ECT2 and RASAL2 Mediate Mesenchymal-Amoeboid Transition In Human Astrocytoma Cells

Weeks, Adrienne; Okolowsky, Nadia; Golbourn, Brian; Ivanchuk, Stacey; Smith, Christian A.; Rutka, James T.

doi:10.1016/j.ajpath.2012.04.011

Cited by 41 publications

(55 citation statements)

References 41 publications

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“…The data are consistent with a general role for these proteins in many different types of cancer. This is consistent with the hypothesis that these proteins may play a fundamental role in either cancer progression or metastasis and with recent data, suggesting a role for RASAL2 and NENF in cancer (14,16).…”

Section: Biologic Functions Of Novel Liver Cancer Candidate Genes Hypsupporting

confidence: 80%

“…Functional consequences of RASAL2 or NENF depletion in bladder and breast cancer cells We then showed that targeting NENF and RASAL2 has an effect beyond liver cancer confirming previous data (14,16). Depletion of RASAL2 or NENF in invasive T24 bladder and MDA-MB-231 breast cancer cells (Fig.…”

Section: Biologic Functions Of Novel Liver Cancer Candidate Genes Hypsupporting

confidence: 75%

“…To define the functional role of the identified novel putative cancer targets in cellular transformation, we used siRNA/ shRNA-mediated depletion in liver cancer cell lines as a tractable cellular model for human liver tumors where these genes were found to be hypomethylated and activated. We first focused on 2 genes, RASAL2 and NENF because previous literature data suggested their involvement in MAPK and/or AKT signal transduction pathways and their likely important role in carcinogenesis and metastasis (14,16).…”

Section: Biologic Functions Of Novel Liver Cancer Candidate Genes Hypmentioning

confidence: 99%

“…RASAL2 is a protein containing the GAP-related domain (GRD) that is a characteristic domain of GTPase-activating proteins (GAP) that were shown to be crucial for AKT activity and bind to AKT inducing its phosphorylation via integrin-linked kinase (13). RASAL2 was recently shown to interact with ECT2, a guanine nucleotide exchange factor that is overexpressed in primary astrocytomas, activating promigratory RHO family members (14). Knockdown of RASAL2 decreases ECT2 activity toward RHO in astrocytoma cells and leads to mesenchymal-amoeboid transition, altering the invasive properties of the cells.…”

Section: Introductionmentioning

confidence: 99%

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Genome-Wide Study of Hypomethylated and Induced Genes in Patients with Liver Cancer Unravels Novel Anticancer Targets

Stefańska

Cheishvili

Suderman

et al. 2014

Clinical Cancer Research

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Purpose: We utilized whole-genome mapping of promoters that are activated by DNA hypomethylation in hepatocellular carcinoma (HCC) clinical samples to shortlist novel targets for anticancer therapeutics. We provide a proof of principle of this approach by testing six genes short-listed in our screen for their essential role in cancer growth and invasiveness.Experimental Design: We used siRNA-or shRNA-mediated depletion to determine whether inhibition of these genes would reduce human tumor xenograft growth in mice as well as cell viability, anchorageindependent growth, invasive capacities, and state of activity of nodal signaling pathways in liver, breast, and bladder cancer cell lines.Results: Depletion of EXOSC4, RNMT, SENP6, WBSCR22, RASAL2, and NENF effectively and specifically inhibits cancer cell growth and cell invasive capacities in different types of cancer, but, remarkably, there is no effect on normal cell growth, suggesting a ubiquitous causal role for these genes in driving cancer growth and metastasis. Depletion of RASAL2 and NENF in vitro reduces their growth as explants in vivo in mice. RASAL2 and NENF depletion interferes with AKT, WNT, and MAPK signaling pathways as well as regulation of epigenetic proteins that were previously demonstrated to drive cancer growth and metastasis.Conclusion: Our results prove that genes that are hypomethylated and induced in tumors are candidate targets for anticancer therapeutics in multiple cancer cell types. Because these genes are particularly activated in cancer, they constitute a group of targets for specific pharmacologic inhibitors of cancer and cancer metastasis. Clin Cancer Res; 20(12); 3118-32. Ó2014 AACR.

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Section: Biologic Functions Of Novel Liver Cancer Candidate Genes Hypsupporting

confidence: 80%

Section: Biologic Functions Of Novel Liver Cancer Candidate Genes Hypsupporting

confidence: 75%

Section: Biologic Functions Of Novel Liver Cancer Candidate Genes Hypmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genome-Wide Study of Hypomethylated and Induced Genes in Patients with Liver Cancer Unravels Novel Anticancer Targets

Stefańska

Cheishvili

Suderman

et al. 2014

Clinical Cancer Research

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“…This finding is consistent with in vitro experiments demonstrating that Ect2 has GEF activity towards Cdc42, in addition to RhoA and Rac1 (Solski et al, 2004;Tatsumoto et al, 1999). Moreover, expression of dominant-negative Ect2 in Xenopus oocytes (Zhang et al, 2008a), or Ect2 knockdown in malignant glioblastoma cells or astrocytomas (Fortin et al, 2012;Weeks et al, 2012), leads to a decrease in Cdc42 activity. It is not clear in these examples whether Ect2 impacts Cdc42 activity directly.…”

Section: A Novel Role For Ect-2 In Cdc-42-mediated Polarizationsupporting

confidence: 78%

Mechanisms of CDC-42 activation during contact-induced cell polarization

Chan

Nance

2013

Journal of Cell Science

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SummaryPolarization of early embryos provides a foundation to execute essential patterning and morphogenetic events. In Caenorhabditis elegans, cell contacts polarize early embryos along their radial axis by excluding the cortical polarity protein PAR-6 from sites of cell contact, thereby restricting PAR-6 to contact-free cell surfaces. Radial polarization requires the cortically enriched Rho GTPase CDC-42, which in its active form recruits PAR-6 through direct binding. The Rho GTPase activating protein (RhoGAP) PAC-1, which localizes specifically to cell contacts, triggers radial polarization by inactivating CDC-42 at these sites. The mechanisms responsible for activating CDC-42 at contact-free surfaces are unknown. Here, in an overexpression screen of Rho guanine nucleotide exchange factors (RhoGEFs), which can activate Rho GTPases, we identify CGEF-1 and ECT-2 as RhoGEFs that act through CDC-42 to recruit PAR-6 to the cortex. We show that ECT-2 and CGEF-1 localize to the cell surface and that removing their activity causes a reduction in levels of cortical PAR-6. Through a structure-function analysis, we show that the tandem DH-PH domains of CGEF-1 and ECT-2 are sufficient for GEF activity, but that regions outside of these domains target each protein to the cell surface. Finally, we provide evidence suggesting that the N-terminal region of ECT-2 may direct its in vivo preference for CDC-42 over another known target, the Rho GTPase RHO-1. We propose that radial polarization results from a competition between RhoGEFs, which activate CDC-42 throughout the cortex, and the RhoGAP PAC-1, which inactivates CDC-42 at cell contacts.

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FilGAP, a Rac‐specific Rho GTPase‐activating protein, is a novel prognostic factor for follicular lymphoma

et al. 2015

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FilGAP, a Rho GTPase-activating protein (GAP), acts as a mediator of Rho/ROCK (Rho-associated protein kinase)-dependent amoeboid movement, and its knockdown results in Rac-driven mesenchymal morphology. Herein, we focus on the possible roles of FilGAP expression in normal and malignant lymphocytes. Eighty-three cases of follicular lymphoma (FL), 84 of diffuse large B-cell lymphoma (DLBCL), and 25 of peripheral T-cell lymphoma (PTCL), as well as 10 of normal lymph nodes, were immunohistochemically investigated. In normal lymph nodes, FilGAP immunoreactivity was significantly higher in lymphocytes in the mantle zone as compared to those in the germinal center and paracortical areas. In contrast, the expression levels of both cytoplasmic and perinuclear Rac1 were significantly lower in the germinal center as compared to paracortical regions, suggesting that changes in the FilGAP/Rac axis may occur in B-cell lineages. In malignant lymphomas, FilGAP expression was significantly higher in B-cell lymphomas than PTCL, and the immunohistochemical scores were positively correlated with cytoplasmic Rac1 scores in FL and DLBCL, but not in PTCL. Patients with FL and germinal center B-cell-like (GCB)-type DLBCL showing high FilGAP scores had poor overall survival rates as compared to the low-score patients. Moreover, multivariate Cox regression analysis showed that a high FilGAP score was a significant and independent unfavorable prognostic factor in FL, but not in DLBCL. In conclusion, FilGAP may contribute to change in cell motility of B-lymphocytes. In addition, its expression appears to be useful for predicting the behavior of B-cell lymphoma, in particular FL.

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ECT2 and RASAL2 Mediate Mesenchymal-Amoeboid Transition In Human Astrocytoma Cells

Cited by 41 publications

References 41 publications

Genome-Wide Study of Hypomethylated and Induced Genes in Patients with Liver Cancer Unravels Novel Anticancer Targets

Genome-Wide Study of Hypomethylated and Induced Genes in Patients with Liver Cancer Unravels Novel Anticancer Targets

Mechanisms of CDC-42 activation during contact-induced cell polarization

FilGAP, a Rac‐specific Rho GTPase‐activating protein, is a novel prognostic factor for follicular lymphoma

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