scholarly journals Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease

Oncogene ◽  
2013 ◽  
Vol 33 (31) ◽  
pp. 4021-4035 ◽  
Author(s):  
D R Cook ◽  
K L Rossman ◽  
C J Der
Keyword(s):  
Rho Gtpase ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Gtpase Activity ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

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 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 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 The Emerging Role of Rho Guanine Nucleotide Exchange Factors in Cardiovascular Disorders: Insights Into Atherosclerosis: A Mini Review

2022 ◽  
Vol 8 ◽  
Author(s):  
Mengqi Li ◽  
Qingzheng Jiao ◽  
Wenqiang Xin ◽  
Shulin Niu ◽  
Mingming Liu ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Rho Gtpase ◽  
Guanine Nucleotide Exchange Factors ◽  
Atherosclerotic Cardiovascular Disease ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

Atherosclerosis is a leading cause of cardiovascular disease, and atherosclerotic cardiovascular disease accounts for one-third of global deaths. However, the mechanism of atherosclerosis is not fully understood. It is well-known that the Rho GTPase family, especially Rho A, plays a vital role in the development and progression of arteriosclerosis. Rho guanine nucleotide exchange factors (Rho GEFs), which act upstream of Rho GTPases, are also involved in the atheromatous pathological process. Despite some research on the role of Rho GEFS in the regulation of atherosclerosis, the number of studies is small relative to studies on the essential function of Rho GEFs. Some studies have preliminarily revealed Rho GEF regulation of atherosclerosis by experiments in vivo and in vitro. Herein, we review the advances in research on the relationship and interaction between Rho GEFs and atheroma to provide a potential reference for further study of atherosclerosis.

scholarly journals Trp56of Rac1 Specifies Interaction with a Subset of Guanine Nucleotide Exchange Factors

2001 ◽  
Vol 276 (50) ◽  
pp. 47530-47541 ◽  
Author(s):  
Yuan Gao ◽  
Jingchuan Xing ◽  
Michel Streuli ◽  
Thomas L. Leto ◽  
Yi Zheng
Keyword(s):  
Rho Gtpase ◽  
Specific Inhibitor ◽  
Guanine Nucleotide Exchange Factors ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Binding Interaction ◽  
Critical Determinant ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors

Signaling specificity of Rho GTPase pathways is achieved in part by selective interaction between members of the Dbl family guanine nucleotide exchange factors (GEFs) and their Rho GTPase substrates. For example, Trio, GEF-H1, and Tiam1 are a subset of GEFs that specifically activate Rac1 but not the closely related Cdc42. The Rac1 specificity of these GEFs appears to be governed by Rac1-GEF binding interaction. To understand the detailed mechanism underlying the GEF specificity issue, we have analyzed a panel of chimeras made between Rac1 and Cdc42 and examined a series of point mutants of Rac1 made at the switch I, switch II, and β2/β3regions for their ability to interact with and to be activated by the GEFs. The results reveal that Rac1 residues of both the switch I and switch II regions are involved in GEF docking and GEF-mediated nucleotide disruption, because mutation of Asp38, Asn39, Gln61, Tyr64, or Arg66/Leu67into Ala results in the loss of GEF binding, whereas mutation at Tyr32, Asp65, or Leu70/Ser71leads to the loss of GEF catalysis while retaining the binding capability. The region between amino acids 53–72 of Rac1 is required for specific recognition and activation by the GEFs, and Trp56in β3appears to be the critical determinant. Introduction of Trp56to Cdc42 renders it fully responsive to the Rac-specific GEFin vitroand in cells. Further, a polypeptide derived from the β3region of Rac1 including the Trp56residue serves as a specific inhibitor for Rac1 interaction with the GEFs. Taken together, these results indicate that Trp56is the necessary and sufficient determinant of Rac1 for discrimination by the subset of Rac1-specific GEFs and suggest that a compound mimicking Trp56action could be explored as an interfering reagent specifically targeting Rac1 activation.

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
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