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Rho GTPases in primary brain tumor malignancy and invasion

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Abstract

Gliomas are the most common type of malignant primary brain tumor in humans, accounting for 80 % of malignant cases. Expression and activity of Rho GTPases, which coordinate several cellular processes including cell-cycle progression and cell migration, are commonly altered in many types of primary brain tumor. Here we review the suggested effects of deregulated Rho GTPase signaling on brain tumor malignancy, highlighting the controversy in the field. For instance, whereas expression of RhoA and RhoB has been found to be significantly reduced in astrocytic tumors, other studies have reported Rho-dependent LPA-induced migration in glioma cells. Moreover, whereas the Rac1 expression level has been found to be reduced in astrocytic tumor, it was overexpressed and induced invasion in medulloblastoma tumors. In addition to the Rho GTPases themselves, several of their downstream effectors (including ROCK, mDia, and N-WASP) and upstream regulators (including GEFs, GAPs, PI3K, and PTEN) have also been implicated in primary brain tumors.

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References

  1. American Cancer Society (2010) Cancer facts & figures 2010. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-026238.pdf. Accessed 25 Nov 2010

  2. Horner M et al (2009) SEER cancer statistics review, 1975–2006. http://seer.cancer.gov/csr/1975_2006/. Accessed 21 Jan 2011

  3. Louis DN et al (2007) WHO classification of tumours of the central nervous system. WHO classification of tumours, vol 1, 4th edn. World Health Organization, IARC, Lyon

  4. CBTRUS (2011) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2004–2007

  5. DeAngelis LM (2001) Brain tumors. N Engl J Med 344(2):114–123

    Article  PubMed  CAS  Google Scholar 

  6. Takai Y, Sasaki T, Matozaki T (2001) Small GTP-binding proteins. Physiol Rev 81(1):153–208

    PubMed  CAS  Google Scholar 

  7. Rojas AM et al (2012) Evolution: the Ras protein superfamily: evolutionary tree and role of conserved amino acids. J Cell Biol 196(2):189–201

    Article  PubMed  CAS  Google Scholar 

  8. Madaule P, Axel R (1985) A novel ras-related gene family. Cell 41(1):31–40

    Article  PubMed  CAS  Google Scholar 

  9. Ridley AJ (2012) Historical overview of Rho GTPases. Methods Mol Biol 827:3–12

    Article  PubMed  Google Scholar 

  10. Shinjo K et al (1990) Molecular cloning of the gene for the human placental GTP-binding protein Gp (G25K): identification of this GTP-binding protein as the human homolog of the yeast cell-division-cycle protein CDC42. Proc Natl Acad Sci USA 87(24):9853–9857

    Article  PubMed  CAS  Google Scholar 

  11. Ridley AJ et al (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70(3):401–410

    Article  PubMed  CAS  Google Scholar 

  12. Ridley AJ, Hall A (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70(3):389–399

    Article  PubMed  CAS  Google Scholar 

  13. Elias M, Klimes V (2012) Rho GTPases: deciphering the evolutionary history of a complex protein family. Methods Mol Biol 827:13–34

    Article  PubMed  Google Scholar 

  14. Boureux A et al (2007) Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol Biol Evol 24(1):203–216

    Article  PubMed  CAS  Google Scholar 

  15. Guilluy C, Garcia-Mata R, Burridge K (2011) Rho protein crosstalk: another social network? Trends Cell Biol 21(12):718–726

    Article  PubMed  CAS  Google Scholar 

  16. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420(6916):629–635

    Article  PubMed  CAS  Google Scholar 

  17. Bishop AL, Hall A (2000) Rho GTPases and their effector proteins. Biochem J 348(Pt 2):241–255

    Article  PubMed  CAS  Google Scholar 

  18. Machacek M et al (2009) Coordination of Rho GTPase activities during cell protrusion. Nature 461(7260):99–103

    Article  PubMed  CAS  Google Scholar 

  19. Gardiner EM et al (2002) Spatial and temporal analysis of Rac activation during live neutrophil chemotaxis. Curr Biol 12(23):2029–2034

    Article  PubMed  CAS  Google Scholar 

  20. Bourne HR, Sanders DA, McCormick F (1990) The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348(6297):125–132

    Article  PubMed  CAS  Google Scholar 

  21. Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279(5350):509–514

    Article  PubMed  CAS  Google Scholar 

  22. Rosenblatt AE et al (2011) Inhibition of the Rho GTPase, Rac1, decreases estrogen receptor levels and is a novel therapeutic strategy in breast cancer. Endocr Relat Cancer 18(2):207–219

    PubMed  CAS  Google Scholar 

  23. Bustelo XR, Sauzeau V, Berenjeno IM (2007) GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. BioEssays 29(4):356–370

    Article  PubMed  CAS  Google Scholar 

  24. Leung R, Glogauer M (2012) Rho GTPase techniques in osteoclastogenesis. Methods Mol Biol 827:167–179

    Article  PubMed  Google Scholar 

  25. Mulloy JC et al (2010) Rho GTPases in hematopoiesis and hemopathies. Blood 115(5):936–947

    Article  PubMed  CAS  Google Scholar 

  26. Wennerberg K, Der CJ (2004) Rho-family GTPases: it’s not only Rac and Rho (and I like it). J Cell Sci 117(Pt 8):1301–1312

    Article  PubMed  CAS  Google Scholar 

  27. Doye A, Mettouchi A, Lemichez E (2012) Assessing ubiquitylation of Rho GTPases in mammalian cells. Methods Mol Biol 827:77–86

    Article  PubMed  Google Scholar 

  28. Boulter E et al (2010) Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1. Nat Cell Biol 12(5):477–483

    Article  PubMed  CAS  Google Scholar 

  29. Schmidt A, Hall A (2002) Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev 16(13):1587–1609

    Article  PubMed  CAS  Google Scholar 

  30. Zheng Y et al (1996) The pleckstrin homology domain mediates transformation by oncogenic dbl through specific intracellular targeting. J Biol Chem 271(32):19017–19020

    Article  PubMed  CAS  Google Scholar 

  31. Bustelo XR (2000) Regulatory and signaling properties of the Vav family. Mol Cell Biol 20(5):1461–1477

    Article  PubMed  CAS  Google Scholar 

  32. Das B et al (2000) Control of intramolecular interactions between the pleckstrin homology and Dbl homology domains of Vav and Sos1 regulates Rac binding. J Biol Chem 275(20):15074–15081

    Article  PubMed  CAS  Google Scholar 

  33. Yohe ME et al (2007) Auto-inhibition of the Dbl family protein Tim by an N-terminal helical motif. J Biol Chem 282(18):13813–13823

    Article  PubMed  CAS  Google Scholar 

  34. Yohe ME, Rossman K, Sondek J (2008) Role of the C-terminal SH3 domain and N-terminal tyrosine phosphorylation in regulation of Tim and related Dbl-family proteins. Biochemistry 47(26):6827–6839

    Article  PubMed  CAS  Google Scholar 

  35. Aghazadeh B et al (2000) Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Cell 102(5):625–633

    Article  PubMed  CAS  Google Scholar 

  36. Zamir E, Geiger B (2001) Molecular complexity and dynamics of cell-matrix adhesions. J Cell Sci 114(Pt 20):3583–3590

    PubMed  CAS  Google Scholar 

  37. DeMali KA, Burridge K (2003) Coupling membrane protrusion and cell adhesion. J Cell Sci 116(Pt 12):2389–2397

    Article  PubMed  CAS  Google Scholar 

  38. Ren XD et al (2000) Focal adhesion kinase suppresses Rho activity to promote focal adhesion turnover. J Cell Sci 113(Pt 20):3673–3678

    PubMed  CAS  Google Scholar 

  39. Tomar A et al (2009) A FAK–p120RasGAP–p190RhoGAP complex regulates polarity in migrating cells. J Cell Sci 122(Pt 11):1852–1862

    Article  PubMed  CAS  Google Scholar 

  40. Chrzanowska-Wodnicka M, Burridge K (1996) Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J Cell Biol 133(6):1403–1415

    Article  PubMed  CAS  Google Scholar 

  41. Kimura K et al (1996) Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273(5272):245–248

    Article  PubMed  CAS  Google Scholar 

  42. Amano M, Nakayama M, Kaibuchi K (2010) Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarity. Cytoskeleton (Hoboken) 67(9):545–554

    CAS  Google Scholar 

  43. Amano M et al (1997) Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science 275(5304):1308–1311

    Article  PubMed  CAS  Google Scholar 

  44. Watanabe N et al (1999) Cooperation between mDia1 and ROCK in Rho-induced actin reorganization. Nat Cell Biol 1(3):136–143

    Article  PubMed  CAS  Google Scholar 

  45. Mori K et al (2009) Rho-kinase contributes to sustained RhoA activation through phosphorylation of p190A RhoGAP. J Biol Chem 284(8):5067–5076

    Article  PubMed  CAS  Google Scholar 

  46. Burridge K, Wennerberg K (2004) Rho and Rac take center stage. Cell 116(2):167–179

    Article  PubMed  CAS  Google Scholar 

  47. Maekawa M et al (1999) Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285(5429):895–898

    Article  PubMed  CAS  Google Scholar 

  48. Bernard O (2007) Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol 39(6):1071–1076

    Article  PubMed  CAS  Google Scholar 

  49. Takaishi K et al (1995) Translocation of activated Rho from the cytoplasm to membrane ruffling area, cell–cell adhesion sites and cleavage furrows. Oncogene 11(1):39–48

    PubMed  CAS  Google Scholar 

  50. Antoine-Bertrand J et al (2011) The activation of ezrin–radixin–moesin proteins is regulated by netrin-1 through Src kinase and RhoA/Rho kinase activities and mediates netrin-1-induced axon outgrowth. Mol Biol Cell 22(19):3734–3746

    Article  PubMed  CAS  Google Scholar 

  51. Sanders LC et al (1999) Inhibition of myosin light chain kinase by p21-activated kinase. Science 283(5410):2083–2085

    Article  PubMed  CAS  Google Scholar 

  52. Edwards DC et al (1999) Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics. Nat Cell Biol 1(5):253–259

    Article  PubMed  CAS  Google Scholar 

  53. Nutt CL et al (2003) Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res 63(7):1602–1607

    PubMed  CAS  Google Scholar 

  54. Forget MA et al (2002) The expression of rho proteins decreases with human brain tumor progression: potential tumor markers. Clin Exp Metastasis 19(1):9–15

    Article  PubMed  CAS  Google Scholar 

  55. Hwang SL et al (2005) Rac2 expression and mutation in human brain tumors. Acta Neurochir (Wien) 147(5): 551-554 (discussion 554)

    Google Scholar 

  56. Zavarella S et al (2009) Role of Rac1-regulated signaling in medulloblastoma invasion: laboratory investigation. J Neurosurg Pediatr 4(2):97–104

    Article  PubMed  Google Scholar 

  57. Senger DL et al (2002) Suppression of Rac activity induces apoptosis of human glioma cells but not normal human astrocytes. Cancer Res 62(7):2131–2140

    PubMed  CAS  Google Scholar 

  58. Hwang SL et al (2004) Rac1 gene mutations in human brain tumours. Eur J Surg Oncol 30(1):68–72

    PubMed  CAS  Google Scholar 

  59. Ding Q et al (2002) Promotion of malignant astrocytoma cell migration by osteopontin expressed in the normal brain: differences in integrin signaling during cell adhesion to osteopontin versus vitronectin. Cancer Res 62(18):5336–5343

    PubMed  CAS  Google Scholar 

  60. Goldberg L, Kloog Y (2006) A Ras inhibitor tilts the balance between Rac and Rho and blocks phosphatidylinositol 3-kinase-dependent glioblastoma cell migration. Cancer Res 66(24):11709–11717

    Article  PubMed  CAS  Google Scholar 

  61. Manning TJ Jr, Parker JC, Sontheimer H (2000) Role of lysophosphatidic acid and rho in glioma cell motility. Cell Motil Cytoskelet 45(3):185–199

    Article  CAS  Google Scholar 

  62. Malchinkhuu E et al (2009) Role of Rap1B and tumor suppressor PTEN in the negative regulation of lysophosphatidic acid-induced migration by isoproterenol in glioma cells. Mol Biol Cell 20(24):5156–5165

    Article  PubMed  CAS  Google Scholar 

  63. Yiin JJ et al (2009) Slit2 inhibits glioma cell invasion in the brain by suppression of Cdc42 activity. Neuro Oncol 11(6):779–789

    Article  PubMed  CAS  Google Scholar 

  64. Werbowetski-Ogilvie TE et al (2006) Inhibition of medulloblastoma cell invasion by Slit. Oncogene 25(37):5103–5112

    PubMed  CAS  Google Scholar 

  65. Furukawa K et al (2006) PTEN gene transfer suppresses the invasive potential of human malignant gliomas by regulating cell invasion-related molecules. Int J Oncol 29(1):73–81

    PubMed  CAS  Google Scholar 

  66. Malchinkhuu E et al (2005) Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells. Oncogene 24(44):6676–6688

    Article  PubMed  CAS  Google Scholar 

  67. Rattan R et al (2006) Rho/ROCK pathway as a target of tumor therapy. J Neurosci Res 83(2):243–255

    Article  PubMed  CAS  Google Scholar 

  68. Deng L et al (2010) Rho-kinase inhibitor, fasudil, suppresses glioblastoma cell line progression in vitro and in vivo. Cancer Biol Ther 9(11):875–884

    Article  PubMed  CAS  Google Scholar 

  69. Nakabayashi H, Shimizu K (2011) HA1077, a Rho kinase inhibitor, suppresses glioma-induced angiogenesis by targeting the Rho-ROCK and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signal pathways. Cancer Sci 102(2):393–399

    Article  PubMed  CAS  Google Scholar 

  70. Oellers P et al (2009) ROCKs are expressed in brain tumors and are required for glioma-cell migration on myelinated axons. Glia 57(5):499–509

    Article  PubMed  Google Scholar 

  71. Lin CC et al (2009) Danthron inhibits the migration and invasion of human brain glioblastoma multiforme cells through the inhibition of mRNA expression of focal adhesion kinase, Rho kinases-1 and metalloproteinase-9. Oncol Rep 22(5):1033–1037

    PubMed  CAS  Google Scholar 

  72. Salhia B et al (2005) Inhibition of Rho-kinase affects astrocytoma morphology, motility, and invasion through activation of Rac1. Cancer Res 65(19):8792–8800

    Article  PubMed  CAS  Google Scholar 

  73. Yamana N et al (2006) The Rho-mDia1 pathway regulates cell polarity and focal adhesion turnover in migrating cells through mobilizing Apc and c-Src. Mol Cell Biol 26(18):6844–6858

    Article  PubMed  CAS  Google Scholar 

  74. Belot N et al (2002) Extracellular S100A4 stimulates the migration rate of astrocytic tumor cells by modifying the organization of their actin cytoskeleton. Biochim Biophys Acta 1600(1–2):74–83

    PubMed  CAS  Google Scholar 

  75. Yuan L et al (2010) ERK activation of p21 activated kinase-1 (Pak1) is critical for medulloblastoma cell migration. Clin Exp Metastasis 27(7):481–491

    Article  PubMed  CAS  Google Scholar 

  76. The Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068

    Article  Google Scholar 

  77. Guerreiro AS et al (2008) Targeting the PI3K p110alpha isoform inhibits medulloblastoma proliferation, chemoresistance, and migration. Clin Cancer Res 14(21):6761–6769

    Article  PubMed  CAS  Google Scholar 

  78. Witte HT et al (2009) Modeling glioma growth and invasion in Drosophila melanogaster. Neoplasia 11(9):882–888

    PubMed  CAS  Google Scholar 

  79. Moon SY, Zang H, Zheng Y (2003) Characterization of a brain-specific Rho GTPase-activating protein, p200RhoGAP. J Biol Chem 278(6):4151–4159

    Article  PubMed  CAS  Google Scholar 

  80. McDonald KL et al (2007) IQGAP1 and IGFBP2: valuable biomarkers for determining prognosis in glioma patients. J Neuropathol Exp Neurol 66(5):405–417

    Article  PubMed  CAS  Google Scholar 

  81. Hu B et al (2009) ADP-ribosylation factor 6 regulates glioma cell invasion through the IQ-domain GTPase-activating protein 1-Rac1-mediated pathway. Cancer Res 69(3):794–801

    Article  PubMed  CAS  Google Scholar 

  82. Jarzynka MJ et al (2007) ELMO1 and Dock180, a bipartite Rac1 guanine nucleotide exchange factor, promote human glioma cell invasion. Cancer Res 67(15):7203–7211

    Article  PubMed  CAS  Google Scholar 

  83. Salhia B et al (2008) The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. Am J Pathol 173(6):1828–1838

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Dr Jonathan M. Backer for valuable intellectual input to the manuscript.

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The authors declare they have no conflict of interest.

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Correspondence to Mirvat El-Sibai.

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Khalil, B.D., El-Sibai, M. Rho GTPases in primary brain tumor malignancy and invasion. J Neurooncol 108, 333–339 (2012). https://doi.org/10.1007/s11060-012-0866-8

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