key Effector of RhoG Microtubule-Dependent Cellular Activity. Mol Cell Biol. 2001 Dec;21(23):8022–34. doi: 10.1128/mcb.21.23.8022-8034.2001.; Neudauer CL, Joberty G, Macara IG. PIST: A Novel PDZ/Coiled-Coil Domain Binding Partner for the Rho-Family GTPase TC10. Biochemical and Biophysical Research Communications. 2001 Jan;280(2):541–7. doi: 10.1006/bbrc.2000.4160.; Kim C, Dinauer MC. Rac2 is an essential regulator of neutrophil nicotinamide adenine dinucleotide phosphate oxidase activation in response to specific signaling pathways. J Immunol. 2001 Jan 15;166(2):1223–32. doi: 10.4049/jimmunol.166.2.1223. PMID: 11145705.; Sumi T, Matsumoto K, Nakamura T. Specific Activation of LIM kinase 2 via Phosphorylation of Threonine 505 by ROCK, a Rho-dependent Protein Kinase. Journal of Biological Chemistry. 2001 Jan;276(1):670–6. doi: 10.1074/jbc.m007074200.; Reynaud C, Fabre S, Jalinot P. The PDZ Protein TIP-1 Interacts with the Rho Effector Rhotekin and Is Involved in Rho Signaling to the Serum Response Element. Journal of Biological Chemistry. 2000 Oct;275(43):33962–8. doi: 10.1074/jbc.m000465200.; Hamaguchi T, Ito M, Feng J, Seko T, Koyama M, Machida H, Takase K, Amano M, Kaibuchi K, Hartshorne DJ, Nakano T. Phosphorylation of CPI-17, an Inhibitor of Myosin Phosphatase, by Protein Kinase N. Biochemical and Biophysical Research Communications. 2000 Aug;274(3):825–30. doi: 10.1006/bbrc.2000.3225.; Lei M, Lu W, Meng W, Parrini MC, Eck MJ, Mayer BJ, Harrison SC. Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch. Cell. 2000 Aug 04;102(3):387–97. doi: 10.1016/s0092-8674(00)00043-x. PMID: 10975528.; Flynn P, Mellor H, Casamassima A, Parker PJ. Rho GTPase Control of Protein Kinase C-related Protein Kinase Activation by 3-Phosphoinositide-dependent Protein Kinase. Journal of Biological Chemistry. 2000 Apr;275(15):11064–70. doi: 10.1074/jbc.275.15.11064.; Ohashi K, Nagata K, Maekawa M, Ishizaki T, Narumiya S, Mizuno K. Rho-associated Kinase ROCK Activates LIM-kinase 1 by Phosphorylation at Threonine 508 within the Activation Loop. Journal of Biological Chemistry. 2000 Feb;275(5):3577–82. doi: 10.1074/jbc.275.5.3577.; Fujita A, Nakamura K, Kato T, Watanabe N, Ishizaki T, Kimura K, Mizoguchi A, Narumiya S. Ropporin, a sperm-specific binding protein of rhophilin, that is localized in the fibrous sheath of sperm flagella. J Cell Sci. 2000 Jan;113 ( Pt 1)():103–12. doi: 10.1242/jcs.113.1.103. PMID: 10591629.; Maesaki R, Ihara K, Shimizu T, Kuroda S, Kaibuchi K, Hakoshima T. The structural basis of Rho effector recognition revealed by the crystal structure of human RhoA complexed with the effector domain of PKN/PRK1. Mol Cell. 1999 Nov;4(5):793–803. doi: 10.1016/s1097-2765(00)80389-5. PMID: 10619026.; Daniels RH, Bokoch GM. p21-activated protein kinase: a crucial component of morphological signaling? Trends Biochem Sci. 1999 Sep;24(9):350–5. doi: 10.1016/s0968-0004(99)01442-5. PMID: 10470034.; Edwards DC, Sanders LC, Bokoch GM, Gill GN. Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol. 1999 Sep;1(5):253–9. doi: 10.1038/12963. PMID: 10559936.; Zong H, Raman N, Mickelson-Young LA, Atkinson SJ, Quilliam LA. Loop 6 of RhoA Confers Specificity for Effector Binding, Stress Fiber Formation, and Cellular Transformation. Journal of Biological Chemistry. 1999 Feb;274(8):4551–60. doi: 10.1074/jbc.274.8.4551.; 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. Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity. 1999 Feb;10(2):183–96. doi: 10.1016/s1074-7613(00)80019-9. PMID: 10072071.; Takahashi M, Mukai H, Toshimori M, Miyamoto M, Ono Y. Proteolytic activation of PKN by caspase-3 or related protease during apoptosis. Proc. Natl. Acad. Sci. U.S.A. 1998 Sep 29;95(20):11566–71. doi: 10.1073/pnas.95.20.11566.; 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. Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin- mediated cell-cell adhesion. Science. 1998 Aug 07;281(5378):832–5. doi: 10.1126/science.281.5378.832. PMID: 9694656.; Zhang B, Chernoff J, Zheng Y. Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA. J Biol Chem. 1998 Apr 10;273(15):8776–82. doi: 10.1074/jbc.273.15.8776. PMID: 9535855.; Fukata M, Kuroda S, Fujii K, Nakamura T, Shoji I, Matsuura Y, Okawa K, Iwamatsu A, Kikuchi A, Kaibuchi K. Regulation of Cross-linking of Actin Filament by IQGAP1, a Target for Cdc42. Journal of Biological Chemistry. 1997 Nov;272(47):29579–83. doi: 10.1074/jbc.272.47.29579.; Bashour AM, Fullerton AT, Hart MJ, Bloom GS. IQGAP1, a Rac- and Cdc42-binding protein, directly binds and cross-links microfilaments. J Cell Biol. 1997 Jun 30;137(7):1555–66. PMID: 9199170; PMCID: PMC2137827.; Leung T, Chen X, Manser E, Lim L. The p160 RhoA-Binding Kinase ROKa Is a Member of a Kinase Family and Is Involved in the Reorganization of the Cytoskeleton. Molecular and Cellular Biology. 1996 Oct 01;16(10):5313–27. doi: 10.1128/mcb.16.10.5313.; Kuroda S, Fukata M, Kobayashi K, Nakafuku M, Nomura N, Iwamatsu A, Kaibuchi K. Identification of IQGAP as a Putative Target for the Small GTPases, Cdc42 and Rac1. Journal of Biological Chemistry. 1996 Sep;271(38):23363–7. doi: 10.1074/jbc.271.38.23363.; Brill S, Li S, Lyman CW, Church DM, Wasmuth JJ, Weissbach L, Bernards A, Snijders AJ. The Ras GTPase-Activating-Protein-Related Human Protein IQGAP2 Harbors a Potential Actin Binding Domain and Interacts with Calmodulin and Rho Family GTPases. Molecular and Cellular Biology. 1996 Sep 01;16(9):4869–78. doi: 10.1128/mcb.16.9.4869.; Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T, Matsuura Y, Kaibuchi K. Phosphorylation and Activation of Myosin by Rho-associated Kinase (Rho-kinase). Journal of Biological Chemistry. 1996 Aug;271(34):20246–9. doi: 10.1074/jbc.271.34.20246.; Hotta K, Tanaka K, Mino A, Kohno H, Takai Y. Interaction of the Rho Family Small G Proteins with Kinectin, an Anchoring Protein of Kinesin Motor. Biochemical and Biophysical Research Communications. 1996 Aug;225(1):69–74. doi: 10.1006/bbrc.1996.1132.; Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S. The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. The EMBO Journal. 1996 Apr;15(8):1885–93. doi: 10.1002/j.1460-2075.1996.tb00539.x.; Watanabe G, Saito Y, Madaule P, Ishizaki T, Fujisawa K, Morii N, Mukai H, Ono Y, Kakizuka A, Narumiya S. Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho. Science. 1996 Feb 02;271(5249):645–8. doi: 10.1126/science.271.5249.645. PMID: 8571126.; Madaule P, Furuyashiki T, Reid T, Ishizaki T, Watanabe G, Morii N, Narumiya S. A novel partner for the GTP-bound forms of rho and rac. FEBS Letters. 1995 Dec 18;377(2):243–8. doi: 10.1016/0014-5793(95)01351-2.; Manser E, Chong C, Zhao Z, Leung T, Michael G, Hall C, Lim L. Molecular Cloning of a New Member of the p21-Cdc42/Rac-activated Kinase (PAK) Family. Journal of Biological Chemistry. 1995 Oct;270(42):25070–8. doi: 10.1074/jbc.270.42.25070.; Manser E, Leung T, Salihuddin H, Zhao ZS, Lim L. A brain serine/threonine protein kinase activated by Cdc42 and Rac1. Nature. 1994 Jan 06;367(6458):40–6. doi: 10.1038/367040a0. PMID: 8107774.; Knaus UG, Heyworth PG, Evans T, Curnutte JT, Bokoch GM. Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2. Science. 1991 Dec 06;254(5037):1512–5. doi: 10.1126/science.1660188. PMID: 1660188.

Metabolites

Calcium cation

Formula: Ca (39.962591)

CAS ID: 14127-61-8

Magnesium cation

Formula: Mg (23.98505)

CAS ID: 22537-22-0

ATP(4-)

Formula: C10H12N5O13P3 (502.9644492)

CAS ID:

GTP(4-)

Formula: C10H12N5O14P3 (518.9593642)

CAS ID: 86527-72-2

ADP(3-)

Formula: C10H12N5O10P2 (424.0059412)

CAS ID:



Enzyme

EC Number name full name note
3.6.4.-
2.7.1.137 phosphatidylinositol 3-kinase ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase
2.7.10.2 non-specific protein-tyrosine kinase ATP:[protein]-L-tyrosine O-phosphotransferase (non-specific)
2.7.11.1 non-specific serine/threonine protein kinase ATP:protein phosphotransferase (non-specific)
2.7.11.24 mitogen-activated protein kinase ATP:protein phosphotransferase (MAPKK-activated)


Proteins

Protein ID name full name