Rho GTPases and Their Activators, Guanine Nucleotide Exchange Factors (GEFs): Their Roles in Glioma Cell Invasion

  • Bo Hu
  • Marc Symons
  • Bodour Salhia
  • Shannon P. Fortin
  • Nhan L. Tran
  • James Rutka
  • Shi-Yuan Cheng
Chapter

Abstract

Accumulated studies showed that constitutively activated Rho GTPases such as Rac1 in malignant human glioblastomas are responsible for the highly invasive phenotype observed in these aggressive brain cancers. Notably, no activating mutations of Rac1 have been reported in human glioblastomas or other types of cancers. Moreover, Rac1 and several GEFs have been implicated in cell invasion and metastasis of glioblastomas and other types of human cancers. Mechanistically, the functions of the Rho GTPases are regulated by three distinct classes of molecules. Among them, guanine nucleotide exchange factors (GEFs) are the activators for Rho GTPases. Here, we review the role of Rho GTPases, particularly Rac1 and several GEFs including Trio, SWAP-70, Ect2, Vav3 and Dock180-ELMO1 in ­glioblastoma cell invasion. Since studies of Rho GTPases and their GEFs in ­glioblastomas are just emerging, we place specific emphasis on the current knowledge of their roles in cell motility and cancer cell invasion as well as potential response to extracellular stimuli that promotes glioma cell invasion. Additionally, we include studies of two membrane receptor proteins, Fn14 and TROY that promote glioma cell invasion through activation of Rho GTPases. Lastly, we discuss future directions for understanding the functions of Rac1 and GEFs in glioma cell invasion and implications to establish these key modulators as potential targets to inhibit diffusely invasive glioblastomas in the brain. The insight provided by this review will help to develop new therapeutic approaches to treat patients with ­malignant gliomas.

Keywords

Glioma Cell Anaplastic Large Cell Lymphoma Rac1 Activation Tumor Necrosis Factor Receptor Superfamily Glioma Cell Migration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

BAI-1

Brain-specific angiogenesis inhibitor-1

Crk

v-crk sarcoma virus CT10 oncogene homolog

Dbl

Diffuse B-cell lypmphoma

DD

Death domain

DH domain

Dbl homology (DH) domain

DHR domain

Dock-homology region

Dock

Dedicator of cytokinesis

Ect2

Epithelial cell transforming sequence 2

EGFR

Epithelial growth factor receptor

ELMO1

Engulfment and cell motility-1

Fn14

Fibroblast growth factor inducible 14

GAP

GTPase-activating protein

GBM

Glioblastoma multiforme

GDI

Guanine nucleotide dissociation inhibitor

GEF

Guanine nucleotide exchange factor (GDP–GTP exchange factor)

p130Cas

crk-associate substrate 130 kDa protein

PDGFR

Platelet-derived growth factor receptor

PH domain

Pleckstrin homology domain

PtdIns

Phosphatidylinositol

Pyk

proline-rich tyrosine kinase

RNAi

RNA interference

ROCK

Rho kinase

SH2 or 3

src homologous domain 2 or 3

SWAP

switching B-cell complex 70 kDa subunit

TNF

Tumor necrosis factor

TNFRSF

Tumor necrosis factor receptor superfamily

TRAF

Tumor necrosis factor receptor associated factor

Trio

Triple function domains (PTPRF interacting)

TROY/Tnfrsf19

Tumor necrosis factor receptor superfamily member 19

TSC

Triple sex combs

TWEAK

Tumor necrosis factor-like weak inducer of apoptosis

Vav3

vav 3 guanine nucleotide exchange factor

VEGFR

Vascular endothelial growth factor receptor

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Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Bo Hu
    • 1
    • 2
  • Marc Symons
    • 3
  • Bodour Salhia
    • 4
  • Shannon P. Fortin
    • 4
  • Nhan L. Tran
    • 4
  • James Rutka
    • 5
  • Shi-Yuan Cheng
    • 1
    • 6
  1. 1.Cancer InstituteUniversity of Pittsburgh, School of MedicinePittsburghUSA
  2. 2.Department of MedicineUniversity of Pittsburgh, School of MedicinePittsburghUSA
  3. 3.Center for Oncology and Cell BiologyThe Feinstein Institute for Medical Research at North Shore-LIJManhassetUSA
  4. 4.Translational Genomics Research InstitutePhoenixUSA
  5. 5.The Arthur and Sonia Labatt Brain Tumor Research CenterHospital for Sick ChildrenTorontoCanada
  6. 6.Department of PathologyUniversity of Pittsburgh, School of MedicinePittsburghUSA

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