Implications of Rho GTPase signaling in glioma cell invasion and tumor progression

Frontiers in Oncology

Volumn 3 OCT, Issue , 2013, Pages

  Fortin Ensign, Shannon Patricia ^a,b   Mathews, Ian T ^a   Symons, Marc H ^c   Berens, Michael E ^a   Tran, Nhan L ^a  

^a TRANSLATIONAL GENOMICS RESEARCH INSTITUTE   (United States)

^b UNIVERSITY OF ARIZONA   (United States)

^c FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH   (United States)

Author keywords

Cdc42; GEFs; Glioblastoma; Invasion; Rac1; RhoA; RhoGTPase; Survival

Indexed keywords

DOCK PROTEIN; DYNAMIN II; ECT2 PROTEIN; GUANINE NUCLEOTIDE EXCHANGE FACTOR; MYOSIN LIGHT CHAIN; NEUROPILIN 1; PROTEASOME; PROTEIN; PROTEIN CDC42; PROTEIN SH3; RAC PROTEIN; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; RHOA GUANINE NUCLEOTIDE BINDING PROTEIN; SEMAPHORIN; SLIT2 PROTEIN; SWAP 70 PROTEIN; TUMOR NECROSIS FACTOR RECEPTOR; UNCLASSIFIED DRUG; VAV PROTEIN;

APOPTOSIS; CANCER SURVIVAL; CELL FUNCTION; CELL GROWTH; CELL INVASION; CELL POLARITY; DNA BINDING; GLIOMA; HUMAN; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; TUMOR GROWTH; UBIQUITINATION;

EID: 84891057493     PISSN: None     EISSN: 2234943X     Source Type: Journal    
DOI: 10.3389/fonc.2013.00241     Document Type: Review

References (151)

1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (2007) 114:97-109. doi: 10.1007/s00401-007-0278-6
2. Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS. The central nervous system. In: Frosch MP, Anthony DC, De Girolami U, editors. Robbins and Cotran Pathologic Basis of Disease, 8th ed. Philadelphia: Elsevier Saunders (2010). p. 1279-344.
3. Louis DN. Molecular pathology of malignant gliomas. Annu Rev Pathol (2006) 1:97-117. doi:10.1146/annurev.pathol.1.110304.100043
4. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol (2009) 10:459-66. doi:10.1016/S1470-2045(09)70025-7
5. Munson JM, Fried L, Rowson SA, Bonner MY, Karumbaiah L, Diaz B, et al. Anti-invasive adjuvant therapy with imipramine blue enhances chemotherapeutic efficacy against glioma. Sci Transl Med (2012) 4:127ra136. doi:10.1126/scitranslmed.3003016
6. Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, et al. A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell (2012) 150:165-78. doi:10.1016/j.cell.2012.04.042
7. Alexander S, Friedl P. Cancer invasion and resistance: interconnected processes of disease progression and therapy failure. Trends Mol Med (2012) 18:13-26. doi:10.1016/j.molmed.2011.11.003
8. Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB, Berens ME. Molecular targets of glioma invasion. Cell Mol Life Sci (2007) 64:458-78. doi:10.1007/s00018-007-6342-5
9. Kwiatkowska A, Symons M. Signaling determinants of glioma cell invasion. Adv Exp Med Biol (2013) 986:121-41. doi:10.1007/978-94-007-4719-7_7
10. Zhai GG, Malhotra R, Delaney M, Latham D, Nestler U, Zhang M, et al. Radiation enhances the invasive potential of primary glioblastoma cells via activation of the Rho signaling pathway. J Neurooncol (2006) 76:227-37. doi:10.1007/s11060-005-6499-4
11. Boureux A, Vignal E, Faure S, Fort P. Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol Biol Evol (2007) 24:203-16. doi:10.1093/molbev/msl145
12. Rossman KL, Der CJ, Sondek J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol (2005) 6:167-80. doi:10.1038/nrm1587
13. Etienne-Manneville S, Hall A. Rho GTPases in cell biology. Nature (2002) 420:629-35. doi:10.1038/nature01148
14. Vega FM, Ridley AJ. SnapShot: Rho family GTPases. Cell (2007) 129:1430. doi:10.1016/j.cell.2007.06.021
15. Riou P, Villalonga P, Ridley AJ. Rnd proteins: multifunctional regulators of the cytoskeleton and cell cycle progression. Bioessays (2010) 32:986-92. doi:10.1002/bies.201000060
16. Chardin P. Function and regulation of Rnd proteins. Nat Rev Mol Cell Biol (2006) 7:54-62. doi:10.1038/nrm1788
17. Nobes CD, Hall A. Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell (1995) 81:53-62. doi:10.1016/0092-8674(95)90370-4
18. Ando S, Kaibuchi K, Sasaki T, Hiraoka K, Nishiyama T, Mizuno T, et al. Post-translational processing of rac p21s is important both for their interaction with the GDP/GTP exchange proteins and for their activation of NADPH oxidase. J Biol Chem (1992) 267:25709-13.
19. Seabra MC. Membrane association and targeting of prenylated Ras-like GTPases. Cell Signal (1998) 10:167-72. doi:10.1016/S0898-6568(97)00120-4
20. Olofsson B. Rho guanine dissociation inhibitors: pivotal molecules in cellular signalling. Cell Signal (1999) 11:545-54. doi:10.1016/S0898-6568(98)00063-1
21. Wennerberg K, Der CJ. Rho-family GTPases: it's not only Rac and Rho (and I like it). J Cell Sci (2004) 117:1301-12. doi:10.1242/jcs.01118
22. Ding F, Yin Z, Wang HR. Ubiquitination in Rho signaling. Curr Top Med Chem (2011) 11:2879-87. doi:10.2174/156802611798281357
23. Boulter E, Garcia-Mata R, Guilluy C, Dubash A, Rossi G, Brennwald PJ, et al. Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1. Nat Cell Biol (2010) 12:477-83. doi:10.1038/ncb2049
24. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell (1992) 70:401-10.
25. Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell (1992) 70:389-99. doi:10.1016/0092-8674(92)90164-8
26. Kozma R, Ahmed S, Best A, Lim L. The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts. Mol Cell Biol (1995) 15:1942-52.
27. Guilluy C, Garcia-Mata R, Burridge K. Rho protein crosstalk: another social network? Trends Cell Biol (2011) 21:718-26. doi:10.1016/j.tcb.2011.08.002
28. Katoh H, Negishi M. RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature (2003) 424:461-4. doi:10.1038/nature01817
29. Katoh H, Hiramoto K, Negishi M. Activation of Rac1 by RhoG regulates cell migration. J Cell Sci (2006) 119:56-65. doi:10.1242/jcs.02720
30. Hiramoto K, Negishi M, Katoh H. Dock4 is regulated by RhoG and promotes Rac-dependent cell migration. Exp Cell Res (2006) 312:4205-16. doi:10.1016/j.yexcr.2006.09.006
31. Wennerberg K, Ellerbroek SM, Liu RY, Karnoub AE, Burridge K, Der CJ. RhoG signals in parallel with Rac1 and Cdc42. J Biol Chem (2002) 277:47810-7. doi:10.1074/jbc.M203816200
32. Raftopoulou M, Hall A. Cell migration: Rho GTPases lead the way. Dev Biol (2004) 265:23-32. doi:10.1016/j.ydbio.2003.06.003
33. Etienne-Manneville S, Hall A. Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta. Cell (2001) 106:489-98. doi:10.1016/S0092-8674(01)00471-8
34. Srinivasan S, Wang F, Glavas S, Ott A, Hofmann F, Aktories K, et al. Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis. J Cell Biol (2003) 160:375-85. doi:10.1083/jcb.200208179
35. Cotteret S, Chernoff J. The evolutionary history of effectors downstream of Cdc42 and Rac. Genome Biol (2002) 3:REVIEWS0002. doi:10.1186/gb-2002-3-2-reviews0002
36. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science (1996) 273:245-8. doi:10.1126/science.273.5272.245
37. Chrzanowska-Wodnicka M, Burridge K. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J Cell Biol (1996) 133:1403-15. doi:10.1083/jcb.133.6.1403
38. Riento K, Ridley AJ. Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol (2003) 4:446-56. doi:10.1038/nrm1128
39. Amano M, Chihara K, Kimura K, Fukata Y, Nakamura N, Matsuura Y, et al. Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science (1997) 275:1308-11. doi:10.1126/science.275.5304.1308
40. Watanabe N, Kato T, Fujita A, Ishizaki T, Narumiya S. Cooperation between mDia1 and ROCK in Rho-induced actin reorganization. Nat Cell Biol (1999) 1:136-43. doi:10.1038/11056
41. Pankova K, Rosel D, Novotny M, Brabek J. The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells. Cell Mol Life Sci (2010) 67:63-71. doi:10.1007/s00018-009-0132-1
42. Sanz-Moreno V, Marshall CJ. The plasticity of cytoskeletal dynamics underlying neoplastic cell migration. Curr Opin Cell Biol (2010) 22:690-6. doi:10.1016/j.ceb.2010.08.020
43. Machacek M, Hodgson L, Welch C, Elliott H, Pertz O, Nalbant P, et al. Coordination of Rho GTPase activities during cell protrusion. Nature (2009) 461:99-103. doi:10.1038/nature08242
44. Shimizu T, Ihara K, Maesaki R, Kuroda S, Kaibuchi K, Hakoshima T. 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. J Biol Chem (2000) 275:18311-7. doi:10.1074/jbc.M910274199
45. Schmidt A, Hall A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev (2002) 16:1587-609.
46. Cote JF, Vuori K. Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity. J Cell Sci (2002) 115:4901-13. doi:10.1242/jcs.00219
47. Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, et al. Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat Cell Biol (2002) 4:574-82.
48. Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, et al. Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet (2012) 44:1006-14. doi:10.1038/ng.2359
49. Davis MJ, Ha BH, Holman EC, Halaban R, Schlessinger J, Boggon TJ. RAC1P29S is a spontaneously activating cancer-associated GTPase. Proc Natl Acad Sci USA (2013) 110:912-7. doi:10.1073/pnas.1220895110
50. Salhia B, Tran NL, Chan A, Wolf A, Nakada M, Rutka F, et al. The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. Am J Pathol (2008) 173:1828-38. doi:10.2353/ajpath.2008.080043
51. Tran NL, McDonough WS, Savitch BA, Fortin SP, Winkles JA, Symons M, et al. Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-kappaB and correlate with poor patient outcome. Cancer Res (2006) 66:9535-42. doi:10.1158/0008-5472.CAN-06-0418
52. Chan AY, Coniglio SJ, Chuang YY, Michaelson D, Knaus UG, Philips MR, et al. Roles of the Rac1 and Rac3 GTPases in human tumor cell invasion. Oncogene (2005) 24:7821-9. doi:10.1038/sj.onc.1208909
53. Tran NL, McDonough WS, Savitch BA, Sawyer TF, Winkles JA, Berens ME. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression. J Biol Chem (2005) 280:3483-92. doi:10.1074/jbc.M409906200
54. Fortin SP, Ennis MJ, Savitch BA, Carpentieri D, McDonough WS, Winkles JA, et al. Tumor necrosis factor-like weak inducer of apoptosis stimulation of glioma cell survival is dependent on Akt2 function. Mol Cancer Res (2009) 7:1871-81. doi:10.1158/1541-7786.MCR-09-0194
55. Fortin SP, Ennis MJ, Schumacher CA, Zylstra-Diegel CR, Williams BO, Ross JT, et al. Cdc42 and the guanine nucleotide exchange factors Ect2 and Trio mediate Fn14-induced migration and invasion of glioblastoma cells. Mol Cancer Res (2012) 10(7):958-68. doi:10.1158/1541-7786.MCR-11-0616
56. Fortin Ensign SP, Mathews IT, Eschbacher JM, Loftus JC, Symons MH, Tran NL. The Src homology 3 domain-containing guanine nucleotide exchange factor is overexpressed in high-grade gliomas and promotes tumor necrosis factor-like weak inducer of apoptosis-fibroblast growth factor-inducible 14-induced cell migration and invasion via tumor necrosis factor receptor-associated factor 2. J Biol Chem (2013) 288(30):21887-97. doi:10.1074/jbc.M113.468686
57. Paulino VM, Yang Z, Kloss J, Ennis MJ, Armstrong BA, Loftus JC, et al. TROY (TNFRSF19) is overexpressed in advanced glial tumors and promotes glioblastoma cell invasion via Pyk2-Rac1 signaling. Mol Cancer Res (2010) 8:1558-67. doi:10.1158/1541-7786.MCR-10-0334
58. Servotte S, Camby I, Debeir O, Deroanne C, Lambert CA, Lapiere CM, et al. The in vitro influences of neurotensin on the motility characteristics of human U373 glioblastoma cells. Neuropathol Appl Neurobiol (2006) 32:575-84. doi:10.1111/j.1365-2990.2006.00760.x
59. Bagci T, Wu JK, Pfannl R, Ilag LL, Jay DG. Autocrine semaphorin 3A signaling promotes glioblastoma dispersal. Oncogene (2009) 28:3537-50. doi:10.1038/onc.2009.204
60. Li X, Law JW, Lee AY. Semaphorin 5A and plexin-B3 regulate human glioma cell motility and morphology through Rac1 and the actin cytoskeleton. Oncogene (2012) 31:595-610. doi:10.1038/onc.2011.256
61. Li X, Lee AY. Semaphorin 5A and plexin-B3 inhibit human glioma cell motility through RhoGDIalpha-mediated inactivation of Rac1 GTPase. J Biol Chem (2010) 285:32436-45. doi:10.1074/jbc.M110.120451
62. Nakada M, Drake KL, Nakada S, Niska JA, Berens ME. Ephrin-B3 ligand promotes glioma invasion through activation of Rac1. Cancer Res (2006) 66:8492-500. doi:10.1158/0008-5472.CAN-05-4211
63. Gimona M, Buccione R, Courtneidge SA, Linder S. Assembly and biological role of podosomes and invadopodia. Curr Opin Cell Biol (2008) 20:235-41. doi:10.1016/j.ceb.2008.01.005
64. Chuang YY, Tran NL, Rusk N, Nakada M, Berens ME, Symons M. Role of synaptojanin 2 in glioma cell migration and invasion. Cancer Res (2004) 64:8271-5. doi:10.1158/0008-5472.CAN-04-2097
65. Wang Q, Wang JY, Zhang XP, Lv ZW, Fu D, Lu YC, et al. RLIP76 is overexpressed in human glioblastomas and is required for proliferation, tumorigenesis and suppression of apoptosis. Carcinogenesis (2013) 34:916-26. doi:10.1093/carcin/bgs401
66. Zhou X, Qian J, Hua L, Shi Q, Liu Z, Xu Y, et al. Geranylgeranyltransferase I promotes human glioma cell growth through Rac1 membrane association and activation. J Mol Neurosci (2013) 49:130-9. doi:10.1007/s12031-012-9905-3
67. Feng H, Hu B, Jarzynka MJ, Li Y, Keezer S, Johns TG, et al. Phosphorylation of dedicator of cytokinesis 1 (Dock180) at tyrosine residue Y722 by Src family kinases mediates EGFRvIII-driven glioblastoma tumorigenesis. Proc Natl Acad Sci USA (2012) 109:3018-23. doi:10.1073/pnas.1121457109
68. Feng H, Hu B, Vuori K, Sarkaria JN, Furnari FB, Cavenee WK, et al. EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180. Oncogene (2013). doi:10.1038/onc.2013.198
69. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell (2010) 17:98-110. doi:10.1016/j.ccr.2009.12.020
70. Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci USA (1994) 91:7727-31. doi:10.1073/pnas.91.16.7727
71. The Cancer Genome Atlas (TCGA) Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature (2008) 455:1061-8. doi:10.1038/nature07385
72. Feng H, Hu B, Liu KW, Li Y, Lu X, Cheng T, et al. Activation of Rac1 by Src-dependent phosphorylation of Dock180(Y1811) mediates PDGFRalpha-stimulated glioma tumorigenesis in mice and humans. J Clin Invest (2011) 121:4670-84. doi:10.1172/JCI58559
73. Hu B, Shi B, Jarzynka MJ, Yiin JJ, D'Souza-Schorey C, Cheng SY. ADP-ribosylation factor 6 regulates glioma cell invasion through the IQ-domain GTPase-activating protein 1-Rac1-mediated pathway. Cancer Res (2009) 69:794-801. doi:10.1158/0008-5472.CAN-08-2110
74. Nishimura T, Yamaguchi T, Kato K, Yoshizawa M, Nabeshima Y, Ohno S, et al. PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol (2005) 7:270-7. doi:10.1038/ncb1227
75. Wang Z, Oh E, Thurmond DC. Glucose-stimulated Cdc42 signaling is essential for the second phase of insulin secretion. J Biol Chem (2007) 282:9536-46. doi:10.1074/jbc.M610553200
76. Jarzynka MJ, Hu B, Hui KM, Bar-Joseph I, Gu W, Hirose T, et al. ELMO1 and Dock180, a bipartite Rac1 guanine nucleotide exchange factor, promote human glioma cell invasion. Cancer Res (2007) 67:7203-11. doi:10.1158/0008-5472.CAN-07-0473
77. Kwiatkowska A, Didier S, Fortin S, Chuang Y, White T, Berens ME, et al. The small GTPase RhoG mediates glioblastoma cell invasion. Mol Cancer (2012) 11:65. doi:10.1186/1476-4598-11-65
78. Feng H, Liu KW, Guo P, Zhang P, Cheng T, McNiven MA, et al. Dynamin 2 mediates PDGFRalpha-SHP-2-promoted glioblastoma growth and invasion. Oncogene (2012) 31:2691-702. doi:10.1038/onc.2011.436
79. Hirata E, Yukinaga H, Kamioka Y, Arakawa Y, Miyamoto S, Okada T, et al. In vivo fluorescence resonance energy transfer imaging reveals differential activation of Rho-family GTPases in glioblastoma cell invasion. J Cell Sci (2012) 125:858-68. doi:10.1242/jcs.089995
80. Kim JY, Oh MH, Bernard LP, Macara IG, Zhang H. The RhoG/ELMO1/Dock180 signaling module is required for spine morphogenesis in hippocampal neurons. J Biol Chem (2011) 286:37615-24. doi:10.1074/jbc.M111.268029
81. Franke K, Otto W, Johannes S, Baumgart J, Nitsch R, Schumacher S. miR-124-regulated RhoG reduces neuronal process complexity via ELMO/Dock180/Rac1 and Cdc42 signalling. EMBO J (2012) 31:2908-21. doi:10.1038/emboj.2012.130
82. Samson T, Welch C, Monaghan-Benson E, Hahn KM, Burridge K. Endogenous RhoG is rapidly activated after epidermal growth factor stimulation through multiple guanine-nucleotide exchange factors. Mol Biol Cell (2010) 21:1629-42. doi:10.1091/mbc.E09-09-0809
83. Bass MD, Williamson RC, Nunan RD, Humphries JD, Byron A, Morgan MR, et al. A syndecan-4 hair trigger initiates wound healing through caveolin-and RhoG-regulated integrin endocytosis. Dev Cell (2011) 21:681-93. doi:10.1016/j.devcel.2011.08.007
84. Iden S, Collard JG. Crosstalk between small GTPases and polarity proteins in cell polarization. Nat Rev Mol Cell Biol (2008) 9:846-59. doi:10.1038/nrm2521
85. Berzat A, Hall A. Cellular responses to extracellular guidance cues. EMBO J (2010) 29:2734-45. doi:10.1038/emboj.2010.170
86. Meller J, Vidali L, Schwartz MA. Endogenous RhoG is dispensable for integrin-mediated cell spreading but contributes to Rac-independent migration. J Cell Sci (2008) 121:1981-9. doi:10.1242/jcs.025130
87. Bigarella CL, Borges L, Costa FF, Saad ST. ARHGAP21 modulates FAK activity and impairs glioblastoma cell migration. Biochim Biophys Acta (2009) 1793:806-16. doi:10.1016/j.bbamcr.2009.02.010
88. Yiin JJ, Hu B, Jarzynka MJ, Feng H, Liu KW, Wu JY, et al. Slit2 inhibits glioma cell invasion in the brain by suppression of Cdc42 activity. Neuro Oncol (2009) 11:779-89. doi:10.1215/15228517-2008-017
89. Yan B, Chour HH, Peh BK, Lim C, Salto-Tellez M. RhoA protein expression correlates positively with degree of malignancy in astrocytomas. Neurosci Lett (2006) 407:124-6. doi:10.1016/j.neulet.2006.08.032
90. Malchinkhuu E, Sato K, Maehama T, Mogi C, Tomura H, Ishiuchi S, et al. S1P(2) receptors mediate inhibition of glioma cell migration through Rho signaling pathways independent of PTEN. Biochem Biophys Res Commun (2008) 366:963-8. doi:10.1016/j.bbrc.2007.12.054
91. Johnston AL, Lun X, Rahn JJ, Liacini A, Wang L, Hamilton MG, et al. The p75 neurotrophin receptor is a central regulator of glioma invasion. PLoS Biol (2007) 5:e212. doi:10.1371/journal.pbio.0050212
92. Salhia B, Rutten F, Nakada M, Beaudry C, Berens M, Kwan A, et al. Inhibition of Rho-kinase affects astrocytoma morphology, motility, and invasion through activation of Rac1. Cancer Res (2005) 65:8792-800. doi:10.1158/0008-5472.CAN-05-0160
93. Manning TJ Jr, Parker JC, Sontheimer H. Role of lysophosphatidic acid and rho in glioma cell motility. Cell Motil Cytoskeleton (2000) 45:185-99. doi:10.1002/(SICI)1097-0169(200003)45:3<185::AID-CM2%gt;3.0.CO;2-G
94. Seasholtz TM, Radeff-Huang J, Sagi SA, Matteo R, Weems JM, Cohen AS, et al. Rho-mediated cytoskeletal rearrangement in response to LPA is functionally antagonized by Rac1 and PIP2. J Neurochem (2004) 91:501-12. doi:10.1111/j.1471-4159.2004.02749.x
95. Goldberg L, Kloog Y. A Ras inhibitor tilts the balance between Rac and Rho and blocks phosphatidylinositol 3-kinase-dependent glioblastoma cell migration. Cancer Res (2006) 66:11709-17. doi:10.1158/0008-5472.CAN-06-1878
96. Ramis G, Thomas-Moya E, Fernandez de Mattos S, Rodriguez J, Villalonga P. EGFR inhibition in glioma cells modulates Rho signaling to inhibit cell motility and invasion and cooperates with temozolomide to reduce cell growth. PLoS ONE (2012) 7:e38770. doi:10.1371/journal.pone.0038770
97. Lefranc F, Sauvage S, Van Goietsenoven G, Megalizzi V, Lamoral-Theys D, Debeir O, et al. Narciclasine, a plant growth modulator, activates Rho and stress fibers in glioblastoma cells. Mol Cancer Ther (2009) 8:1739-50. doi:10.1158/1535-7163.MCT-08-0932
98. Danussi C, Akavia UD, Niola F, Jovic A, Lasorella A, Pe'er D, et al. RHPN2 drives mesenchymal transformation in malignant glioma by triggering RhoA activation. Cancer Res (2013) 73(16):5140-50. doi:10.1158/0008-5472.CAN-13-1168-T
99. Yamazaki D, Kurisu S, Takenawa T. Involvement of Rac and Rho signaling in cancer cell motility in 3D substrates. Oncogene (2009) 28:1570-83. doi:10.1038/onc.2009.2
100. Mertsch S, Oellers P, Wendling M, Stracke W, Thanos S. Dissecting the inter-substrate navigation of migrating glioblastoma cells with the stripe assay reveals a causative role of ROCK. Mol Neurobiol (2013) 48(1):169-79. doi:10.1007/s12035-013-8429-3
101. Seol HJ, Smith CA, Salhia B, Rutka JT. The guanine nucleotide exchange factor SWAP-70 modulates the migration and invasiveness of human malignant glioma cells. Transl Oncol (2009) 2:300-9.
102. Tatsumoto T, Xie X, Blumenthal R, Okamoto I, Miki T. Human ECT2 is an exchange factor for Rho GTPases, phosphorylated in G2/M phases, and involved in cytokinesis. J Cell Biol (1999) 147:921-8. doi:10.1083/jcb.147.5.921
103. Matthews HK, Delabre U, Rohn JL, Guck J, Kunda P, Baum B. Changes in Ect2 localization couple actomyosin-dependent cell shape changes to mitotic progression. Dev Cell (2012) 23:371-83. doi:10.1016/j.devcel.2012.06.003
104. Weeks A, Okolowsky N, Golbourn B, Ivanchuk S, Smith C, Rutka JT. ECT2 and RASAL2 mediate mesenchymal-amoeboid transition in human astrocytoma cells. Am J Pathol (2012) 181:662-74. doi:10.1016/j.ajpath.2012.04.011
105. Frank SR, Hansen SH. The PIX-GIT complex: a G protein signaling cassette in control of cell shape. Semin Cell Dev Biol (2008) 19:234-44. doi:10.1016/j.semcdb.2008.01.002
106. Wang H, Han M, Whetsell W Jr, Wang J, Rich J, Hallahan D, et al. Tax-interacting protein 1 coordinates the spatiotemporal activation of Rho GTPases and regulates the infiltrative growth of human glioblastoma. Oncogene (2013). doi:10.1038/onc.2013.97
107. Borggrefe T, Wabl M, Akhmedov AT, Jessberger R. A B-cell-specific DNA recombination complex. J Biol Chem (1998) 273:17025-35. doi:10.1074/jbc.273.27.17025
108. Qi H, Fournier A, Grenier J, Fillion C, Labrie Y, Labrie C. Isolation of the novel human guanine nucleotide exchange factor Src homology 3 domain-containing guanine nucleotide exchange factor (SGEF) and of C-terminal SGEF, an N-terminally truncated form of SGEF, the expression of which is regulated by androgen in prostate cancer cells. Endocrinology (2003) 144:1742-52.
109. Ellerbroek SM, Wennerberg K, Arthur WT, Dunty JM, Bowman DR, DeMali KA, et al. SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis. Mol Biol Cell (2004) 15:3309-19. doi:10.1091/mbc.E04-02-0146
110. Krishna Subbaiah V, Massimi P, Boon SS, Myers MP, Sharek L, Garcia-Mata R, et al. The invasive capacity of HPV transformed cells requires the hDlg-dependent enhancement of SGEF/RhoG activity. PLoS Pathog (2012) 8:e1002543. doi:10.1371/journal.ppat.1002543
111. Garcia JL, Couceiro J, Gomez-Moreta JA, Gonzalez Valero JM, Briz AS, Sauzeau V, et al. Expression of VAV1 in the tumour microenvironment of glioblastoma multiforme. J Neurooncol (2012) 110:69-77. doi:10.1007/s11060-012-0936-y
112. Bagchi S, Liao Z, Gonzalez FA, Chorna NE, Seye CI, Weisman GA, et al. The P2Y2 nucleotide receptor interacts with alphav integrins to activate Go and induce cell migration. J Biol Chem (2005) 280:39050-7. doi:10.1074/jbc.M504819200
113. Debant A, Serra-Pages C, Seipel K, O'Brien S, Tang M, Park SH, et al. The multidomain protein Trio binds the LAR transmembrane tyrosine phosphatase, contains a protein kinase domain, and has separate rac-specific and rho-specific guanine nucleotide exchange factor domains. Proc Natl Acad Sci USA (1996) 93:5466-71. doi:10.1073/pnas.93.11.5466
114. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell (2006) 9:157-73. doi:10.1016/j.ccr.2006.02.019
115. Meller N, Westbrook MJ, Shannon JD, Guda C, Schwartz MA. Function of the N-terminus of zizimin1: autoinhibition and membrane targeting. Biochem J (2008) 409:525-33. doi:10.1042/BJ20071263
116. Meller N, Irani-Tehrani M, Kiosses WB, Del Pozo MA, Schwartz MA. Zizimin1, a novel Cdc42 activator, reveals a new GEF domain for Rho proteins. Nat Cell Biol (2002) 4:639-47. doi:10.1038/ncb835
117. Kuramoto K, Negishi M, Katoh H. Regulation of dendrite growth by the Cdc42 activator Zizimin1/Dock9 in hippocampal neurons. J Neurosci Res (2009) 87:1794-805. doi:10.1002/jnr.21997
118. Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SA, Fack F, et al. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA (2011) 108:3749-54. doi:10.1073/pnas.1014480108
119. Brat DJ, Castellano-Sanchez AA, Hunter SB, Pecot M, Cohen C, Hammond EH, et al. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population. Cancer Res (2004) 64:920-7. doi:10.1158/0008-5472.CAN-03-2073
120. Rong Y, Durden DL, Van Meir EG, Brat DJ. 'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J Neuropathol Exp Neurol (2006) 65:529-39. doi:10.1097/00005072-200606000-00001
121. Leon SP, Folkerth RD, Black PM. Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer (1996) 77:362-72. doi:10.1002/(SICI)1097-0142(19960115)77:2<362::AID-CNCR20>3.0.CO;2-Z
122. Hoelzinger DB, Mariani L, Weis J, Woyke T, Berens TJ, McDonough WS, et al. Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets. Neoplasia (2005) 7:7-16. doi:10.1593/neo.04535
123. Mariani L, Beaudry C, McDonough WS, Hoelzinger DB, Demuth T, Ross KR, et al. Glioma cell motility is associated with reduced transcription of proapoptotic and proliferation genes: a cDNA microarray analysis. J Neurooncol (2001) 53:161-76. doi:10.1023/A:1012253317934
124. Kislin KL, McDonough WS, Eschbacher JM, Armstrong BA, Berens ME. NHERF-1: modulator of glioblastoma cell migration and invasion. Neoplasia (2009) 11:377-87.
125. Zhang B, Gu F, She C, Guo H, Li W, Niu R, et al. Reduction of Akt2 inhibits migration and invasion of glioma cells. Int J Cancer (2009) 125:585-95. doi:10.1002/ijc.24314
126. Brassesco MS, Roberto GM, Morales AG, Oliveira JC, Delsin LE, Pezuk JA, et al. Inhibition of NF-kappa B by dehydroxymethylepoxyquinomicin suppresses invasion and synergistically potentiates temozolomide and gamma-radiation cytotoxicity in glioblastoma cells. Chemother Res Pract (2013) 2013:593020.
127. Loftus JC, Dhruv H, Tuncali S, Kloss J, Yang Z, Schumacher CA, et al. TROY (TNFRSF19) promotes glioblastoma cell survival signaling and therapeutic resistance. Mol Cancer Res (2013) 11(8):865-74. doi:10.1158/1541-7786.MCR-13-0008
128. Beier D, Schulz JB, Beier CP. Chemoresistance of glioblastoma cancer stem cells-much more complex than expected. Mol Cancer (2011) 10:128. doi:10.1186/1476-4598-10-128
129. Yoon CH, Hyun KH, Kim RK, Lee H, Lim EJ, Chung HY, et al. The small GTPase Rac1 is involved in the maintenance of stemness and malignancies in glioma stem-like cells. FEBS Lett (2011) 585:2331-8. doi:10.1016/j.febslet.2011.05.070
130. Zheng M, Morgan-Lappe SE, Yang J, Bockbrader KM, Pamarthy D, Thomas D, et al. Growth inhibition and radiosensitization of glioblastoma and lung cancer cells by small interfering RNA silencing of tumor necrosis factor receptor-associated factor 2. Cancer Res (2008) 68:7570-8. doi:10.1158/0008-5472.CAN-08-0632
131. Yang HJ, Youn H, Seong KM, Jin YW, Kim J, Youn B. Phosphorylation of ribosomal protein S3 and antiapoptotic TRAF2 protein mediates radioresistance in non-small cell lung cancer cells. J Biol Chem (2013) 288:2965-75. doi:10.1074/jbc.M112.385989
132. Lin WJ, Su YW, Lu YC, Hao Z, Chio II, Chen NJ, et al. Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFkappaB2 signaling that contributes to autoimmunity. Proc Natl Acad Sci USA (2011) 108:18354-9. doi:10.1073/pnas.1109427108
133. Jang KW, Lee KH, Kim SH, Jin T, Choi EY, Jeon HJ, et al. Ubiquitin ligase CHIP induces TRAF2 proteasomal degradation and NF-kappaB inactivation to regulate breast cancer cell invasion. J Cell Biochem (2011) 112:3612-20. doi:10.1002/jcb.23292
134. Natoli G, Costanzo A, Guido F, Moretti F, Bernardo A, Burgio VL, et al. Nuclear factor kB-independent cytoprotective pathways originating at tumor necrosis factor receptor-associated factor 2. J Biol Chem (1998) 273:31262-72. doi:10.1074/jbc.273.47.31262
135. Rothe M, Sarma V, Dixit VM, Goeddel DV. TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40. Science (1995) 269:1424-7. doi:10.1126/science.7544915
136. Liu ZG, Hsu H, Goeddel DV, Karin M. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell (1996) 87:565-76. doi:10.1016/S0092-8674(00)81375-6
137. Natoli G, Costanzo A, Ianni A, Templeton DJ, Woodgett JR, Balsano C, et al. Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Science (1997) 275:200-3. doi:10.1126/science.275.5297.200
138. Nomura N, Nomura M, Mizuki N, Hamada J. Rac1 mediates phorbol 12-myristate 13-acetate-induced migration of glioblastoma cells via paxillin. Oncol Rep (2008) 20:705-11.
139. Hwang SY, Jung JW, Jeong JS, Kim YJ, Oh ES, Kim TH, et al. Dominant-negative Rac increases both inherent and ionizing radiation-induced cell migration in C6 rat glioma cells. Int J Cancer (2006) 118:2056-63. doi:10.1002/ijc.21574
140. Golubovskaya VM, Huang G, Ho B, Yemma M, Morrison CD, Lee J, et al. Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide. Mol Cancer Ther (2013) 12:162-72. doi:10.1158/1535-7163.MCT-12-0701
141. Vega FM, Ridley AJ. Rho GTPases in cancer cell biology. FEBS Lett (2008) 582:2093-101. doi:10.1016/j.febslet.2008.04.039
142. Senger DL, Tudan C, Guiot MC, Mazzoni IE, Molenkamp G, LeBlanc R, et al. Suppression of Rac activity induces apoptosis of human glioma cells but not normal human astrocytes. Cancer Res (2002) 62:2131-40.
143. Surviladze Z, Young SM, Sklar LA. High-throughput flow cytometry bead-based multiplex assay for identification of Rho GTPase inhibitors. Methods Mol Biol (2012) 827:253-70. doi:10.1007/978-1-61779-442-1_17
144. Marchioni F, Zheng Y. Targeting rho GTPases by peptidic structures. Curr Pharm Des (2009) 15:2481-7. doi:10.2174/138161209788682334
145. Nassar N, Cancelas J, Zheng J, Williams DA, Zheng Y. Structure-function based design of small molecule inhibitors targeting Rho family GTPases. Curr Top Med Chem (2006) 6:1109-16. doi:10.2174/156802606777812095
146. Montalvo-Ortiz BL, Castillo-Pichardo L, Hernandez E, Humphries-Bickley T, De la Mota-Peynado A, Cubano LA, et al. Characterization of EHop-016, novel small molecule inhibitor of Rac GTPase. J Biol Chem (2012) 287:13228-38. doi:10.1074/jbc.M111.334524
147. Ortiz-Sanchez JM, Nichols SE, Sayyah J, Brown JH, McCammon JA, Grant BJ. Identification of potential small molecule binding pockets on Rho family GTPases. PLoS ONE (2012) 7:e40809. doi:10.1371/journal.pone.0040809
148. Murray BW, Guo C, Piraino J, Westwick JK, Zhang C, Lamerdin J, et al. Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth. Proc Natl Acad Sci USA (2010) 107:9446-51. doi:10.1073/pnas.0911863107
149. Blangy A, Fort P. Using a modified yeast two-hybrid system to screen for chemical GEF inhibitors. Methods Mol Biol (2012) 928:81-95. doi:10.1007/978-1-62703-008-3_7
150. Schmidt S, Diriong S, Mery J, Fabbrizio E, Debant A. Identification of the first Rho-GEF inhibitor, TRIPalpha, which targets the RhoA-specific GEF domain of Trio. FEBS Lett (2002) 523:35-42. doi:10.1016/S0014-5793(02)02928-9
151. Bouquier N, Vignal E, Charrasse S, Weill M, Schmidt S, Leonetti JP, et al. A cell active chemical GEF inhibitor selectively targets the Trio/RhoG/Rac1 signaling pathway. Chem Biol (2009) 16:657-66. doi:10.1016/j.chembiol.2009.04.012