Epac proteins: specific ligands and role in cardiac remodelling

2014 ◽  
Vol 42 (2) ◽  
pp. 257-264 ◽  
Author(s):  
Malik Bisserier ◽  
Jean-Paul Blondeau ◽  
Frank Lezoualc’h
Keyword(s):  
High Throughput Screening ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Guanine Nucleotide Exchange Factors ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Cardiac Pathophysiology ◽  
Cardiac Disorders

Epacs (exchange proteins directly activated by cAMP) act as guanine-nucleotide-exchange factors for the Ras-like small G-proteins Rap1 and Rap2, and are now recognized as incontrovertible factors leading to complex and diversified cAMP signalling pathways. Given the critical role of cAMP in the regulation of cardiac function, several studies have investigated the functional role of Epacs in the heart, providing evidence that Epacs modulate intracellular Ca2+ and are involved in several cardiac pathologies such as cardiac hypertrophy and arrhythmia. The present review summarizes recent data on the Epac signalling pathway and its role in cardiac pathophysiology. We also discuss recent advances in the discovery of novel pharmacological modulators of Epacs that were identified by high-throughput screening and their therapeutic potential for the treatment of cardiac disorders.

scholarly journals The Phosphatidylinositol (3,4,5)-Trisphosphate-dependent Rac Exchanger 1·Ras-related C3 Botulinum Toxin Substrate 1 (P-Rex1·Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells

2015 ◽  
Vol 290 (34) ◽  
pp. 20827-20840 ◽  
Author(s):  
Christina M. Lucato ◽  
Michelle L. Halls ◽  
Lisa M. Ooms ◽  
Heng-Jia Liu ◽  
Christina A. Mitchell ◽  
...  
Keyword(s):  
Botulinum Toxin ◽  
Tyrosine Kinases ◽  
Critical Role ◽  
Structural Data ◽  
Guanine Nucleotide Exchange Factors ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Rac Gtpases ◽  
G Protein Coupled

The P-Rex (phosphatidylinositol (3,4,5)-trisphosphate (PIP3)-dependent Rac exchanger) family (P-Rex1 and P-Rex2) of the Rho guanine nucleotide exchange factors (Rho GEFs) activate Rac GTPases to regulate cell migration, invasion, and metastasis in several human cancers. The family is unique among Rho GEFs, as their activity is regulated by the synergistic binding of PIP3 and Gβγ at the plasma membrane. However, the molecular mechanism of this family of multi-domain proteins remains unclear. We report the 1.95 Å crystal structure of the catalytic P-Rex1 DH-PH tandem domain in complex with its cognate GTPase, Rac1 (Ras-related C3 botulinum toxin substrate-1). Mutations in the P-Rex1·Rac1 interface revealed a critical role for this complex in signaling downstream of receptor tyrosine kinases and G protein-coupled receptors. The structural data indicated that the PIP3/Gβγ binding sites are on the opposite surface and markedly removed from the Rac1 interface, supporting a model whereby P-Rex1 binding to PIP3 and/or Gβγ releases inhibitory C-terminal domains to expose the Rac1 binding site.

scholarly journals The Abl-interactor Abi suppresses the function of the BRAG2 GEF family member Schizo

2020 ◽  
Author(s):  
Stefanie Lübke ◽  
Carina Braukmann ◽  
Karl-Heinz Rexer ◽  
Lubjinka Cigoja ◽  
Susanne F. Önel
Keyword(s):  
Family Member ◽  
Guanine Nucleotide Exchange Factors ◽  
Actin Dynamics ◽  
Nucleotide Exchange ◽  
Ph Domain ◽  
Loss Of Function ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Arf Gtpases

AbstractGuanine nucleotide exchange factors (GEF) of the BRAG subfamily activate small Arf GTPases, which are pivotal regulators of intracellular membrane traffic and actin dynamics. Here, we demonstrate a novel interaction between the Abl-interactor (Abi) and the BRAG family member Schizo. We mapped the SH3 domain of Abi to interact with the N-terminal region of Schizo. This region is additionally involved in the binding of the cytodomain of the cell adhesion molecule N-cadherin. In schizo loss of function mutants, we detected increased amounts of N-cadherin. In contrast, the expression of the GEF (Sec7) and the membrane-binding (pleckstrin homology) domains decreased amounts of N-cadherin, indicating a crucial role of the Sec7-PH module in regulating N-cadherin levels. Unlike other Sec7 GEFs, where the catalytic Sec7 domain is autoinhibited, the Sec7 and PH domain of BRAG2 are constitutively accessible, raising the question how GEF activity is controlled in a spatial and temporal manner. Our genetic analyzes demonstrate that the nature of the Abi Schizo interaction is to antagonize Schizo function and to restore wild-type amounts of N-cadherin.

scholarly journals Ral GTPases Contribute to Regulation of Cyclin D1 through Activation of NF-κB

2000 ◽  
Vol 20 (21) ◽  
pp. 8084-8092 ◽  
Author(s):  
Dale O. Henry ◽  
Serge A. Moskalenko ◽  
Kiran J. Kaur ◽  
Maofu Fu ◽  
Richard G. Pestell ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
Guanine Nucleotide Exchange Factors ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Effector Pathway ◽  
Ral Gtpases ◽  
Phospholipase D1 ◽  
Induced Signal

ABSTRACT Ral GTPases have been implicated as mediators of Ras-induced signal transduction from observations that Ral-specific guanine nucleotide exchange factors associate with Ras and are activated by Ras. The cellular role of Ral family proteins is unclear, as is the contribution that Ral may make to Ras-dependent signaling. Here we show that expression of activated Ral in quiescent rodent fibroblasts is sufficient to induce activation of NF-κB-dependent gene expression and cyclin D1 transcription, two key convergence points for mitogenic and survival signaling. The regulation of cyclin D1 transcription by Ral is dependent on NF-κB activation and is mediated through an NF-κB binding site in the cyclin D1 promoter. Ral activation of these responses is likely through an as yet uncharacterized effector pathway, as we find activation of NF-κB and the cyclin D1 promoter by Ral is independent of association of Ral with active phospholipase D1 or Ral-binding protein 1, two proteins proposed to mediate Ral function in cells.

scholarly journals RalB directly triggers invasion downstream Ras by mobilizing the Wave complex

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Giulia Zago ◽  
Irina Veith ◽  
Manish Kumar Singh ◽  
Laetitia Fuhrmann ◽  
Simon De Beco ◽  
...  
Keyword(s):  
Potential Role ◽  
Guanine Nucleotide Exchange Factors ◽  
Breast Cancers ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Ral Gtpases ◽  
Regulatory Complex ◽  
Wave Complex

The two Ral GTPases, RalA and RalB, have crucial roles downstream Ras oncoproteins in human cancers; in particular, RalB is involved in invasion and metastasis. However, therapies targeting Ral signalling are not available yet. By a novel optogenetic approach, we found that light-controlled activation of Ral at plasma-membrane promotes the recruitment of the Wave Regulatory Complex (WRC) via its effector exocyst, with consequent induction of protrusions and invasion. We show that active Ras signals to RalB via two RalGEFs (Guanine nucleotide Exchange Factors), RGL1 and RGL2, to foster invasiveness; RalB contribution appears to be more important than that of MAPK and PI3K pathways. Moreover, on the clinical side, we uncovered a potential role of RalB in human breast cancers by determining that RalB expression at protein level increases in a manner consistent with progression toward metastasis. This work highlights the Ras-RGL1/2-RalB-exocyst-WRC axis as appealing target for novel anticancer strategies.

scholarly journals “DOCK3 is a dosage-sensitive regulator of skeletal muscle and Duchenne muscular dystrophy-associated pathologies”

2020 ◽  
Author(s):  
Andrea L. Reid ◽  
Yimin Wang ◽  
Adrienne Samani ◽  
Rylie M. Hightower ◽  
Michael A. Lopez ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Myogenic Differentiation ◽  
Guanine Nucleotide Exchange Factors ◽  
Nucleotide Exchange ◽  
Dystrophic Muscle ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factors ◽  
Muscle Histology ◽  
Muscle Health

AbstractDOCK3 is a member of the DOCK family of guanine nucleotide exchange factors that function to regulate cell migration, fusion, and overall viability. Previously, we identified a miR-486/Dock3 signaling cascade that was dysregulated in dystrophin-deficient muscle which resulted in the overexpression of DOCK3, however not much else is known about the role of DOCK3 in muscle. In this work, we characterize the functional role of DOCK3 in normal and dystrophic skeletal muscle. By utilizing Dock3 global knockout (Dock3 KO) mice, we found reducing Dock3 gene via haploinsufficiency in DMD mice improved dystrophic muscle histology, however complete loss of Dock3 worsened overall muscle function on a dystrophin-deficient background. Consistent with this, Dock3 KO mice have impaired muscle architecture and myogenic differentiation defects. Moreover, transcriptomic analyses of Dock3 knockout muscles reveal a decrease in factors known for myogenesis, suggesting a possible mechanism of action. These studies identify DOCK3 as a novel modulator of muscle fusion and muscle health and may yield additional therapeutic targets for treating dystrophic muscle symptoms.

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.

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