Regulation of Rho GTPases by RhoGDIs in Human Cancers
Abstract
:1. Introduction
2. Regulation of Rho GTPases by RhoGDIs
3. Regulation of RhoGDIs Activity
3.1. Regulation of RhoGDIs by Phospholipids
3.2. Regulation of RhoGDIs by Protein–Protein Interaction
3.3. Regulation of RhoGDIs by Post-Translational Modifications
4. Functions of RhoGDIs in Human Cancers
5. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
- Nobes, C.D.; Hall, A. Rho, rac and cdc42 GTPases: Regulators of actin structures, cell adhesion and motility. Biochem. Soc. Trans. 1995, 23, 456–459. [Google Scholar] [CrossRef]
- Etienne-Manneville, S.; Hall, A. RhoGTPases in cell biology. Nature 2002, 420, 629–635. [Google Scholar] [CrossRef]
- Vega, F.M.; Ridley, A.J. RhoGTPases in cancer cell biology. FEBS Lett. 2008, 582, 2093–2101. [Google Scholar] [CrossRef]
- Gómez del Pulgar, T.; Benitah, S.A.; Valeron, P.F.; Espina, C.; Lacal, J.C. Rho GTPase expression in tumourigenesis: Evidence for a significant link. Bioessays 2005, 27, 602–613. [Google Scholar] [CrossRef]
- Hodge, R.G.; Ridley, A.J. Regulating Rho GTPases and their regulators. Nat. Rev. Mol. Cell Biol. 2016, 17, 496–510. [Google Scholar] [CrossRef]
- Schmidt, A.; Hall, A. Guanine nucleotide exchange factors for Rho GTPases: Turning on the switch. Genes Dev. 2002, 16, 1587–1609. [Google Scholar] [CrossRef]
- Moon, S.Y.; Zheng, Y. Rho GTPase-activation proteins in cell regulation. Trends Cell Biol. 2003, 13, 13–22. [Google Scholar] [CrossRef]
- Dovas, A.; Couchman, J.R. RhoGDI: Multiple functions in the regulation of Rho family GTPase activities. Biochem. J. 2005, 390, 1–9. [Google Scholar] [CrossRef]
- Olofsson, B. Rho guanine dissociation inhibitors: Pivotal molecules in cellular signalling. Cell Signal. 1999, 11, 545–554. [Google Scholar] [CrossRef]
- Leonard, D.; Hart, M.J.; Platko, J.V.; Eva, A.; Henzel, W.; Evans, T.; Cerione, R.A. The identification and characterization of a GDP-dissociation inhibitor (GDI) for the Cdc42Hs proteins. J. Biol. Chem. 1992, 267, 22860–22868. [Google Scholar]
- Lelias, J.M.; Adra, C.N.; Wulf, G.M.; Guillemot, J.C.; Khagad, M.; Caput, D.; Lim, B. cDNA cloning of a human mRNA preferentially expressed in hematopoietic cells and with homology to a GDP-dissociation inhibitor for the rho GTP-binding proteins. Proc. Natl. Acad. Sci. USA 1993, 90, 1479–1483. [Google Scholar] [CrossRef]
- Scherle, P.; Behrens, T.; Staudt, L.M. Ly-GDI, a GDP-dissociation inhibitor of the RhoA GTP-binding protein, is expressed preferentially in lymphocytes. Proc. Natl. Acad. Sci. USA 1993, 90, 7568–7572. [Google Scholar] [CrossRef]
- Zalcman, G.; Closson, V.; Camonis, J.; Honoré, N.; Rousseau-Merck, M.F.; Tavitian, A.; Olofsson, B. 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. J. Biol. Chem. 1996, 271, 30366–30374. [Google Scholar] [CrossRef]
- Adra, C.N.; Manor, D.; Ko, J.L.; Zhu, S.; Horiuchi, T.; Van Aelst, L.; Cerione, R.A.; Lim, B. RhoGDIgamma: A GDP-dissociation inhibitor for Rho proteins with preferential expression in brain and pancreas. Proc. Natl. Acad. Sci. USA 1997, 94, 4279–4284. [Google Scholar] [CrossRef]
- DerMardirossian, C.; Bokoch, G.M. GDIs: Central regulatory molecules in Rho GTPase activation. Trends Cell Biol. 2005, 15, 356–363. [Google Scholar] [CrossRef]
- Dransart, E.; Olofsson, B.; Cherfils, J. RhoGDIs revisited: Novel roles in Rho regulation. Traffic 2005, 6, 957–966. [Google Scholar] [CrossRef]
- Garcia-Mata, R.; Boulter, E.; Burridge, K. The ‘invisible hand’: Regulation of RHO GTPases by RHOGDIs. Nat. Rev. Mol. Cell Biol. 2011, 12, 493–504. [Google Scholar] [CrossRef]
- Cho, H.J.; Baek, K.E.; Yoo, J. RhoGDI2 as a therapeutic target in cancer. Expert Opin. Ther. Targets 2010, 14, 67–75. [Google Scholar] [CrossRef]
- Xie, F.; Shao, S.; Aziz, A.U.R.; Zhang, B.; Wang, H.; Liu, B. Role of Rho-specific guanine nucleotide dissociation inhibitor α regulation in cell migration. Acta Histochem. 2017, 119, 183–189. [Google Scholar] [CrossRef]
- Harding, M.A.; Theodorescu, D. RhoGDI signaling provides targets for cancer therapy. Eur. J. Cancer 2010, 46, 1252–1259. [Google Scholar] [CrossRef]
- Hoffman, G.R.; Nassar, N.; Cerione, R.A. Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI. Cell 2000, 100, 345–356. [Google Scholar] [CrossRef]
- Scheffzek, K.; Stephan, I.; Jensen, O.N.; Illenberger, D.; Gierschik, P. The Rac-RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI. Nat. Struct. Biol. 2000, 7, 122–126. [Google Scholar] [CrossRef]
- Vetter, I.R.; Wittinghofer, A. The guanine nucleotide-binding switch in three dimensions. Science 2001, 294, 1299–1304. [Google Scholar] [CrossRef]
- Keep, N.H.; Barnes, M.; Barsukov, I.; Badii, R.; Lian, L.Y.; Segal, A.W.; Moody, P.C.; Roberts, G.C. A modulator of rho family G proteins, rhoGDI, binds these G proteins via an immunoglobulin-like domain and a flexible N-terminal arm. Structure 1997, 5, 623–633. [Google Scholar] [CrossRef] [Green Version]
- Gosser, Y.Q.; Nomanbhoy, T.K.; Aghazadeh, B.; Manor, D.; Combs, C.; Cerione, R.A.; Rosen, M.K. C-terminal binding domain of Rho GDP-dissociation inhibitor directs N-terminal inhibitory peptide to GTPases. Nature 1997, 387, 814–819. [Google Scholar] [CrossRef]
- Robbe, K.; Otto-Bruc, A.; Chardin, P.; Antonny, B. Dissociation of GDP dissociation inhibitor and membrane translocation are required for efficient activation of Rac by the Dbl homology-pleckstrin homology region of Tiam. J. Biol. Chem. 2003, 278, 4756–4762. [Google Scholar] [CrossRef]
- Smithers, C.C.; Overduin, M. Structural Mechanisms and Drug Discovery Prospects of Rho GTPases. Cells 2016, 5, E26. [Google Scholar] [CrossRef]
- Lawson, C.D.; Ridley, A.J. Rho GTPase signaling complexes in cell migration and invasion. J. Cell Biol. 2018, 217, 447–457. [Google Scholar] [CrossRef]
- Boulter, E.; Garcia-Mata, R. RhoGDI: A rheostat for the Rho switch. Small GTPases 2010, 1, 65–68. [Google Scholar] [CrossRef]
- Cox, A.D.; Der, C.J. Protein prenylation: More than just glue? Curr. Opin. Cell Biol. 1992, 4, 1008–1016. [Google Scholar] [CrossRef]
- Boulter, E.; Garcia-Mata, R.; Guilluy, C.; Dubash, A.; Rossi, G.; Brennwald, P.J.; Burridge, K. Regulation of RhoGTPase crosstalk, degradation and activity by RhoGDI1. Nat. Cell Biol. 2010, 12, 477–483. [Google Scholar] [CrossRef]
- Chianale, F.; Rainero, E.; Cianflone, C.; Bettio, V.; Pighini, A.; Porporato, P.E.; Filigheddu, N.; Serini, G.; Sinigaglia, F.; Baldanzi, G.; et al. Diacylglycerol kinase alpha mediates HGF-induced Rac activation and membrane ruffling by regulating atypical PKC and RhoGDI. Proc. Natl. Acad. Sci. USA 2010, 107, 4182–4187. [Google Scholar] [CrossRef]
- Lin, Q.; Fuji, R.N.; Yang, W.; Cerione, R.A. RhoGDI is required for Cdc42-mediated cellular transformation. Curr. Biol. 2003, 13, 1469–1479. [Google Scholar] [CrossRef]
- Chuang, T.H.; Bohl, B.P.; Bokoch, G.M. Biologically active lipids are regulators of Rac.GDI complexation. J. Biol. Chem. 1993, 268, 26206–26211. [Google Scholar]
- Fauré, J.; Vignais, P.V.; Dagher, M.C. Phosphoinositide-dependent activation of Rho A involves partial opening of the RhoA/Rho-GDI complex. Eur. J. Biochem. 1999, 262, 879–889. [Google Scholar] [CrossRef]
- Yonemura, S.; Matsui, T.; Tsukita, S.; Tsukita, S. Rho-dependent and -independent activation mechanisms of ezrin/radixin/moesin proteins: An essential role for polyphosphoinositides in vivo. J. Cell Sci. 2002, 115, 2569–2580. [Google Scholar]
- Fievet, B.T.; Gautreau, A.; Roy, C.; Del Maestro, L.; Mangeat, P.; Louvard, D.; Arpin, M. Phosphoinositide binding and phosphorylation act sequentially in the activation mechanism of ezrin. J. Cell Biol. 2004, 164, 653–659. [Google Scholar] [CrossRef] [Green Version]
- Abramovici, H.; Mojtabaie, P.; Parks, R.J.; Zhong, X.P.; Koretzky, G.A.; Topham, M.K.; Gee, S.H. Diacylglycerol kinase zeta regulates actin cytoskeleton reorganization through dissociation of Rac1 from RhoGDI. Mol. Biol. Cell 2009, 20, 2049–2059. [Google Scholar] [CrossRef]
- Takahashi, K.; Sasaki, T.; Mammoto, A.; Takaishi, K.; Kameyama, T.; Tsukita, S.; Takai, Y. Direct interaction of the Rho GDP dissociation inhibitor with ezrin/radixin/moesin initiates the activation of the Rho small G protein. J. Biol. Chem. 1997, 272, 23371–23375. [Google Scholar] [CrossRef]
- Pu, J.; Mao, Y.; Lei, X.; Yan, Y.; Lu, X.; Tian, J.; Yin, X.; Zhao, G.; Zhang, B. FERM domain containing protein 7 interacts with the Rho GDP dissociation inhibitor and specifically activates Rac1 signaling. PLoS ONE 2013, 8, e73108. [Google Scholar] [CrossRef]
- Kim, O.; Yang, J.; Qiu, Y. Selective activation of small GTPase RhoA by tyrosine kinase Etk through its pleckstrin homology domain. J. Biol. Chem. 2002, 277, 30066–30071. [Google Scholar] [CrossRef]
- Yamashita, T.; Tohyama, M. The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat. Neurosci. 2003, 6, 461–467. [Google Scholar] [CrossRef]
- Lu, Y.; Liu, X.; Zhou, J.; Huang, A.; Zhou, J.; He, C. TROY interacts with Rho guanine nucleotide dissociation inhibitor α (RhoGDIα) to mediate Nogo-induced inhibition of neurite outgrowth. J. Biol. Chem. 2013, 288, 34276–34286. [Google Scholar] [CrossRef]
- Cho, H.J.; Hwang, Y.S.; Yoon, J.; Lee, M.; Lee, H.G.; Daar, I.O. EphrinB1 promotes cancer cell migration and invasion through the interaction with RhoGDI1. Oncogene 2018, 37, 861–872. [Google Scholar] [CrossRef]
- Zhu, G.F.; Xu, Y.W.; Li, J.; Niu, H.L.; Ma, W.X.; Xu, J.; Zhou, P.R.; Liu, X.; Ye, D.L.; Liu, X.R.; et al. Mir20a/106a-WTX axis regulates RhoGDIa/CDC42 signaling and colon cancer progression. Nat. Commun. 2019, 10, 112. [Google Scholar] [CrossRef]
- DerMardirossian, C.; Rocklin, G.; Seo, J.Y.; Bokoch, G.M. Phosphorylation of RhoGDI by Src regulates Rho GTPase binding and cytosol-membrane cycling. Mol. Biol. Cell 2006, 17, 4760–4768. [Google Scholar] [CrossRef]
- Dovas, A.; Choi, Y.; Yoneda, A.; Multhaupt, H.A.; Kwon, S.H.; Kang, D.; Oh, E.S.; Couchman, J.R. Serine 34 phosphorylation of rho guanine dissociation inhibitor (RhoGDIalpha) links signaling from conventional protein kinase C to RhoGTPase in cell adhesion. J. Biol. Chem. 2010, 285, 23296–23308. [Google Scholar] [CrossRef]
- Sabbatini, M.E.; Williams, J.A. Cholecystokinin-mediated RhoGDI phosphorylation via PKCα promotes both RhoA and Rac1 signaling. PLoS ONE 2013, 8, e66029. [Google Scholar] [CrossRef]
- DerMardirossian, C.; Schnelzer, A.; Bokoch, G.M. Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase. Mol. Cell 2004, 15, 117–127. [Google Scholar] [CrossRef]
- Fei, F.; Kweon, S.M.; Haataja, L.; De Sepulveda, P.; Groffen, J.; Heisterkamp, N. The Fer tyrosine kinase regulates interactions of Rho GDP-Dissociation Inhibitor α with the small GTPase Rac. BMC Biochem. 2010, 11, 48. [Google Scholar] [CrossRef]
- Lee, H.S.; Cheerathodi, M.; Chaki, S.P.; Reyes, S.B.; Zheng, Y.; Lu, Z.; Paidassi, H.; DerMardirossian, C.; Lacy-Hulbert, A.; Rivera, G.M.; et al. Protein tyrosine phosphatase-PEST and β8 integrin regulate spatiotemporal patterns of RhoGDI1 activation in migrating cells. Mol. Cell. Biol. 2015, 35, 1401–1413. [Google Scholar] [CrossRef]
- Ha, B.H.; Morse, E.M.; Turk, B.E.; Boggon, T.J. Signaling, Regulation, and Specificity of the Type II p21-activated Kinases. J. Biol. Chem. 2015, 290, 12975–12983. [Google Scholar] [CrossRef] [Green Version]
- Oishi, A.; Makita, N.; Sato, J.; Iiri, T. Regulation of RhoA signaling by the cAMP-dependent phosphorylation of RhoGDIα. J. Biol. Chem. 2012, 287, 38705–38715. [Google Scholar] [CrossRef]
- Tkachenko, E.; Sabouri-Ghomi, M.; Pertz, O.; Kim, C.; Gutierrez, E.; Machacek, M.; Groisman, A.; Danuser, G.; Ginsberg, M.H. Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells. Nat. Cell Biol. 2011, 13, 660–667. [Google Scholar] [CrossRef]
- Xiao, Y.; Lin, V.Y.; Ke, S.; Lin, G.E.; Lin, F.T.; Lin, W.C. 14-3-3τ promotes breast cancer invasion and metastasis by inhibiting RhoGDIα. Mol. Cell. Biol. 2014, 34, 2635–2649. [Google Scholar] [CrossRef]
- Cho, H.J.; Kim, J.T.; Lee, S.J.; Hwang, Y.S.; Park, S.Y.; Kim, B.Y.; Yoo, J.; Hong, K.S.; Min, J.K.; Lee, C.H.; et al. Protein phosphatase 1B dephosphorylates Rho guanine nucleotide dissociation inhibitor 1 and suppresses cancer cell migration and invasion. Cancer Lett. 2018, 417, 141–151. [Google Scholar] [CrossRef]
- Flotho, A.; Melchior, F. Sumoylation: A regulatory protein modification in health and disease. Ann. Rev. Biochem. 2013, 82, 357–385. [Google Scholar] [CrossRef]
- Geiss-Friedlander, R.; Melchior, F. Concepts in sumoylation: A decade on. Nat. Rev. Mol. Cell Biol. 2007, 8, 947–956. [Google Scholar] [CrossRef]
- Yu, J.; Zhang, D.; Liu, J.; Li, J.; Yu, Y.; Wu, X.R.; Huang, C. RhoGDI SUMOylation at Lys-138 increases its binding activity to Rho GTPase and its inhibiting cancer cell motility. J. Biol. Chem. 2012, 287, 13752–13760. [Google Scholar] [CrossRef]
- Cao, Z.; Li, X.; Li, J.; Kang, B.; Chen, J.; Luo, W.; Huang, C. SUMOylation of RhoGDIα is required for its repression of cyclin D1 expression and anchorage-independent growth of cancer cells. Mol. Oncol. 2014, 8, 285–296. [Google Scholar] [CrossRef]
- Su, L.; Lineberry, N.; Huh, Y.; Soares, L.; Fathman, C.G. A novel E3 ubiquitin ligase substrate screen identifies Rho guanine dissociation inhibitor as a substrate of gene related to anergy in lymphocytes. J. Immunol. 2006, 177, 7559–7566. [Google Scholar] [CrossRef]
- Kuhlmann, N.; Wroblowski, S.; Scislowski, L.; Lammers, M. RhoGDIα Acetylation at K127 and K141 Affects Binding toward Nonprenylated RhoA. Biochemistry 2016, 55, 304–312. [Google Scholar] [CrossRef]
- Kuhlmann, N.; Wroblowski, S.; Knyphausen, P.; de Boor, S.; Brenig, J.; Zienert, A.Y.; Meyer-Teschendorf, K.; Praefcke, G.J.; Nolte, H.; Krüger, M.; et al. Structural and Mechanistic Insights into the Regulation of the Fundamental Rho Regulator RhoGDIα by Lysine Acetylation. J. Biol. Chem. 2016, 291, 5484–5499. [Google Scholar] [CrossRef]
- Kim, J.G.; Kwon, H.J.; Wu, G.; Park, Y.; Lee, J.Y.; Kim, J.; Kim, S.C.; Choe, M.; Kang, S.G.; Seo, G.Y.; et al. RhoA GTPase oxidation stimulates cell proliferation via nuclear factor-κB activation. Free Radic. Biol. Med. 2017, 103, 57–68. [Google Scholar] [CrossRef]
- Zhao, L.; Wang, H.; Li, J.; Liu, Y.; Ding, Y. Overexpression of Rho GDP-dissociation inhibitor alpha is associated with tumor progression and poor prognosis of colorectal cancer. J. Proteome Res. 2008, 7, 3994–4003. [Google Scholar] [CrossRef]
- Huang, D.; Lu, W.; Zou, S.; Wang, H.; Jiang, Y.; Zhang, X.; Li, P.; Songyang, Z.; Wang, L.; Wang, J.; et al. Rho GDP-dissociation inhibitor α is a potential prognostic biomarker and controls telomere regulation in colorectal cancer. Cancer Sci. 2017, 108, 1293–1302. [Google Scholar] [CrossRef]
- Wang, H.; Wang, B.; Liao, Q.; An, H.; Li, W.; Jin, X.; Cui, S.; Zhao, L. Overexpression of RhoGDI, a novel predictor of distant metastasis, promotes cell proliferation and migration in hepatocellular carcinoma. FEBS Lett. 2014, 588, 503–508. [Google Scholar] [CrossRef]
- Song, Q.; Xu, Y.; Yang, C.; Chen, Z.; Jia, C.; Chen, J.; Zhang, Y.; Lai, P.; Fan, X.; Zhou, X.; et al. miR-483-5p promotes invasion and metastasis of lung adenocarcinoma by targeting RhoGDI1 and ALCAM. Cancer Res. 2014, 74, 3031–3042. [Google Scholar] [CrossRef]
- Forget, M.A.; Desrosiers, R.R.; Del, M.; Moumdjian, R.; Shedid, D.; Berthelet, F.; Béliveau, R. The expression of rho proteins decreases with human brain tumor progression: Potential tumor markers. Clin. Exp. Metastasis 2002, 19, 9–15. [Google Scholar] [CrossRef]
- Fritz, G.; Just, I.; Kaina, B. Rho GTPases are over-expressed in human tumors. Int. J. Cancer 1999, 81, 682–687. [Google Scholar] [CrossRef]
- Jiang, W.G.; Watkins, G.; Lane, J.; Cunnick, G.H.; Douglas-Jones, A.; Mokbel, K.; Mansel, R.E. Prognostic value of rho GTPases and rho guanine nucleotide dissociation inhibitors in human breast cancers. Clin. Cancer Res. 2003, 9, 6432–6440. [Google Scholar]
- Zhang, B.; Zhang, Y.; Dagher, M.C.; Shacter, E. Rho GDP dissociation inhibitor protects cancer cells against drug-induced apoptosis. Cancer Res. 2005, 65, 6054–6062. [Google Scholar] [CrossRef]
- Hooshmand, S.; Ghaderi, A.; Yusoff, K.; Karrupiah, T.; Rosli, R.; Mojtahedi, Z. Downregulation of RhoGDIα increased migration and invasion of ER (+) MCF7 and ER (-) MDA-MB-231 breast cancer cells. Cell Adhes. Migr. 2013, 7, 297–303. [Google Scholar] [CrossRef]
- Hooshmand, S.; Ghaderi, A.; Yusoff, K.; Thilakavathy, K.; Rosli, R.; Mojtahedi, Z. Differentially expressed proteins in ER+ MCF7 and ER- MDA- MB-231 human breast cancer cells by RhoGDI-α silencing and overexpression. Asian Pac. J. Cancer Prev. 2014, 15, 3311–3317. [Google Scholar] [CrossRef]
- Ma, L.; Xu, G.; Sotnikova, A.; Szczepanowski, M.; Giefing, M.; Krause, K.; Krams, M.; Siebert, R.; Jin, J.; Klapper, W. Loss of expression of LyGDI (ARHGDIB), a rho GDP-dissociation inhibitor, in Hodgkin lymphoma. Br. J. Haematol. 2007, 139, 217–223. [Google Scholar] [CrossRef]
- Gildea, J.J.; Seraj, M.J.; Oxford, G.; Harding, M.A.; Hampton, G.M.; Moskaluk, C.A.; Frierson, H.F.; Conaway, M.R.; Theodorescu, D. RhoGDI2 is an invasion and metastasis suppressor gene in human cancer. Cancer Res. 2002, 62, 6418–6423. [Google Scholar]
- Ahmed, M.; Sottnik, J.L.; Dancik, G.M.; Sahu, D.; Hansel, D.E.; Theodorescu, D.; Schwartz, M.A. An Osteopontin/CD44 Axis in RhoGDI2-Mediated Metastasis Suppression. Cancer Cell. 2016, 30, 432–443. [Google Scholar] [CrossRef] [Green Version]
- Tapper, J.; Kettunen, E.; El-Rifai, W.; Seppälä, M.; Andersson, L.C.; Knuutila, S. Changes in gene expression during progression of ovarian carcinoma. Cancer Genet. Cytogenet. 2001, 128, 1–6. [Google Scholar] [CrossRef]
- Cho, H.J.; Baek, K.E.; Park, S.M.; Kim, I.K.; Choi, Y.L.; Cho, H.J.; Nam, I.K.; Hwang, E.M.; Park, J.Y.; Han, J.Y.; et al. RhoGDI2 expression is associated with tumor growth and malignant progression of gastric cancer. Clin. Cancer Res. 2009, 15, 2612–2619. [Google Scholar] [CrossRef]
- Cho, H.J.; Kim, I.K.; Park, S.M.; Baek, K.E.; Nam, I.K.; Park, S.H.; Ryu, K.J.; Choi, J.; Ryu, J.; Hong, S.C.; et al. VEGF-C mediates RhoGDI2-induced gastric cancer cell metastasis and cisplatin resistance. Int. J. Cancer 2014, 135, 1553–1563. [Google Scholar]
- Cho, H.J.; Baek, K.E.; Park, S.M.; Kim, I.K.; Nam, I.K.; Choi, Y.L.; Park, S.H.; Im, M.J.; Choi, J.; Ryu, J.; et al. RhoGDI2 confers gastric cancer cells resistance against cisplatin-induced apoptosis by upregulation of Bcl-2 expression. Cancer Lett. 2011, 311, 48–56. [Google Scholar] [CrossRef]
- Singh, M.P.; Cho, H.J.; Kim, J.T.; Baek, K.E.; Lee, H.G.; Kang, S.C. Morin Hydrate Reverses Cisplatin Resistance by Impairing PARP1/HMGB1-Dependent Autophagy in Hepatocellular Carcinoma. Cancers (Basel) 2019, 11, E986. [Google Scholar] [CrossRef]
- Pasini, S.; Liu, J.; Corona, C.; Peze-Heidsieck, E.; Shelanski, M.; Greene, L.A. Activating Transcription Factor 4 (ATF4) modulates Rho GTPase levels and function via regulation of RhoGDIα. Sci. Rep. 2016, 6, 36952. [Google Scholar] [CrossRef]
- Zeng, P.; Sun, S.; Li, R.; Xiao, Z.X.; Chen, H. HER2 Upregulates ATF4 to Promote Cell Migration via Activation of ZEB1 and Downregulation of E-Cadherin. Int. J. Mol. Sci. 2019, 20, E2223. [Google Scholar] [CrossRef]
- Ding, J.; Huang, S.; Wu, S.; Zhao, Y.; Liang, L.; Yan, M.; Ge, C.; Yao, J.; Chen, T.; Wan, D.; et al. Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA. Nat. Cell Biol. 2010, 12, 390–399. [Google Scholar] [CrossRef]
- Wang, C.; Wang, X.; Su, Z.; Fei, H.; Liu, X.; Pan, Q. MiR-25 promotes hepatocellular carcinoma cell growth, migration and invasion by inhibiting RhoGDI1. Oncotarget 2015, 6, 36231–36244. [Google Scholar] [CrossRef]
- Lin, X.; Yang, B.; Liu, W.; Tan, X.; Wu, F.; Hu, P.; Jiang, T.; Bao, Z.; Yuan, J.; Qiang, B.; et al. Interplay between PCBP2 and miRNA modulates ARHGDIA expression and function in glioma migration and invasion. Oncotarget 2016, 7, 19483–19498. [Google Scholar] [CrossRef]
- Zhu, J.; Li, Y.; Chen, C.; Ma, J.; Sun, W.; Tian, Z.; Li, J.; Xu, J.; Liu, C.S.; Zhang, D.; et al. NF-κB p65 Overexpression Promotes Bladder Cancer Cell Migration via FBW7-Mediated Degradation of RhoGDIα Protein. Neoplasia 2017, 19, 672–683. [Google Scholar] [CrossRef]
- Dai, F.; Qi, Y.; Guan, W.; Meng, G.; Liu, Z.; Zhang, T.; Yao, W. RhoGDI stability is regulated by SUMOylation and ubiquitination via the AT1 receptor and participates in Ang II-induced smooth muscle proliferation and vascular remodeling. Atherosclerosis 2019, 288, 124–136. [Google Scholar] [CrossRef]
PTMs | Regulator | Target Site | Effects | Refs. |
---|---|---|---|---|
Phosphorylation | Src PAK1 PKCα PKA FER | Tyr27, Tyr156 Ser101, Ser174 Ser34, Ser96 Ser174 ND | Promotes release of RhoA, Rac1, and Cdc42 Promotes release of Rac1 Promotes release of RhoA and RhoG Induces the complex formation with RhoA Prevents the interaction with Rac1 | [45,47,48,49,50,53] |
Dephosphorylation | PTP-PEST PPM1B | Tyr156 Ser174 | Inactivation of Rac1 and Cdc42 Inactivation of RhoA, Rac1, and Cdc42 | [51,56] |
Sumoylation | ND | Lys138 | Increases the binding to RhoA, Rac1 and Cdc42 | [59] |
Ubiquitination | GRAIL | ND | Inhibits RhoA activation | [61] |
Acetylation | p300, pCAF | Lys127, Lys141 | Promotes release of RhoA | [62,63] |
Oxidation | ND | ND | Promotes RhoA activation | [64] |
RhoGDIs | Tumor | RNA/Protein | Expression | Correlation | Refs. |
---|---|---|---|---|---|
RhoGDI1 | Colorectal cancer Hepatocellular carcinoma Lung adenocarcinoma Brain cancer Breast cancer | Protein Protein RNA RNA Protein RNA, Protein | Up Up Down Down Down Up | St, M M M ND M ND | [65,66,67,68,69,70,71] |
RhoGDI2 | Hodgkin’s lymphoma Bladder cancer Ovarian cancer Gastric cancer Breast cancer | Protein RNA, Protein RNA Protein Protein | Down Down Up Up Up | A M St St, M M | [75,76,77,78,79,80,82] |
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Cho, H.J.; Kim, J.-T.; Baek, K.E.; Kim, B.-Y.; Lee, H.G. Regulation of Rho GTPases by RhoGDIs in Human Cancers. Cells 2019, 8, 1037. https://doi.org/10.3390/cells8091037
Cho HJ, Kim J-T, Baek KE, Kim B-Y, Lee HG. Regulation of Rho GTPases by RhoGDIs in Human Cancers. Cells. 2019; 8(9):1037. https://doi.org/10.3390/cells8091037
Chicago/Turabian StyleCho, Hee Jun, Jong-Tae Kim, Kyoung Eun Baek, Bo-Yeon Kim, and Hee Gu Lee. 2019. "Regulation of Rho GTPases by RhoGDIs in Human Cancers" Cells 8, no. 9: 1037. https://doi.org/10.3390/cells8091037