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

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Signaling Pathways and Molecular Mediators in Metastasis

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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.

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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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Authors and Affiliations

  1. Cancer Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA, 15213-1862, USA

    Bo Hu & Shi-Yuan Cheng

  2. Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, PA, 15213-1862, USA

    Bo Hu

  3. Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, 350 Community Drive, Manhasset, NY, 11030, USA

    Marc Symons

  4. Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ, 85004, USA

    Bodour Salhia, Shannon P. Fortin & Nhan L. Tran

  5. The Arthur and Sonia Labatt Brain Tumor Research Center, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada

    James Rutka

  6. Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, 15213-1862, USA

    Shi-Yuan Cheng

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    Alessandro Fatatis

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Hu, B. et al. (2011). Rho GTPases and Their Activators, Guanine Nucleotide Exchange Factors (GEFs): Their Roles in Glioma Cell Invasion. In: Fatatis, A. (eds) Signaling Pathways and Molecular Mediators in Metastasis. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2558-4_6

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