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Gene Review

Rhoa  -  ras homolog gene family, member A

Mus musculus

Synonyms: Arha, Arha1, Arha2, RhoA, Transforming protein RhoA
 
 
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Disease relevance of Rhoa

 

High impact information on Rhoa

  • YpkA inhibits nucleotide exchange in Rac1 and RhoA, and mutations that disrupt the YpkA-GTPase interface abolish this activity in vitro and impair in vivo YpkA-induced cytoskeletal disruption [6].
  • Activated alleles of Cdc42 and Rac1, but not RhoA, stimulate pp70S6k activity in multiple cell types [7].
  • Analysis by mass spectrometry and amino-acid sequencing of proteolytic peptides derived from CNF1-treated RhoA indicate that CNF1 induces deamidation of a glutamine residue at position 63 (Gln 63) to give constitutively active Rho protein [8].
  • Overexpression of RhoA or activated RhoA in NIH 3T3 cells increased phosphorylation of MBS and MLC [9].
  • In lymphoid cells transfected with formyl peptide or interleukin-8 receptors, agonist stimulation activated nucleotide exchange on the small guanosine triphosphate-binding protein RhoA in seconds [10].
 

Chemical compound and disease context of Rhoa

 

Biological context of Rhoa

 

Anatomical context of Rhoa

  • A recent study showed that microtubule-bound GEF-H1, a RhoA-specific guanine nucleotide exchange factor, was converted to its active form by microtubule destabilization, and this sequence of events resulted in RhoA stimulation [1].
  • Unexpectedly, deletion of Rac1 also abolished actin stress fibers in the cells without detectable alteration of endogenous RhoA activity [16].
  • Dendrite development in neurons is one of the bases for the formation of a complex neuronal network in the nervous system, and involvement of the Rho family GTPases, including Rac1, Cdc42, and RhoA, in dendrite formation has been demonstrated [19].
  • RhoA GTPase regulates L-type Ca2+ currents in cardiac myocytes [20].
  • RhoA GTPase regulates B cell receptor signaling [21].
 

Associations of Rhoa with chemical compounds

 

Physical interactions of Rhoa

  • Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA [23].
  • The RhoA/RhoGDI complex, purified to greater than 98% at high yield from the yeast cytosolic fraction, could be stoichiometrically ADP-ribosylated by Clostridium botulinum C3 exoenzyme, contained stoichiometric GDP, and could be nucleotide exchanged fully with [3H]GDP or partially with GTP in the presence of submicromolar Mg2+ [24].
  • We have developed a Rho activation assay that is based on the specific binding of active RhoA to its downstream effector Rho-kinase (ROK) [25].
 

Regulatory relationships of Rhoa

  • In the present study, using NIH3T3 cells stably transfected with CCK-A receptors as a model cell, we demonstrate that CCK can induce actin stress fibers through a G13- and RhoA-dependent mechanism [26].
  • CCK-A receptor activates RhoA through G alpha 12/13 in NIH3T3 cells [26].
  • RhoA/ROCK signaling regulates Sox9 expression and actin organization during chondrogenesis [27].
  • Thus, mNET1 can activate signalling pathways in addition to those directly controlled by activated RhoA [28].
  • RhoA signaling was activated as early as 5 min following TGF-beta addition [29].
  • Foxj1 expression coincided with actin web formation, activated RhoA and RhoB, and persisted despite RhoA inhibition, suggesting that Foxj1 promoted RhoA during ciliogenesis [30].
 

Other interactions of Rhoa

  • By contrast, Galpha(13)Q226L activated RhoA but not Rac1 or Cdc42 [31].
  • Our data clearly show that G12/G13 as well as Gq/G11 alone can couple GPCRs to the rapid activation of RhoA [32].
  • The central nervous system abnormalities of Jip3-/- mice may be accounted for in part by a reduction in signal transduction by RhoA and its effector ROCK [33].
  • Finally, EphB-mediated RhoA activation is disrupted by FAK knock-down [34].
  • Expression of the constitutively active mutant form of p115RhoGEF (guanine nucleotide exchange factor) was found to activate RhoA and JNK1 activities [5].
 

Analytical, diagnostic and therapeutic context of Rhoa

References

  1. Enteropathogenic Escherichia coli activates the RhoA signaling pathway via the stimulation of GEF-H1. Matsuzawa, T., Kuwae, A., Yoshida, S., Sasakawa, C., Abe, A. EMBO J. (2004) [Pubmed]
  2. Rac1/Cdc42 and RhoA GTPases antagonistically regulate chondrocyte proliferation, hypertrophy, and apoptosis. Wang, G., Beier, F. J. Bone Miner. Res. (2005) [Pubmed]
  3. Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity. Leung, T.H., Ching, Y.P., Yam, J.W., Wong, C.M., Yau, T.O., Jin, D.Y., Ng, I.O. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. RhoA-dependent murine prostate cancer cell proliferation and apoptosis: role of protein kinase Czeta. Ghosh, P.M., Bedolla, R., Mikhailova, M., Kreisberg, J.I. Cancer Res. (2002) [Pubmed]
  5. G alpha 13 signals via p115RhoGEF cascades regulating JNK1 and primitive endoderm formation. Lee, Y.N., Malbon, C.C., Wang, H.Y. J. Biol. Chem. (2004) [Pubmed]
  6. Yersinia virulence depends on mimicry of host rho-family nucleotide dissociation inhibitors. Prehna, G., Ivanov, M.I., Bliska, J.B., Stebbins, C.E. Cell (2006) [Pubmed]
  7. The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac1. Chou, M.M., Blenis, J. Cell (1996) [Pubmed]
  8. Gln 63 of Rho is deamidated by Escherichia coli cytotoxic necrotizing factor-1. Schmidt, G., Sehr, P., Wilm, M., Selzer, J., Mann, M., Aktories, K. Nature (1997) [Pubmed]
  9. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Kimura, K., Ito, M., Amano, M., Chihara, K., Fukata, Y., Nakafuku, M., Yamamori, B., Feng, J., Nakano, T., Okawa, K., Iwamatsu, A., Kaibuchi, K. Science (1996) [Pubmed]
  10. Role of Rho in chemoattractant-activated leukocyte adhesion through integrins. Laudanna, C., Campbell, J.J., Butcher, E.C. Science (1996) [Pubmed]
  11. A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. Leung, T., Manser, E., Tan, L., Lim, L. J. Biol. Chem. (1995) [Pubmed]
  12. Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy*. Richardson, K.E., Tannous, P., Berenji, K., Nolan, B., Bayless, K.J., Davis, G.E., Rothermel, B.A., Hill, J.A. J. Investig. Med. (2005) [Pubmed]
  13. RhoB expression is induced after the transient upregulation of RhoA and Cdc42 during neuronal differentiation and influenced by culture substratum and microtubule integrity. Laplante, I., Paquin, J., Béliveau, R. Brain Res. Dev. Brain Res. (2001) [Pubmed]
  14. p116Rip is a novel filamentous actin-binding protein. Mulder, J., Poland, M., Gebbink, M.F., Calafat, J., Moolenaar, W.H., Kranenburg, O. J. Biol. Chem. (2003) [Pubmed]
  15. Inhibition of Rho-kinase protects the heart against ischemia/reperfusion injury. Bao, W., Hu, E., Tao, L., Boyce, R., Mirabile, R., Thudium, D.T., Ma, X.L., Willette, R.N., Yue, T.L. Cardiovasc. Res. (2004) [Pubmed]
  16. Genetic deletion of Rac1 GTPase reveals its critical role in actin stress fiber formation and focal adhesion complex assembly. Guo, F., Debidda, M., Yang, L., Williams, D.A., Zheng, Y. J. Biol. Chem. (2006) [Pubmed]
  17. Downstream components of RhoA required for signal pathway of superoxide formation during phagocytosis of serum opsonized zymosans in macrophages. Kim, J.S., Kim, J.G., Jeon, C.Y., Won, H.Y., Moon, M.Y., Seo, J.Y., Kim, J.I., Kim, J., Lee, J.Y., Choi, S.Y., Park, J., Yoon Park, J.H., Ha, K.S., Kim, P.H., Park, J.B. Exp. Mol. Med. (2005) [Pubmed]
  18. Galpha12/13 is essential for directed cell migration and localized Rho-Dia1 function. Goulimari, P., Kitzing, T.M., Knieling, H., Brandt, D.T., Offermanns, S., Grosse, R. J. Biol. Chem. (2005) [Pubmed]
  19. Pak1 is involved in dendrite initiation as a downstream effector of Rac1 in cortical neurons. Hayashi, K., Ohshima, T., Mikoshiba, K. Mol. Cell. Neurosci. (2002) [Pubmed]
  20. RhoA GTPase regulates L-type Ca2+ currents in cardiac myocytes. Yatani, A., Irie, K., Otani, T., Abdellatif, M., Wei, L. Am. J. Physiol. Heart Circ. Physiol. (2005) [Pubmed]
  21. RhoA GTPase regulates B cell receptor signaling. Saci, A., Carpenter, C.L. Mol. Cell (2005) [Pubmed]
  22. The Rho GTPase effector ROCK regulates cyclin A, cyclin D1, and p27Kip1 levels by distinct mechanisms. Croft, D.R., Olson, M.F. Mol. Cell. Biol. (2006) [Pubmed]
  23. Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. Booden, M.A., Siderovski, D.P., Der, C.J. Mol. Cell. Biol. (2002) [Pubmed]
  24. Human RhoA/RhoGDI complex expressed in yeast: GTP exchange is sufficient for translocation of RhoA to liposomes. Read, P.W., Liu, X., Longenecker, K., Dipierro, C.G., Walker, L.A., Somlyo, A.V., Somlyo, A.P., Nakamoto, R.K. Protein Sci. (2000) [Pubmed]
  25. Activation of RhoA by lysophosphatidic acid and Galpha12/13 subunits in neuronal cells: induction of neurite retraction. Kranenburg, O., Poland, M., van Horck, F.P., Drechsel, D., Hall, A., Moolenaar, W.H. Mol. Biol. Cell (1999) [Pubmed]
  26. CCK-A receptor activates RhoA through G alpha 12/13 in NIH3T3 cells. Le Page, S.L., Bi, Y., Williams, J.A. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  27. RhoA/ROCK signaling regulates Sox9 expression and actin organization during chondrogenesis. Woods, A., Wang, G., Beier, F. J. Biol. Chem. (2005) [Pubmed]
  28. Activation of RhoA and SAPK/JNK signalling pathways by the RhoA-specific exchange factor mNET1. Alberts, A.S., Treisman, R. EMBO J. (1998) [Pubmed]
  29. RhoA modulates Smad signaling during transforming growth factor-beta-induced smooth muscle differentiation. Chen, S., Crawford, M., Day, R.M., Briones, V.R., Leader, J.E., Jose, P.A., Lechleider, R.J. J. Biol. Chem. (2006) [Pubmed]
  30. RhoA-mediated apical actin enrichment is required for ciliogenesis and promoted by Foxj1. Pan, J., You, Y., Huang, T., Brody, S.L. J. Cell. Sci. (2007) [Pubmed]
  31. Radixin stimulates Rac1 and Ca2+/calmodulin-dependent kinase, CaMKII: cross-talk with Galpha13 signaling. Liu, G., Voyno-Yasenetskaya, T.A. J. Biol. Chem. (2005) [Pubmed]
  32. Receptor-dependent RhoA activation in G12/G13-deficient cells: genetic evidence for an involvement of Gq/G11. Vogt, S., Grosse, R., Schultz, G., Offermanns, S. J. Biol. Chem. (2003) [Pubmed]
  33. Morphogenesis of the telencephalic commissure requires scaffold protein JNK-interacting protein 3 (JIP3). Kelkar, N., Delmotte, M.H., Weston, C.R., Barrett, T., Sheppard, B.J., Flavell, R.A., Davis, R.J. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  34. EphB receptors regulate dendritic spine morphogenesis through the recruitment/phosphorylation of focal adhesion kinase and RhoA activation. Moeller, M.L., Shi, Y., Reichardt, L.F., Ethell, I.M. J. Biol. Chem. (2006) [Pubmed]
  35. Translocation of Src kinase to the cell periphery is mediated by the actin cytoskeleton under the control of the Rho family of small G proteins. Fincham, V.J., Unlu, M., Brunton, V.G., Pitts, J.D., Wyke, J.A., Frame, M.C. J. Cell Biol. (1996) [Pubmed]
  36. High RhoA activity maintains the undifferentiated mesenchymal cell phenotype, whereas RhoA down-regulation by laminin-2 induces smooth muscle myogenesis. Beqaj, S., Jakkaraju, S., Mattingly, R.R., Pan, D., Schuger, L. J. Cell Biol. (2002) [Pubmed]
  37. The monomeric G-proteins Rac1 and/or Cdc42 are required for the inhibition of voltage-dependent calcium current by bradykinin. Wilk-Blaszczak, M.A., Singer, W.D., Quill, T., Miller, B., Frost, J.A., Sternweis, P.C., Belardetti, F. J. Neurosci. (1997) [Pubmed]
  38. Direct interaction of focal adhesion kinase with p190RhoGEF. Zhai, J., Lin, H., Nie, Z., Wu, J., Cañete-Soler, R., Schlaepfer, W.W., Schlaepfer, D.D. J. Biol. Chem. (2003) [Pubmed]
  39. RhoA and RhoC proteins promote both cell proliferation and cell invasion of human oesophageal squamous cell carcinoma cell lines in vitro and in vivo. Faried, A., Faried, L.S., Kimura, H., Nakajima, M., Sohda, M., Miyazaki, T., Kato, H., Usman, N., Kuwano, H. Eur. J. Cancer (2006) [Pubmed]
 
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