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      Spatiotemporal Control of Intracellular Membrane Trafficking by Rho GTPases

      review-article
      , , *
      Cells
      MDPI
      Rho GTPases, secretory pathway, endocytosis, cancer

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          Abstract

          As membrane-associated master regulators of cytoskeletal remodeling, Rho GTPases coordinate a wide range of biological processes such as cell adhesion, motility, and polarity. In the last years, Rho GTPases have also been recognized to control intracellular membrane sorting and trafficking steps directly; however, how Rho GTPase signaling is regulated at endomembranes is still poorly understood. In this review, we will specifically address the local Rho GTPase pools coordinating intracellular membrane trafficking with a focus on the endo- and exocytic pathways. We will further highlight the spatiotemporal molecular regulation of Rho signaling at endomembrane sites through Rho regulatory proteins, the GEFs and GAPs. Finally, we will discuss the contribution of dysregulated Rho signaling emanating from endomembranes to the development and progression of cancer.

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          Most cited references153

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          Membrane recognition by phospholipid-binding domains.

          Many different globular domains bind to the surfaces of cellular membranes, or to specific phospholipid components in these membranes, and this binding is often tightly regulated. Examples include pleckstrin homology and C2 domains, which are among the largest domain families in the human proteome. Crystal structures, binding studies and analyses of subcellular localization have provided much insight into how members of this diverse group of domains bind to membranes, what features they recognize and how binding is controlled. A full appreciation of these processes is crucial for understanding how protein localization and membrane topography and trafficking are regulated in cells.
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            Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?

            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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              • Article: not found

              Targeted protein degradation: expanding the toolbox

              Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                21 November 2019
                December 2019
                : 8
                : 12
                : 1478
                Affiliations
                Institute of Cell Biology and Immunology and Stuttgart Research Center Systems Biology, University of Stuttgart, Allmandring 31, 70569 Stuttgart, Germany; monilola.olayioye@ 123456izi.uni-stuttgart.de (M.A.O.); bettina.noll@ 123456izi.uni-stuttgart.de (B.N.)
                Author notes
                [* ]Correspondence: angelika.hausser@ 123456izi.uni-stuttgart.de ; Tel.: +49-711-685-66995
                Author information
                https://orcid.org/0000-0002-4102-9286
                Article
                cells-08-01478
                10.3390/cells8121478
                6952795
                31766364
                821c9bfc-1eae-43f9-880c-b09227c7a629
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 October 2019
                : 18 November 2019
                Categories
                Review

                rho gtpases,secretory pathway,endocytosis,cancer
                rho gtpases, secretory pathway, endocytosis, cancer

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