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Gene Review

RHOA  -  ras homolog family member A

Homo sapiens

Synonyms: ARH12, ARHA, RHO12, RHOH12, Rho cDNA clone 12, ...
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Disease relevance of RHOA

  • In this report, we have isolated several RHOA cDNAs from a multidrug-resistant MCF-7 human breast cancer cell line [1].
  • Immunohistochemistry and immunoblotting were used to determine RHOA and RND protein expression and localization in nonpregnant, pregnant nonlaboring, and laboring patients at term and patients in spontaneous preterm labor [2].
  • In addition, overexpression of NF-kappaB p50 induced RhoA activity and Rock-mediated formation of stress fiber in melanoma cells [3].
  • Although the RhoA and RhoC proteins comprise an important subset of the Rho GTPase family that have been implicated in invasive breast carcinomas, attributing specific functions to these individual members has been difficult [4].
  • Cell lysates from Sf9 insect cells infected with recombinant baculovirus encoding myr 5 exhibited increased GAP activity for RhoA but not for Cdc42Hs or Rac1 [5].

Psychiatry related information on RHOA

  • We suggest that high expression of RhoA contributes, through RhoA-mediated Ca(2+) sensitization, to the flaccid state of CC that can be reversed by a water-soluble, orally active Rho kinase inhibitor suitable for therapy of erectile dysfunction [6].

High impact information on RHOA

  • Members of the Rho family of small Ras-like GTPases--including RhoA, -B, and -C, Rac1 and -2, and Cdc42--exhibit guanine nucleotide-binding activity and function as molecular switches, cycling between an inactive GDP-bound state and an active GTP-bound state [7].
  • RhoA and hence to ROK through a mechanism involving association of GEF, RhoA, and ROK in multimolecular complexes at the lipid cell membrane [8].
  • We suggest that the RhoA/ROK pathway is constitutively active in a number of organs under physiological conditions; its aberrations play major roles in several disease states, particularly impacting on Ca2+ sensitization of smooth muscle in hypertension and possibly asthma and on cancer neoangiogenesis and cancer progression [8].
  • The effector IpgB2 stimulates cellular responses analogous to GTP-active RhoA, whereas IpgB1 and Map function as the active forms of Rac1 and Cdc42, respectively [9].
  • Furthermore, in 293 cells expressing Kv1.2 and ml muscarinic acetylcholine receptors, inactivating RhoA using C3 exoenzyme blocked the ability of ml receptors to suppress Kv1.2 current [10].

Chemical compound and disease context of RHOA


Biological context of RHOA


Anatomical context of RHOA


Associations of RHOA with chemical compounds

  • We determined the crystal structure of a small GTPase RHOA complexed with GDP in the absence of Mg(2+) at 2.0-A resolution [19].
  • However, in intact PMNs stimulated with N-formyl-1-methionyl-1-leucyl-1-phenylalamine (FMLP) or permeabilized PMNs stimulated with GTP gamma S, C2-ceramide did not inhibit RhoA translocation [20].
  • Exogenous RhoA did not restore ceramide-inhibited PLD activity but bound to membranes despite ceramide treatment [20].
  • Herein, we use protein transduction to identify novel, opposing anti- and pro-cytokine-inducing roles for RhoA in the resting and lipopolysaccharide (LPS)-stimulated human PMN, respectively [21].
  • These observations suggest that, although ceramide may affect RhoA in some systems, ceramide inhibits PLD through another mechanism, perhaps related to the ability of ceramide to inhibit phosphatidylinositol-bisphosphate (PIP2) interaction with PLD [20].

Physical interactions of RHOA

  • Here we report the 2.2 A crystal structure of RhoA bound to an effector domain of protein kinase PKN/PRK1 [22].
  • These results conclusively demonstrate that the C-terminal region of PLD1 contains the RhoA-binding site and suggest that the ARF and PKC interactions occur elsewhere in the protein [23].
  • Herein we describe the atomic structures of the catalytic Dbl homology (DH) and pleckstrin homology (PH) domains of LARG alone and in complex with RhoA [24].
  • Glutathione S-transferase-capture experiments revealed that Rhophilin-1 and Rhophilin-2 interacted with both GDP- and GTP-bound RhoA in vitro [25].
  • An adjacent domain of M-RIP directly binds RhoA in a nucleotide-independent manner [26].

Enzymatic interactions of RHOA

  • Localized suppression of RhoA activity by Tyr31/118-phosphorylated paxillin in cell adhesion and migration [27].
  • Owing to the molecular activity of CNF1, we have investigated the relationship between permanent activation of RhoA catalyzed by CNF1 and subsequent ubiquitylation of RhoA by Smurf1 [28].
  • First, TGF-beta1 phosphorylated RhoA via protein kinase A, leading to inactivation of RhoA [29].

Co-localisations of RHOA

  • Nir2 colocalizes with the small GTPase RhoA in the cleavage furrow and the midbody, and it associates with RhoA in mitotic cells [30].

Regulatory relationships of RHOA

  • In the resting cell, RhoA suppresses Cdc42 activation, IkappaBalpha degradation, nuclear factor-kappaB (NF-kappaB) activation, and induction of TNFalpha and NF-kappaB-dependent chemokines [21].
  • PRK1 (PKN) is a serine/threonine kinase that has been shown to be activated by RhoA (Amano, M., Mukai, H., Ono, Y., Chihara, K., Matsui, T., Hamajima, Y., Okawa, K., Iwamatsu, A., and Kaibuchi, K. (1996) Science 271, 648-650) [31].
  • In this study, we have investigated the proximal events in TNF-alpha-induced RhoA activation [32].
  • In addition, we show that ligand-induced dimerization of Plexin B is sufficient to stimulate endogenous RhoA potently and to induce the reorganization of the cytoskeleton [33].
  • These results suggest that CB2 might play a role in regulating excessive inflammatory response by controlling RhoA activation, thereby suppressing neutrophil migration [34].
  • We also demonstrate that NEP inhibits neuropeptide activation of RhoA [35].

Other interactions of RHOA

  • We show that RhoG(GTP) specifically interacts with the central domain of kinectin, which also contains a RhoA binding domain in its C terminus [36].
  • Instead, IQGAP2 binds Cdc42 and Racl but not RhoA [37].
  • In active R-Ras (38V) cells, the activity of RhoA is increased and accompanied with translocation to plasma membrane, but not that of Rac1 or Cdc42 [38].
  • We have reported that the transient expression of the endogenous RhoB protein is regulated during the cell cycle, contrasting with the permanent RhoA protein expression () [39].
  • The effect of ARF was greater than that of RhoA, although the concentrations for half-maximal stimulation (0.08-0.2 microM) were similar [40].
  • TRPC6-mediated RhoA activity was shown to be dependent on PKCalpha activation [41].

Analytical, diagnostic and therapeutic context of RHOA


  1. Utilization of multiple polyadenylation signals in the human RHOA protooncogene. Moscow, J.A., He, R., Gudas, J.M., Cowan, K.H. Gene (1994) [Pubmed]
  2. Expression of RND proteins in human myometrium. Lartey, J., Gampel, A., Pawade, J., Mellor, H., Bernal, A.L. Biol. Reprod. (2006) [Pubmed]
  3. Prognostic Significance of Nuclear Factor-{kappa}B p105/p50 in Human Melanoma and Its Role in Cell Migration. Gao, K., Dai, D.L., Martinka, M., Li, G. Cancer Res. (2006) [Pubmed]
  4. Functional analysis of the contribution of RhoA and RhoC GTPases to invasive breast carcinoma. Simpson, K.J., Dugan, A.S., Mercurio, A.M. Cancer Res. (2004) [Pubmed]
  5. The rat myosin myr 5 is a GTPase-activating protein for Rho in vivo: essential role of arginine 1695. Müller, R.T., Honnert, U., Reinhard, J., Bähler, M. Mol. Biol. Cell (1997) [Pubmed]
  6. RhoA-mediated Ca2+ sensitization in erectile function. Wang, H., Eto, M., Steers, W.D., Somlyo, A.P., Somlyo, A.V. J. Biol. Chem. (2002) [Pubmed]
  7. Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Kaibuchi, K., Kuroda, S., Amano, M. Annu. Rev. Biochem. (1999) [Pubmed]
  8. Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Somlyo, A.P., Somlyo, A.V. Physiol. Rev. (2003) [Pubmed]
  9. Identification of a bacterial type III effector family with G protein mimicry functions. Alto, N.M., Shao, F., Lazar, C.S., Brost, R.L., Chua, G., Mattoo, S., McMahon, S.A., Ghosh, P., Hughes, T.R., Boone, C., Dixon, J.E. Cell (2006) [Pubmed]
  10. The small GTP-binding protein RhoA regulates a delayed rectifier potassium channel. Cachero, T.G., Morielli, A.D., Peralta, E.G. Cell (1998) [Pubmed]
  11. Effect of Rho and ADP-ribosylation factor GTPases on phospholipase D activity in intact human adenocarcinoma A549 cells. Meacci, E., Vasta, V., Moorman, J.P., Bobak, D.A., Bruni, P., Moss, J., Vaughan, M. J. Biol. Chem. (1999) [Pubmed]
  12. HIF-1alpha mRNA and protein upregulation involves Rho GTPase expression during hypoxia in renal cell carcinoma. Turcotte, S., Desrosiers, R.R., Béliveau, R. J. Cell. Sci. (2003) [Pubmed]
  13. Role of direct RhoA-phospholipase D1 interaction in mediating adenosine-induced protection from cardiac ischemia. Mozzicato, S., Joshi, B.V., Jacobson, K.A., Liang, B.T. FASEB J. (2004) [Pubmed]
  14. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Asanuma, K., Yanagida-Asanuma, E., Faul, C., Tomino, Y., Kim, K., Mundel, P. Nat. Cell Biol. (2006) [Pubmed]
  15. A novel role for RhoGDI as an inhibitor of GAP proteins. Hancock, J.F., Hall, A. EMBO J. (1993) [Pubmed]
  16. Role of p190RhoGAP in beta 2 integrin regulation of RhoA in human neutrophils. Dib, K., Melander, F., Andersson, T. J. Immunol. (2001) [Pubmed]
  17. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Gao, Y., Dickerson, J.B., Guo, F., Zheng, J., Zheng, Y. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  18. Direct genetic demonstration of G alpha 13 coupling to the orphan G protein-coupled receptor G2A leading to RhoA-dependent actin rearrangement. Kabarowski, J.H., Feramisco, J.D., Le, L.Q., Gu, J.L., Luoh, S.W., Simon, M.I., Witte, O.N. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  19. An open conformation of switch I revealed by the crystal structure of a Mg2+-free form of RHOA complexed with GDP. Implications for the GDP/GTP exchange mechanism. Shimizu, T., Ihara, K., Maesaki, R., Kuroda, S., Kaibuchi, K., Hakoshima, T. J. Biol. Chem. (2000) [Pubmed]
  20. Ceramide inhibition of phospholipase D and its relationship to RhoA and ARF1 translocation in GTP gamma S-stimulated polymorphonuclear leukocytes. Mansfield, P.J., Carey, S.S., Hinkovska-Galcheva, V., Shayman, J.A., Boxer, L.A. Blood (2004) [Pubmed]
  21. Dual role for RhoA in suppression and induction of cytokines in the human neutrophil. Fessler, M.B., Arndt, P.G., Just, I., Nick, J.A., Malcolm, K.C., Scott Worthen, G. Blood (2007) [Pubmed]
  22. 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) [Pubmed]
  23. Interaction of the small G protein RhoA with the C terminus of human phospholipase D1. Yamazaki, M., Zhang, Y., Watanabe, H., Yokozeki, T., Ohno, S., Kaibuchi, K., Shibata, H., Mukai, H., Ono, Y., Frohman, M.A., Kanaho, Y. J. Biol. Chem. (1999) [Pubmed]
  24. Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor. Kristelly, R., Gao, G., Tesmer, J.J. J. Biol. Chem. (2004) [Pubmed]
  25. The RhoA-binding protein, rhophilin-2, regulates actin cytoskeleton organization. Peck, J.W., Oberst, M., Bouker, K.B., Bowden, E., Burbelo, P.D. J. Biol. Chem. (2002) [Pubmed]
  26. Myosin phosphatase-Rho interacting protein. A new member of the myosin phosphatase complex that directly binds RhoA. Surks, H.K., Richards, C.T., Mendelsohn, M.E. J. Biol. Chem. (2003) [Pubmed]
  27. Localized suppression of RhoA activity by Tyr31/118-phosphorylated paxillin in cell adhesion and migration. Tsubouchi, A., Sakakura, J., Yagi, R., Mazaki, Y., Schaefer, E., Yano, H., Sabe, H. J. Cell Biol. (2002) [Pubmed]
  28. CNF1-induced ubiquitylation and proteasome destruction of activated RhoA is impaired in Smurf1-/- cells. Boyer, L., Turchi, L., Desnues, B., Doye, A., Ponzio, G., Mege, J.L., Yamashita, M., Zhang, Y.E., Bertoglio, J., Flatau, G., Boquet, P., Lemichez, E. Mol. Biol. Cell (2006) [Pubmed]
  29. Transforming growth factor-beta1 regulates macrophage migration via RhoA. Kim, J.S., Kim, J.G., Moon, M.Y., Jeon, C.Y., Won, H.Y., Kim, H.J., Jeon, Y.J., Seo, J.Y., Kim, J.I., Kim, J., Lee, J.Y., Kim, P.H., Park, J.B. Blood (2006) [Pubmed]
  30. Nir2, a human homolog of Drosophila melanogaster retinal degeneration B protein, is essential for cytokinesis. Litvak, V., Tian, D., Carmon, S., Lev, S. Mol. Cell. Biol. (2002) [Pubmed]
  31. Multiple interactions of PRK1 with RhoA. Functional assignment of the Hr1 repeat motif. Flynn, P., Mellor, H., Palmer, R., Panayotou, G., Parker, P.J. J. Biol. Chem. (1998) [Pubmed]
  32. Spatial Compartmentalization of Tumor Necrosis Factor (TNF) Receptor 1-dependent Signaling Pathways in Human Airway Smooth Muscle Cells: LIPID RAFTS ARE ESSENTIAL FOR TNF-{alpha}-MEDIATED ACTIVATION OF RhoA BUT DISPENSABLE FOR THE ACTIVATION OF THE NF-{kappa}B AND MAPK PATHWAYS. Hunter, I., Nixon, G.F. J. Biol. Chem. (2006) [Pubmed]
  33. Plexin B regulates Rho through the guanine nucleotide exchange factors leukemia-associated Rho GEF (LARG) and PDZ-RhoGEF. Perrot, V., Vazquez-Prado, J., Gutkind, J.S. J. Biol. Chem. (2002) [Pubmed]
  34. Effects of Peripheral Cannabinoid Receptor Ligands on Motility and Polarization in Neutrophil-like HL60 Cells and Human Neutrophils. Kurihara, R., Tohyama, Y., Matsusaka, S., Naruse, H., Kinoshita, E., Tsujioka, T., Katsumata, Y., Yamamura, H. J. Biol. Chem. (2006) [Pubmed]
  35. Neuropeptide-stimulated cell migration in prostate cancer cells is mediated by RhoA kinase signaling and inhibited by neutral endopeptidase. Zheng, R., Iwase, A., Shen, R., Goodman, O.B., Sugimoto, N., Takuwa, Y., Lerner, D.J., Nanus, D.M. Oncogene (2006) [Pubmed]
  36. 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) [Pubmed]
  37. 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, C.W., Church, D.M., Wasmuth, J.J., Weissbach, L., Bernards, A., Snijders, A.J. Mol. Cell. Biol. (1996) [Pubmed]
  38. The COOH-terminal end of R-Ras alters the motility and morphology of breast epithelial cells through Rho/Rho-kinase. Jeong, H.W., Nam, J.O., Kim, I.S. Cancer Res. (2005) [Pubmed]
  39. RhoGDI-3 is a new GDP dissociation inhibitor (GDI). Identification of a non-cytosolic GDI protein interacting with the small GTP-binding proteins RhoB and RhoG. Zalcman, G., Closson, V., Camonis, J., Honoré, N., Rousseau-Merck, M.F., Tavitian, A., Olofsson, B. J. Biol. Chem. (1996) [Pubmed]
  40. Cloning and characterization of phospholipase D from rat brain. Park, S.K., Provost, J.J., Bae, C.D., Ho, W.T., Exton, J.H. J. Biol. Chem. (1997) [Pubmed]
  41. Galphaq-TRPC6-mediated Ca2+ entry induces RhoA activation and resultant endothelial cell shape change in response to thrombin. Singh, I., Knezevic, N., Ahmmed, G.U., Kini, V., Malik, A.B., Mehta, D. J. Biol. Chem. (2007) [Pubmed]
  42. Role of protein kinase C alpha, Arf, and cytoplasmic calcium transients in phospholipase D activation by sodium fluoride in osteoblast-like cells. Bourgoin, S.G., Harbour, D., Poubelle, P.E. J. Bone Miner. Res. (1996) [Pubmed]
  43. The role of geranylgeranylated proteins in human mesangial cell proliferation. Khwaja, A., Sharpe, C.C., Noor, M., Hendry, B.M. Kidney Int. (2006) [Pubmed]
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