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      Autoactivation of small GTPases by the GEF–effector positive feedback modules

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          Abstract

          Small GTPases are organizers of a plethora of cellular processes. The time and place of their activation are tightly controlled by the localization and activation of their regulators, guanine-nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Remarkably, in some systems, the upstream regulators of GTPases are also found downstream of their activity. Resulting feedback loops can generate complex spatiotemporal dynamics of GTPases with important functional consequences. Here we discuss the concept of positive autoregulation of small GTPases by the GEF–effector feedback modules and survey recent developments in this exciting area of cell biology.

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          Most cited references54

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          Rabs and their effectors: achieving specificity in membrane traffic.

          Bianka L Grosshans, Darinel Ortiz, Peter Novick (2006)
          Rab proteins constitute the largest branch of the Ras GTPase superfamily. Rabs use the guanine nucleotide-dependent switch mechanism common to the superfamily to regulate each of the four major steps in membrane traffic: vesicle budding, vesicle delivery, vesicle tethering, and fusion of the vesicle membrane with that of the target compartment. These different tasks are carried out by a diverse collection of effector molecules that bind to specific Rabs in their GTP-bound state. Recent advances have not only greatly extended the number of known Rab effectors, but have also begun to define the mechanisms underlying their distinct functions. By binding to the guanine nucleotide exchange proteins that activate the Rabs certain effectors act to establish positive feedback loops that help to define and maintain tightly localized domains of activated Rab proteins, which then serve to recruit other effector molecules. Additionally, Rab cascades and Rab conversions appear to confer directionality to membrane traffic and couple each stage of traffic with the next along the pathway.
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            Small GTP-binding proteins.

            Y Takai, T. Sasaki, T Matozaki (2001)
            Small GTP-binding proteins (G proteins) exist in eukaryotes from yeast to human and constitute a superfamily consisting of more than 100 members. This superfamily is structurally classified into at least five families: the Ras, Rho, Rab, Sar1/Arf, and Ran families. They regulate a wide variety of cell functions as biological timers (biotimers) that initiate and terminate specific cell functions and determine the periods of time for the continuation of the specific cell functions. They furthermore play key roles in not only temporal but also spatial determination of specific cell functions. The Ras family regulates gene expression, the Rho family regulates cytoskeletal reorganization and gene expression, the Rab and Sar1/Arf families regulate vesicle trafficking, and the Ran family regulates nucleocytoplasmic transport and microtubule organization. Many upstream regulators and downstream effectors of small G proteins have been isolated, and their modes of activation and action have gradually been elucidated. Cascades and cross-talks of small G proteins have also been clarified. In this review, functions of small G proteins and their modes of activation and action are described.
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              The 'invisible hand': regulation of RHO GTPases by RHOGDIs.

              Rafael Garcia-Mata, Etienne Boulter, Keith Burridge (2011)
              The 'invisible hand' is a term originally coined by Adam Smith in The Theory of Moral Sentiments to describe the forces of self-interest, competition and supply and demand that regulate the resources in society. This metaphor continues to be used by economists to describe the self-regulating nature of a market economy. The same metaphor can be used to describe the RHO-specific guanine nucleotide dissociation inhibitor (RHOGDI) family, which operates in the background, as an invisible hand, using similar forces to regulate the RHO GTPase cycle.
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                Author and article information

                Contributors
                Andrew B. Goryachev: Role: ConceptualizationRole: Formal AnalysisRole: Funding AcquisitionRole: SupervisionRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                ORCID: https://orcid.org/0000-0002-1332-4819
                Marcin Leda: Role: ConceptualizationRole: Formal AnalysisRole: Writing – Original Draft PreparationRole: Writing – Review & Editing
                Journal
                Journal ID (nlm-ta): F1000Res
                Journal ID (iso-abbrev): F1000Res
                Journal ID (pmc): F1000Research
                Title: F1000Research
                Publisher: F1000 Research Limited (London, UK )
                ISSN (Electronic): 2046-1402
                Publication date (Electronic): 23 September 2019
                Publication date Collection: 2019
                Volume: 8
                Electronic Location Identifier: F1000 Faculty Rev-1676
                Affiliations
                [1 ]Centre for Synthetic and Systems Biology, Institute for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, UK
                Author notes

                No competing interests were disclosed.

                Author information
                https://orcid.org/0000-0002-1332-4819
                Article
                DOI: 10.12688/f1000research.20003.1
                PMC ID: 6758843
                SO-VID: 777e1bbe-28bb-4be6-8c8d-509f69af7df6
                Copyright © Copyright: © 2019 Goryachev AB and Leda M
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date accepted : 17 September 2019
                Funding
                Funded by: Biotechnology and Biological Sciences Research Council
                Award ID: BB/P01190X
                Award ID: BB/P00650
                Work in the Goryachev lab is supported by Biotechnology and Biosciences Research Council grants BB/P01190X and BB/P00650.
                The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Review
                Subject: Articles

                Keywords: small gtpases,arf gtpases,rab gtpases,cdc42,rho gtpases,cell biology,autoregulation,positive feedback,symmetry breaking
                Data availability:
                Keywords: small gtpases, arf gtpases, rab gtpases, cdc42, rho gtpases, cell biology, autoregulation, positive feedback, symmetry breaking

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