scholarly journals The Regulation of Rab GTPases by Phosphorylation

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1340
Author(s):  
Lejia Xu ◽  
Yuki Nagai ◽  
Yotaro Kajihara ◽  
Genta Ito ◽  
Taisuke Tomita
Keyword(s):  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Effector Proteins ◽  
Regulatory Proteins ◽  
Rab Proteins ◽  
Rab Gtpases ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins

Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated in the switch II region by Rab kinases. As the switch II region of Rab proteins undergoes a conformational change depending on the bound nucleotide, it plays an essential role in their function as a ‘switch’. Initially, the phosphorylation of Rab proteins in the switch II region was shown to inhibit the association with regulatory proteins. However, recent studies suggest that it also regulates the binding of Rab proteins to effector proteins, determining which pathways to regulate. These findings suggest that the regulation of the Rab function may be more dynamically regulated by phosphorylation than just through the association with regulatory proteins. In this review, we summarize the recent findings and discuss the physiological and pathological roles of Rab phosphorylation.

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.

Regulation of Rap GTPases in mammalian neurons

2016 ◽  
Vol 397 (10) ◽  
pp. 1055-1069 ◽  
Author(s):  
Bhavin Shah ◽  
Andreas W. Püschel
Keyword(s):  
Nervous System ◽  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Nucleotide Exchange ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Mature Neurons

Abstract Small GTPases are central regulators of many cellular processes. The highly conserved Rap GTPases perform essential functions in the mammalian nervous system during development and in mature neurons. During neocortical development, Rap1 is required to regulate cadherin- and integrin-mediated adhesion. In the adult nervous system Rap1 and Rap2 regulate the maturation and plasticity of dendritic spine and synapses. Although genetic studies have revealed important roles of Rap GTPases in neurons, their regulation by guanine nucleotide exchange factors (GEFs) that activate them and GTPase activating proteins (GAPs) that inactivate them by stimulating their intrinsic GTPase activity is just beginning to be explored in vivo. Here we review how GEFs and GAPs regulate Rap GTPases in the nervous system with a focus on their in vivo function.

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 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 Function of the N-terminus of zizimin1: autoinhibition and membrane targeting

2007 ◽  
Vol 409 (2) ◽  
pp. 525-533 ◽  
Author(s):  
Nahum Meller ◽  
M. Jody Westbrook ◽  
John D. Shannon ◽  
Chittibabu Guda ◽  
Martin A. Schwartz
Keyword(s):  
Limited Proteolysis ◽  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Pleckstrin Homology Domain ◽  
Membrane Targeting ◽  
Nucleotide Exchange ◽  
Rho Proteins ◽  
Cellular Functions ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

Rho family small GTPases are critical regulators of multiple cellular functions. Dbl-homology-domain-containing proteins are the classical GEFs (guanine nucleotide exchange factors) responsible for activation of Rho proteins. Zizimin1 is a Cdc42-specific GEF that belongs to a second family of mammalian Rho-GEFs, CZH [CDM (Ced-5/DOCK180/Myoblast city)-zizimin homology] proteins, which possess a novel type of GEF domain. CZH proteins can be divided into a subfamily related to DOCK 180 and a subfamily related to zizimin1. The two groups share two conserved regions named the CZH1 (or DHR1) domain and the CZH2 (DHR2 or DOCKER) domains, the latter exhibiting GEF activity. We now show that limited proteolysis of zizimin1 suggests the existence of structural domains that do not correspond to those identified on the basis of homologies. We demonstrate that the N-terminal half binds to the GEF domain through three distinct areas, including the CZH1, to inhibit the interaction with Cdc42. The N-terminal PH (pleckstrin homology) domain binds phosphoinositides and mediates zizimin1 membrane targeting. These results define two novel functions for the N-terminal region of zizimin1.

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

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1676 ◽  
Author(s):  
Andrew B. Goryachev ◽  
Marcin Leda
Keyword(s):  
Cell Biology ◽  
Small Gtpases ◽  
Nucleotide Exchange ◽  
Cellular Processes ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Gtpase Activating Proteins ◽  
Recent Developments ◽  
Functional Consequences ◽  
Exciting Area

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.

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.

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