scholarly journals Rho GTPase signaling complexes in cell migration and invasion

2017 ◽  
Vol 217 (2) ◽  
pp. 447-457 ◽  
Author(s):  
Campbell D. Lawson ◽  
Anne J. Ridley
Keyword(s):  
Cell Migration ◽  
Rho Gtpase ◽  
Guanine Nucleotide Exchange Factors ◽  
Migration And Invasion ◽  
Gtpase Activity ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Dynamic Formation

Cell migration is dependent on the dynamic formation and disassembly of actin filament–based structures, including lamellipodia, filopodia, invadopodia, and membrane blebs, as well as on cell–cell and cell–extracellular matrix adhesions. These processes all involve Rho family small guanosine triphosphatases (GTPases), which are regulated by the opposing actions of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPase activity needs to be precisely tuned at distinct cellular locations to enable cells to move in response to different environments and stimuli. In this review, we focus on the ability of RhoGEFs and RhoGAPs to form complexes with diverse binding partners, and describe how this influences their ability to control localized GTPase activity in the context of migration and invasion.

scholarly journals Hormones Secretion and Rho GTPases in Neuroendocrine Tumors

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1859
Author(s):  
Laura Streit ◽  
Laurent Brunaud ◽  
Nicolas Vitale ◽  
Stéphane Ory ◽  
Stéphane Gasman
Keyword(s):  
Neuroendocrine Tumors ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Secretory Activity ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins

Neuroendocrine tumors (NETs) belong to a heterogeneous group of neoplasms arising from hormone secreting cells. These tumors are often associated with a dysfunction of their secretory activity. Neuroendocrine secretion occurs through calcium-regulated exocytosis, a process that is tightly controlled by Rho GTPases family members. In this review, we compiled the numerous mutations and modification of expression levels of Rho GTPases or their regulators (Rho guanine nucleotide-exchange factors and Rho GTPase-activating proteins) that have been identified in NETs. We discussed how they might regulate neuroendocrine secretion.

scholarly journals Activation of G proteins by guanine nucleotide exchange factors relies on GTPase activity

2015 ◽  
Author(s):  
Rob J Stanley ◽  
Geraint MH Thomas
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Gtpase Activity ◽  
Nucleotide Exchange ◽  
Signalling Molecules ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Experimental Strategies

G proteins are an important family of signalling molecules controlled by guanine nucleotide exchange and GTPase activity in what is commonly called an 'activation/inactivation cycle'. The molecular mechanism by which guanine nucleotide exchange factors (GEFs) catalyse the activation of monomeric G proteins is well-established, however the complete reversibility of this mechanism is often overlooked. Here, we use a theoretical approach to prove that GEFs are unable to positively control G protein systems at steady-state in the absence of GTPase activity. Instead, positive regulation of G proteins must be seen as a product of the competition between guanine nucleotide exchange and GTPase activity -- emphasising a central role for GTPase activity beyond merely signal termination. We conclude that a more accurate description of the regulation of G proteins via these processes is as a 'balance/imbalance' mechanism. This result has implications for the understanding of many intracellular signalling processes, and for experimental strategies that rely on modulating G protein systems.

scholarly journals RAP, a member of the Ras superfamily of small GTPases and its putative GTPase activating proteins and guanine nucleotide exchange factors in raw 264.7 macrophages

2021 ◽  
Author(s):  
Monika Tucholska
Keyword(s):  
Guanine Nucleotide Exchange Factors ◽  
Raw 264.7 ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Fcγ Receptor ◽  
Raw 264.7 Macrophages ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Ras Superfamily

The Fcγ receptor is a cell surface protein essential in the immune response that binds IgG-opsonized particles resulting in phagocytosis. Phagocytosis is a process used to remove pathogens and confine them in a vacuole that will enable their breakdown. The members of the Ras superfamily of small G proteins have been identified in samples where the activated Fcγ receptor complex was captured and analyzed using tandem mass spectrometry. The protein Rap. beloning to the Ras superfamily, guanosine triphosphatases (GTPase) activating proteins (GAPs), which promote the dissociation of GTP, and guanine nucleotide exchange factors (GEFs), that permits the exchange of GDP for GTP, were detected by SEQUEST in RAW 264.7 macrophages and futher analyzed using various methods. In this study, Raps, RasGAPs, and RapGEFs, were observed by tandem mass spectrometry and sequence correlation analysis. The selected isoforms were confirmed by Western blots, live cell confocal microscopy with fluorescent fusion constructs and antibody staining to verify the localization of Ras proetins, specifically Rap1, p120RasGAP and C3G, a RapGEF, to activated Fc reeceptor [sic].

scholarly journals Stress-dependent inhibition of cell polarity through unbalancing the GEF/GAP regulation of Cdc42

2021 ◽  
Author(s):  
Clàudia Salat-Canela ◽  
Mercè Carmona ◽  
Rebeca Martín-García ◽  
Pilar Pérez ◽  
José Ayté ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Gtp Hydrolysis ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Dependent Inhibition ◽  
Stress Dependent

Cdc42 rules cell polarity and growth in fission yeast. It is negatively and positively regulated by GTPase-activating proteins (GAPs) and by Guanine-nucleotide Exchange factors (GEFs), respectively. Active Cdc42-GTP localizes to the poles, where it associates with numerous proteins constituting the polarity module. However, little is known about its down-regulation. We describe here that oxidative stress causes Sty1 kinase-dependent Cdc42 inactivation at cell poles. Both the amount of active Cdc42 at poles and cell length inversely correlate with Sty1 activity, explaining the elongated morphology of Δsty1 cells. We have created stress-blinded cell poles by either eliminating two Cdc42 GAPs or through the constitutive tethering of a GEF to the cell tips, and biochemically demonstrate that Rga3 is a direct substrate of Sty1. We propose that stress-activated Sty1 promotes GTP hydrolysis and prevents GEF activity at the cell tips, thus leading to the inhibition of Cdc42 and polarized growth cessation.

scholarly journals Ancient complement and lineage-specific evolution of the Sec7 ARF GEF proteins in eukaryotes

2019 ◽  
Vol 30 (15) ◽  
pp. 1846-1863 ◽  
Author(s):  
Shweta V. Pipaliya ◽  
Alexander Schlacht ◽  
Christen M. Klinger ◽  
Richard A. Kahn ◽  
Joel Dacks
Keyword(s):  
Membrane Trafficking ◽  
Protein Function ◽  
Phylogenetic Analyses ◽  
Guanine Nucleotide Exchange Factors ◽  
Nucleotide Exchange ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Functionally Diverse

Guanine nucleotide exchange factors (GEFs) are the initiators of signaling by every regulatory GTPase, which in turn act to regulate a wide array of essential cellular processes. To date, each family of GTPases is activated by distinct families of GEFs. Bidirectional membrane trafficking is regulated by ADP-ribosylation factor (ARF) GTPases and the development throughout eukaryotic evolution of increasingly complex systems of such traffic required the acquisition of a functionally diverse cohort of ARF GEFs to control it. We performed phylogenetic analyses of ARF GEFs in eukaryotes, defined by the presence of the Sec7 domain, and found three subfamilies (BIG, GBF1, and cytohesins) to have been present in the ancestor of all eukaryotes. The four other subfamilies (EFA6/PSD, IQSEC7/BRAG, FBX8, and TBS) are opisthokont, holozoan, metazoan, and alveolate/haptophyte specific, respectively, and each is derived from cytohesins. We also identified a cytohesin-derived subfamily, termed ankyrin repeat-containing cytohesin, that independently evolved in amoebozoans and members of the SAR and haptophyte clades. Building on evolutionary data for the ARF family GTPases and their GTPase-­activating proteins allowed the generation of hypotheses about ARF GEF protein function(s) as well as a better understanding of the origins and evolution of cellular complexity in eukaryotes.

ARF small GTPases in the developmental function mediated by ARF regulators GNOM and VAN3

2022 ◽  
Author(s):  
Maciek Adamowski ◽  
Ivana Matijević ◽  
Jiří Friml
Keyword(s):  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Nucleotide Exchange ◽  
Loss Of Function ◽  
Gene Group ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Developmental Patterning ◽  
Branching Angle

ARF small GTPases are molecular switches acting in intracellular trafficking. Their cycles of activity are controlled by regulators, ARF Guanine nucleotide Exchange Factors (ARF-GEFs) and ARF GTPase Activating Proteins (ARF-GAPs). The ARF-GEF GNOM (GN) and the ARF-GAP VAN3 share a prominent function in auxin-mediated developmental patterning, but the ARFs which they might control were not identified. We conducted a loss-of-function and localization-based screening of the ARF/ARF-LIKE gene family in Arabidopsis thaliana with the primary aim of identifying functional partners of GN and VAN3, while extending the limited understanding of this gene group as a whole. We identified a function of ARLA1 in branching angle control. Mutants lacking the variably localized ARLB1, ARFB1, ARFC1, ARFD1, and ARF3, even in high order combinations, do not exhibit any evident phenotypes. Loss of function arfa1 phenotypes support a major role of ARFA1 in growth and development overall, but patterning defects typical to gn loss of function are not found. ARFA1 are not localized at the plasma membrane, where GN and VAN3 carry out developmental patterning function according to current models. Taken together, putative ARF partners of GN and VAN3 in developmental patterning cannot be conclusively identified.

scholarly journals Cdc42 and the Guanine Nucleotide Exchange Factors Ect2 and Trio Mediate Fn14-Induced Migration and Invasion of Glioblastoma Cells

2012 ◽  
Vol 10 (7) ◽  
pp. 958-968 ◽  
Author(s):  
Shannon P. Fortin ◽  
Matthew J. Ennis ◽  
Cassie A. Schumacher ◽  
Cassandra R. Zylstra-Diegel ◽  
Bart O. Williams ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factors ◽  
Migration And Invasion ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Glioblastoma Cells ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

scholarly journals Activation of Rac and Cdc42 Video Imaged by Fluorescent Resonance Energy Transfer-Based Single-Molecule Probes in the Membrane of Living Cells

2002 ◽  
Vol 22 (18) ◽  
pp. 6582-6591 ◽  
Author(s):  
Reina E. Itoh ◽  
Kazuo Kurokawa ◽  
Yusuke Ohba ◽  
Hisayoshi Yoshizaki ◽  
Naoki Mochizuki ◽  
...  
Keyword(s):  
Single Molecule ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Leading Edge ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins

ABSTRACT Rho family G proteins, including Rac and Cdc42, regulate a variety of cellular functions such as morphology, motility, and gene expression. We developed fluorescent resonance energy transfer-based probes which monitored the local balance between the activities of guanine nucleotide exchange factors and GTPase-activating proteins for Rac1 and Cdc42 at the membrane. These probes, named Raichu-Rac and Raichu-Cdc42, consisted of a Cdc42- and Rac-binding domain of Pak, Rac1 or Cdc42, a pair of green fluorescent protein mutants, and a CAAX box of Ki-Ras. With these probes, we video imaged the Rac and Cdc42 activities. In motile HT1080 cells, activities of both Rac and Cdc42 gradually increased toward the leading edge and decreased rapidly when cells changed direction. Under a higher magnification, we observed that Rac activity was highest immediately behind the leading edge, whereas Cdc42 activity was most prominent at the tip of the leading edge. Raichu-Rac and Raichu-Cdc42 were also applied to a rapid and simple assay for the analysis of putative guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) in living cells. Among six putative GEFs and GAPs, we identified KIAA0362/DBS as a GEF for Rac and Cdc42, KIAA1256 as a GEF for Cdc42, KIAA0053 as a GAP for Rac and Cdc42, and KIAA1204 as a GAP for Cdc42. In conclusion, use of these single-molecule probes to determine Rac and Cdc42 activity will accelerate the analysis of the spatiotemporal regulation of Rac and Cdc42 in a living cell.

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