scholarly journals Multiple Types of Guanine Nucleotide Exchange Factors (GEFs) for Rab Small GTPases

2016 ◽  
Vol 41 (2) ◽  
pp. 61-79 ◽  
Author(s):  
Morié Ishida ◽  
Mai E. Oguchi ◽  
Mitsunori Fukuda
Keyword(s):  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

scholarly journals Distinct Subclasses of Small GTPases Interact with Guanine Nucleotide Exchange Factors in a Similar Manner

1998 ◽  
Vol 18 (12) ◽  
pp. 7444-7454 ◽  
Author(s):  
Gwo-Jen Day ◽  
Raymond D. Mosteller ◽  
Daniel Broek
Keyword(s):  
Alpha Helix ◽  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Structural Determinants ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Ras Superfamily

ABSTRACT The Ras-related GTPases are small, 20- to 25-kDa proteins which cycle between an inactive GDP-bound form and an active GTP-bound state. The Ras superfamily includes the Ras, Rho, Ran, Arf, and Rab/YPT1 families, each of which controls distinct cellular functions. The crystal structures of Ras, Rac, Arf, and Ran reveal a nearly superimposible structure surrounding the GTP-binding pocket, and it is generally presumed that the Rab/YPT1 family shares this core structure. The Ras, Rac, Ran, Arf, and Rab/YPT1 families are activated by interaction with family-specific guanine nucleotide exchange factors (GEFs). The structural determinants of GTPases required for interaction with family-specific GEFs have begun to emerge. We sought to determine the sites on YPT1 which interact with GEFs. We found that mutations of YPT1 at position 42, 43, or 49 (effector loop; switch I), position 69, 71, 73, or 75 (switch II), and position 107, 109, or 115 (alpha-helix 3–loop 7 [α3-L7]) are intragenic suppressors of dominant interfering YPT1 mutant N22 (YPT1-N22), suggesting these mutations prevent YPT1-N22 from binding to and sequestering an endogenous GEF. Mutations at these positions prevent interaction with the DSS4 GEF in vitro. Mutations in the switch II and α3-L7 regions do not prevent downstream signaling in yeast when combined with a GTPase-defective (activating) mutation. Together, these results show that the YPT1 GTPase interacts with GEFs in a manner reminiscent of that for Ras and Arf in that these GTPases use divergent sequences corresponding to the switch I and II regions and α3-L7 of Ras to interact with family-specific GEFs. This finding suggests that GTPases of the Ras superfamily each may share common features of GEF-mediated guanine nucleotide exchange even though the GEFs for each of the Ras subfamilies appear evolutionarily unrelated.

scholarly journals Coordination of Grp1 recruitment mechanisms by its phosphorylation

2020 ◽  
Vol 31 (25) ◽  
pp. 2816-2825
Author(s):  
Jian Li ◽  
David G. Lambright ◽  
Victor W. Hsu
Keyword(s):  
Intracellular Transport ◽  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Transport Pathways ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Membrane Compartments ◽  
Adp Ribosylation Factor

Intracellular transport pathways are initiated by the recruitment of guanine nucleotide exchange factors (GEFs) that act on the ADP-Ribosylation Factor (ARF) family of small GTPases to membrane compartments. We have elucidated the complexity of recruitment mechanisms that need to be coordinated in localizing an ARF GEF for this process.

Regulation of Ras in lymphocytes: get a GRP

2006 ◽  
Vol 34 (5) ◽  
pp. 858-861 ◽  
Author(s):  
J.C. Stone
Keyword(s):  
Cell Receptor ◽  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
C1 Domain ◽  
Ef Hands ◽  
Ras Signalling

RasGRPs (guanine nucleotide releasing proteins) are a family of four GEFs (guanine nucleotide-exchange factors) (Ras GEFs) that positively regulate Ras and related small GTPases. RasGRP1 possesses a catalytic region consisting of a REM (Ras exchange motif) and a CDC25 (cell division cycle 25) domain. RasGRP1 also possesses a DAG (diacylglycerol)-binding C1 domain and a pair of EF hands that bind calcium. RasGRP1 is selectively expressed in lymphocytes as well as in some cells of the brain, kidney and skin. Functional analysis supports the hypothesis that RasGRP1 serves to couple TCR (T-cell receptor) stimulation and phospholipase C activation with Ras signalling. In B-cells, both RasGRP1 and RasGRP3 play a similar role downstream of the B-cell receptor. RasGRP2 acts on the Ras-related protein Rap and functions in platelet adhesion. RasGRP4 is expressed in mast cells and certain myeloid leukaemia cells. Membrane DAG regulates RasGRPs directly by recruitment to cellular membranes, as well as indirectly by protein kinase C-mediated phosphorylation. The properties of RasGRPs provide a novel view of Ras regulation in lymphocytes and explain several earlier observations. Many experimental results obtained with DAG analogues could be reviewed in light of these findings.

Role of Epac in brain and heart

2012 ◽  
Vol 40 (1) ◽  
pp. 51-57 ◽  
Author(s):  
Anne-Coline Laurent ◽  
Magali Breckler ◽  
Magali Berthouze ◽  
Frank Lezoualc'h
Keyword(s):  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Signalling Pathways ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
New Sensors ◽  
Kinase A

Epacs (exchange proteins directly activated by cAMP) are guanine-nucleotide-exchange factors for the Ras-like small GTPases Rap1 and Rap2. Epacs were discovered in 1998 as new sensors for the second messenger cAMP acting in parallel to PKA (protein kinase A). As cAMP regulates many important physiological functions in brain and heart, the existence of Epacs raises many questions regarding their role in these tissues. The present review focuses on the biological roles and signalling pathways of Epacs in neurons and cardiac myocytes. We discuss the potential involvement of Epacs in the manifestation of cardiac and central diseases such as cardiac hypertrophy and memory disorders.

scholarly journals A High-Throughput Assay for Rho Guanine Nucleotide Exchange Factors Based on the Transcreener GDP Assay

2015 ◽  
Vol 20 (10) ◽  
pp. 1294-1299 ◽  
Author(s):  
Melvin Reichman ◽  
Amanda Schabdach ◽  
Meera Kumar ◽  
Tom Zielinski ◽  
Preston S. Donover ◽  
...  
Keyword(s):  
Steady State ◽  
High Throughput ◽  
Small Gtpases ◽  
Guanine Nucleotide Exchange Factors ◽  
Assay Method ◽  
Migration And Invasion ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

Ras homologous (Rho) family GTPases act as molecular switches controlling cell growth, movement, and gene expression by cycling between inactive guanosine diphosphate (GDP)- and active guanosine triphosphate (GTP)-bound conformations. Guanine nucleotide exchange factors (GEFs) positively regulate Rho GTPases by accelerating GDP dissociation to allow formation of the active, GTP-bound complex. Rho proteins are directly involved in cancer pathways, especially cell migration and invasion, and inhibiting GEFs holds potential as a therapeutic strategy to diminish Rho-dependent oncogenesis. Methods for measuring GEF activity suitable for high-throughput screening (HTS) are limited. We developed a simple, generic biochemical assay method for measuring GEF activity based on the fact that GDP dissociation is generally the rate-limiting step in the Rho GTPase catalytic cycle, and thus addition of a GEF causes an increase in steady-state GTPase activity. We used the Transcreener GDP Assay, which relies on selective immunodetection of GDP, to measure the GEF-dependent stimulation of steady-state GTP hydrolysis by small GTPases using Dbs (Dbl’s big sister) as a GEF for Cdc42, RhoA, and RhoB. The assay is well suited for HTS, with a homogenous format and far red fluorescence polarization (FP) readout, and it should be broadly applicable to diverse Rho GEF/GTPase pairs.

scholarly journals Involvement of the Switch 2 Domain of Ras in Its Interaction with Guanine Nucleotide Exchange Factors

1996 ◽  
Vol 271 (19) ◽  
pp. 11076-11082 ◽  
Author(s):  
Lawrence A. Quilliam ◽  
Mark M. Hisaka ◽  
Sheng Zhong ◽  
Amy Lowry ◽  
Raymond D. Mosteller ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

scholarly journals Essential Role of Vav Family Guanine Nucleotide Exchange Factors in EphA Receptor-Mediated Angiogenesis

2006 ◽  
Vol 26 (13) ◽  
pp. 4830-4842 ◽  
Author(s):  
Sonja G. Hunter ◽  
Guanglei Zhuang ◽  
Dana Brantley-Sieders ◽  
Wojciech Swat ◽  
Christopher W. Cowan ◽  
...  
Keyword(s):  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Rac1 Gtpase ◽  
Rho Family ◽  
Epha Receptor

ABSTRACT Angiogenesis, the process by which new blood vessels are formed from preexisting vasculature, is critical for vascular remodeling during development and contributes to the pathogenesis of diseases such as cancer. Prior studies from our laboratory demonstrate that the EphA2 receptor tyrosine kinase is a key regulator of angiogenesis in vivo. The EphA receptor-mediated angiogenic response is dependent on activation of Rho family GTPase Rac1 and is regulated by phosphatidylinositol 3-kinase. Here we report the identification of Vav2 and Vav3 as guanine nucleotide exchange factors (GEFs) that link the EphA2 receptor to Rho family GTPase activation and angiogenesis. Ephrin-A1 stimulation recruits the binding of Vav proteins to the activated EphA2 receptor. The induced association of EphA receptor and Vav proteins modulates the activity of Vav GEFs, leading to activation of Rac1 GTPase. Overexpression of either Vav2 or Vav3 in primary microvascular endothelial cells promotes Rac1 activation, cell migration, and assembly in response to ephrin-A1 stimulation. Conversely, loss of Vav2 and Vav3 GEFs inhibits Rac1 activation and ephrin-A1-induced angiogenic responses both in vitro and in vivo. In addition, embryonic fibroblasts derived from Vav2−/− Vav3−/− mice fail to spread on an ephrin-A1-coated surface and exhibit a significant decrease in the formation of ephrin-A1-induced lamellipodia and filopodia. These findings suggest that Vav GEFs serve as a molecular link between EphA2 receptors and the actin cytoskeleton and provide an important mechanism for EphA2-mediated angiogenesis.

Family-wide Analysis of the Inhibition of Arf Guanine Nucleotide Exchange Factors with Small Molecules: Evidence of Unique Inhibitory Profiles

Biochemistry ◽  
2017 ◽  
Vol 56 (38) ◽  
pp. 5125-5133 ◽  
Author(s):  
Sarah Benabdi ◽  
François Peurois ◽  
Agata Nawrotek ◽  
Jahnavi Chikireddy ◽  
Tatiana Cañeque ◽  
...  
Keyword(s):  
Small Molecules ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors
Sign in / Sign up

Export Citation Format

Share Document