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      Deregulation of Rho GTPases in cancer

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          ABSTRACT

          In vitro and in vivo studies and evidence from human tumors have long implicated Rho GTPase signaling in the formation and dissemination of a range of cancers. Recently next generation sequencing has identified direct mutations of Rho GTPases in human cancers. Moreover, the effects of ablating genes encoding Rho GTPases and their regulators in mouse models, or through pharmacological inhibition, strongly suggests that targeting Rho GTPase signaling could constitute an effective treatment. In this review we will explore the various ways in which Rho signaling can be deregulated in human cancers.

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

          J. Gao, B. A. Aksoy, U Dogrusoz … (2015)
          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            Rational design and characterization of a Rac GTPase-specific small molecule inhibitor.

            Yuan Gao, J Bradley Dickerson, Fukun Guo … (2004)
            The signaling pathways mediated by Rho family GTPases have been implicated in many aspects of cell biology. The specificity of the pathways is achieved in part by the selective interaction between Dbl family guanine nucleotide exchange factors (GEFs) and their Rho GTPase substrates. Here, we report a first-generation small-molecule inhibitor of Rac GTPase targeting Rac activation by GEF. The chemical compound NSC23766 was identified by a structure-based virtual screening of compounds that fit into a surface groove of Rac1 known to be critical for GEF specification. In vitro it could effectively inhibit Rac1 binding and activation by the Rac-specific GEF Trio or Tiam1 in a dose-dependent manner without interfering with the closely related Cdc42 or RhoA binding or activation by their respective GEFs or with Rac1 interaction with BcrGAP or effector PAK1. In cells, it potently blocked serum or platelet-derived growth factor-induced Rac1 activation and lamellipodia formation without affecting the activity of endogenous Cdc42 or RhoA. Moreover, this compound reduced Trio or Tiam1 but not Vav, Lbc, Intersectin, or a constitutively active Rac1 mutant-stimulated cell growth and suppressed Trio, Tiam1, or Ras-induced cell transformation. When applied to human prostate cancer PC-3 cells, it was able to inhibit the proliferation, anchorage-independent growth and invasion phenotypes that require the endogenous Rac1 activity. Thus, NSC23766 constitutes a Rac-specific small-molecule inhibitor that could be useful to study the role of Rac in various cellular functions and to reverse tumor cell phenotypes associated with Rac deregulation.
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              Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?

              Dominico Vigil, Jacqueline Cherfils, Kent Rossman … (2010)
              There is now considerable and increasing evidence for a causal role for aberrant activity of the Ras superfamily of small GTPases in human cancers. These GTPases function as GDP-GTP-regulated binary switches that control many fundamental cellular processes. A common mechanism of GTPase deregulation in cancer is the deregulated expression and/or activity of their regulatory proteins, guanine nucleotide exchange factors (GEFs) that promote formation of the active GTP-bound state and GTPase-activating proteins (GAPs) that return the GTPase to its GDP-bound inactive state. In this Review, we assess the association of GEFs and GAPs with cancer and their druggability for cancer therapeutics.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Small GTPases
                Journal ID (iso-abbrev): Small GTPases
                Journal ID (publisher-id): KSGT
                Journal ID (publisher-id): ksgt20
                Title: Small GTPases
                Publisher: Taylor & Francis
                ISSN (Print): 2154-1248
                ISSN (Electronic): 2154-1256
                Publication date Collection: Jul-Sep 2016
                Publication date (Electronic): 22 April 2016
                Publication date PMC-release: 22 April 2016
                Volume: 7
                Issue: 3
                Pages: 123-138
                Affiliations
                [a ]Cell Signaling Group, Cancer Research UK Manchester Institute, The University of Manchester , Manchester, UK
                [b ]“Cellular and Genetic Etiology, Diagnosis and Treatment of Human Disease” Graduate Program, Medical School, University of Crete , Heraklion, Greece
                Author notes
                [#]

                These authors contributed equally to this review.

                Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/ksgt.

                Angeliki Malliri Angeliki.Malliri@ 123456cruk.manchester.ac.uk Cell Signaling Group, Cancer Research UK Manchester Institute, The University of Manchester , Manchester, UK, M20 4BX
                Article
                Publisher ID: 1173767
                DOI: 10.1080/21541248.2016.1173767
                PMC ID: 5003542
                PubMed ID: 27104658
                SO-VID: 7d6a5010-0b1d-4116-9bba-92a46ec4cb3f
                Copyright © © 2016 The Author(s). Published by Taylor & Francis
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                Date received : 29 December 2015
                Date revision received : 18 March 2016
                Date accepted : 28 March 2016
                Page count
                Figures: 2, Tables: 1, References: 132, Pages: 16
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: cancer,gaps,gdi,gefs,rho gtpases mutations,tumorigenesis
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: cancer, gaps, gdi, gefs, rho gtpases mutations, tumorigenesis

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