ELMO1 and Dock180, a Bipartite Rac1 Guanine Nucleotide Exchange Factor, Promote Human Glioma Cell Invasion

Abstract

A distinct feature of malignant gliomas is the intrinsic ability of single tumor cells to disperse throughout the brain, contributing to the failure of existing therapies to alter the progression and recurrence of these deadly brain tumors. Regrettably, the mechanisms underlying the inherent invasiveness of glioma cells are poorly understood. Here, we report for the first time that engulfment and cell motility 1 (ELMO1) and dedicator of cytokinesis 1 (Dock180), a bipartite Rac1 guanine nucleotide exchange factor (GEF), are evidently linked to the invasive phenotype of glioma cells. Immunohistochemical analysis of primary human glioma specimens showed high expression levels of ELMO1 and Dock180 in actively invading tumor cells in the invasive areas, but not in the central regions of these tumors. Elevated expression of ELMO1 and Dock180 was also found in various human glioma cell lines compared with normal human astrocytes. Inhibition of endogenous ELMO1 and Dock180 expression significantly impeded glioma cell invasion in vitro and in brain tissue slices with a concomitant reduction in Rac1 activation. Conversely, exogenous expression of ELMO1 and Dock180 in glioma cells with low level endogenous expression increased their migratory and invasive capacity in vitro and in brain tissue. These data suggest that the bipartite GEF, ELMO1 and Dock180, play an important role in promoting cancer cell invasion and could be potential therapeutic targets for the treatment of diffuse malignant gliomas. [Cancer Res 2007;67(15):7203-11]

Regulation of NF-κB by NSD1/FBXL11-dependent reversible lysine methylation of p65

“…6B). These two proteins play important roles in transformation, tumorigenesis, and metastasis (11,12). We also show, as a control, that the p65-independent suppressor of tumorigenicity 7 gene (ST7) (13) is not induced upon expression of either wild-type p65 or the K218/221A mutant protein, and that its expression is not downregulated by FBXL11.…”

Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton

“…Significant changes in Hsp27 interaction with the α2 subunit of actin capping protein Cap Z (Casella and Torres 1994), the myosin-binding regulatory subunit 12A (MYPT1) of the phosphatase PP1 that regulates the interaction of actin with myosin, and the ELMO1 component of the Rac1 GEF ELMO/DOCK180 (Jarzynka et al 2007) were also identified. MYPT1 localizes with actin stress fibers in growing endothelial cells and at cell-cell contacts in confluent endothelium (Hirano et al 1999), and it is a target for inhibition of angiogenesis by Rho kinase inhibitors (Somlyo et al 2003).…”

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

“…Because RhoG is known to directly bind ELMO as a downstream effector in its activated state and the ELMO-Dock180 GEF complex has been shown to confer guanine nucleotide exchange directly for Rac1 downstream of RhoG activation (20,21,23), we sought to determine whether TWEAK-induced activation of SGEF and RhoG modulated downstream Rac1 activation. TWEAK induction of Rac1 activity was diminished in U118 and U87 cells with stable knockdown of SGEF expression compared with control cells (Fig.…”