The exchange of GDP to GTP and thus the activation of Rho GTPases is catalyzed by guanine nucleotide exchange factors (GEFs), which act downstream of numerous growth factor receptors, integrins, cytokine receptors, and cadherins. (biomedcentral.com)
Like other members of the RAS superfamily, ARF family proteins can be activated by guanine-nucleotide exchange factors (GEFs) and inactivated by GTPase-activating proteins (GAPs) [ 9 ]. (biomedcentral.com)
One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. (niepokorny.org)
Proteins21
GTPase-activating proteins (GAPs) bind activated forms of Rho GTPases and stimulate GTP hydrolysis. (wikipedia.org)
Like all members of the Ras superfamily, the Rho proteins cycle between active GTP-bound and inactive GDP-bound conformational states. (embl.de)
A structural feature that distinguishes the Rho proteins from other small GTPases is the so-called Rho insert domain located between a β strand and an α helix within the small GTPase domain [ 1 - 3 ]. (biomedcentral.com)
Typically Rho proteins are 190-250 residues long and consist only of the GTPase domain and short terminal C-terminal extensions. (biomedcentral.com)
Within their GTPase domains, they share approximately 30% amino acid identity with the Ras proteins and 40-95% identity within the family. (biomedcentral.com)
In turn, GTP-bound active GTPases can interact with a plethora of different effectors which mediate the different cellular functions of this family of proteins. (biomedcentral.com)
Rho GTPase effectors are a large group of proteins and include actin nucleation promoting molecules, adaptors, as well as kinases. (biomedcentral.com)
Neurofibromin loss potentially hyperactivates classic Ras (H-Ras, N-Ras, K-Ras), M-Ras, and R-Ras (R-Ras, R-Ras2/TC21) subfamily proteins. (biomedcentral.com)
We have shown that classic Ras proteins promote proliferation and survival, but not migration, in malignant peripheral nerve sheath tumor (MPNST) cells. (biomedcentral.com)
Proteins in cells with or without DN R-Ras expression were differentially labeled with SILAC and mass spectrometry was used to identify phosphoproteins and determine their relative quantities in the presence and absence of DN R-Ras. (biomedcentral.com)
R-Ras proteins function distinctly from classic Ras proteins by regulating distinct signaling pathways that promote MPNST tumorigenesis by mediating migration and invasion. (biomedcentral.com)
Mutations of the NF1 gene potentially results in the activation of multiple Ras proteins, which are key regulators of many biologic effects. (biomedcentral.com)
loss of neurofibromin could cause these Ras proteins to become persistently active, leading to the development of cancer. (biomedcentral.com)
We have previously shown that three related Ras proteins (the classic Ras proteins) are highly activated in malignant peripheral nerve sheath tumor (MPNST) cells with neurofibromin loss and that they drive cancer cell proliferation and survival by activating multiple cellular signaling pathways. (biomedcentral.com)
Here, we examined the expression, activation and action of R-Ras proteins in MPNST cells that have lost neurofibromin. (biomedcentral.com)
We examined the activation of cytoplasmic signaling pathways in the presence and absence of R-Ras signaling and found that R-Ras proteins regulated 13 signaling pathways distinct from those regulated by classic Ras proteins. (biomedcentral.com)
Inhibition of R-Ras/R-Ras2 and ROCK1 signaling also triggered the accumulation of abnormal intracellular vesicles, indicating that these signaling molecules regulate the movement of proteins and other molecules in the cellular interior. (biomedcentral.com)
NF1 is a major tumor suppressor gene encoding neurofibromin, a RAS-GAP (GTPase activating protein) that acts as an inhibitor of the RAS-MAPK pathway by allowing RAS proteins to return to inactive confirmation. (institutcochin.fr)
Protein9
Rac GTPase-activating protein 1 is an enzyme that in humans is encoded by the RACGAP1 gene. (wikipedia.org)
It does not share significant sequence homology with other subtypes of small G-protein GEF motifs such as the Cdc25 domain and the Sec7 domain, which specifically interact with Ras and ARF family small GTPases, respectively, nor with other Rho protein interactive motifs, indicating that the Dbl family proteins are evolutionarily unique. (embl.de)
Loss of the Ras GTPase-activating protein neurofibromin promotes nervous system tumor pathogenesis in patients with neurofibromatosis type 1 (NF1). (biomedcentral.com)
Cells were transfected with doxycycline-inducible vectors expressing either a pan-inhibitor of the R-Ras subfamily [dominant negative (DN) R-Ras] or enhanced green fluorescent protein (eGFP). (biomedcentral.com)
Mass spectrometry-based phosphoproteomics identified thirteen protein networks distinctly regulated by DN R-Ras, including multiple networks regulating cellular movement and morphology. (biomedcentral.com)
Closer study of an R-Ras regulated pathway containing the signaling protein ROCK1 showed that inhibition of either R-Ras, R-Ras2 or ROCK1 similarly impaired cellular migration and invasion and altered cellular morphology. (biomedcentral.com)
A ubiquitously expressed G-protein-coupled receptor kinase subtype that has specificity for the agonist-occupied form of BETA-ADRENERGIC RECEPTORS and a variety of other G-PROTEIN-COUPLED RECEPTORS. (lookformedical.com)
A G-protein-coupled receptor kinase subtype that is primarily expressed in the MYOCARDIUM and may play a role in the regulation of cardiac functions. (lookformedical.com)
The Rasd1 protein is a dexamethasone induced monomeric Ras-like G protein that oscillates in the suprachiasmatic nucleus (SCN). (biomedcentral.com)
Inhibitor2
Improved methods and pharmaceutical compositions are provided herein for mobilizing hematopoietic progenitor cells from bone marrow into peripheral blood, comprising the administration of an effective amount of an inhibitor of GTPases, such as Rac1 and Rac2 alone or in combination. (justia.com)
The present invention relates generally to improved methods and pharmaceutical compositions for mobilizing hematopoietic stem and progenitor cell from bone marrow into peripheral blood by administration of at least one inhibitor of a GTPase, such as Rac1 and/or Rac2 GTPase. (justia.com)
Inhibition6
In particular, embodiments of the method involve inhibition of both Rac1 and Rac2 GTPases to increase the numbers of hematopoietic stem cells into a subject's peripheral blood of a subject. (justia.com)
Consistent with classical Ras inhibition, DN R-Ras and R-Ras2 knockdown inhibited proliferation. (biomedcentral.com)
However, DN R-Ras inhibition impaired migration and invasion but not survival. (biomedcentral.com)
Inhibition of R-Ras action inhibited proliferation, migration and invasion but not survival. (biomedcentral.com)
Indeed, covalent KRASG12C inhibitors are known to require GDP-bound inactive KRASG12C for binding, and potential combination therapies by upstream inhibition of RAS activation (e.g., by inhibition of receptor tyrosine kinase or RASGEF activity) have been discussed (11C13). (niepokorny.org)
Together, the data presented here indicate that inhibition of GEFs DprE1-IN-2 may represent a viable approach for targeting RAS-driven tumors. (niepokorny.org)
Pathway1
In addition to bronchial tumors, our team is also interested in the characterization of NF1 mutations and more broadly of negative regulators of the RAS-MAPK pathway in pediatric acute lymphoblastic B leukemia (ALL-B). The activation of the main effectors of the pathway is well described but the alterations of the regulators are still poorly understood. (institutcochin.fr)
RAC12
Similarly, targeting the Rho-GTPase RAC1 has also been suggested as a potential therapeutic target in cancer. (ucm.es)
Moreover, inhibiting RAC1 activity shifts the CAF subtype to a more aggressive phenotype. (ucm.es)
Molecular5
This work investigates the molecular basis of the phenotypic heterogeneity of prion diseases through a multi-omics analysis of the two most common sCJD subtypes: MM1 and VV2. (biomedcentral.com)
The results add to the understanding of the molecular features associated with sporadic CJD and its most common subtypes, revealing strain-specific genetic signatures and functional similarities between VV2 and Parkinson's disease and providing preliminary evidence of RNA editing modifications in human sCJD. (biomedcentral.com)
Two isoforms of Epac, namely Epac 1 (RAPGEF3) and Epac 2 (RAPGEF4), have been identified so far, both of which couple cAMP production to the activation of Rap, a small molecular weight GTPase of the Ras family [11]. (researchensemble.com)
Rho GTPases work as sensitive molecular switches existing either in an inactive, GDP-bound form or an active GTP-bound form. (biomedcentral.com)
Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. (niepokorny.org)
Specificity1
Two factors concur to determine specific Rho GTPase function: tissue specificity of GTPase effectors and distinct intracellular localizations of closely related Rho GTPases, due to different lipid modifications [ 1 ]. (biomedcentral.com)
GAPs1
GAPs may also serve as effector molecules and play a role in signaling downstream of Rho and other Ras-like GTPases. (wikipedia.org)
Intracellular1
Biochemical data have established the role of the conserved DH domain in Rho GTPase interaction and activation, and the role of the tandem PH domain in intracellular targeting and/or regulation of DH domain function. (embl.de)
Distinct2
Esophageal cancer has two main histologic subtypes and they arise in two distinct areas of the esophagus. (biomedcentral.com)
2019). Our objectives are to understand the functional consequences of NF1 inactivation and to identify new potential therapeutic targets in NF1-mutated bronchial carcinomas which represent a distinct subtype of cancer. (institutcochin.fr)
Small2
This review will focus on the role of Rac and Rho small GTPases in cell motility and in the complex relationship driving the reciprocal control between Rac and Rho granting for the opportunistic motile behaviour of aggressive cancer cells. (biomedcentral.com)
Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. (cusabio.com)
Pathways1
Here, a good clusterization of the transcriptomic profiles of the two subtypes was achieved, together with the finding of several differently impaired pathways between the two subtypes. (biomedcentral.com)
GEFs1
Rho GTPases are key integrating molecules from different extracellular signals, as they can be activated by different GEFs. (biomedcentral.com)
Cdc422
Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. (embl.de)
The Rho family GTPases Rho, Rac and CDC42 regulate a diverse array of cellular processes. (embl.de)
Phenotype1
DNA target sequencing identified multiple potential genetic contributors to the disease onset and phenotype, both in terms of coding, damaging-predicted variants, and enriched groups of SNPs in the whole cohort and the two subtypes. (biomedcentral.com)
Cellular processes1
Rho GTPases control a variety of cellular processes. (wikipedia.org)
Pathogenesis2
However, it is unclear whether R-Ras, R-Ras2 and M-Ras are expressed and hyperactivated in MPNSTs and, if so, whether they contribute to MPNST pathogenesis. (biomedcentral.com)
Giannella RA (1981) Pathogenesis of acute bacterial diarrheal disorders. (springer.com)
Family1
First linked to human cancer in 1982 (1C3), members of the RAS family of GTPases (which comprises is the area in the yellow box enlarged, showing hydrogen bonds as thin dashed lines and cationC interaction as a thick dashed line. (niepokorny.org)
Catalytic2
A Ras exchange motif (REM) domain acts as an intramolecular bridge between the regulatory and the catalytic regions to stabilize the guanine nucleotide exchange (GEF) domain name. (researchensemble.com)
A CDC25 homology domain name (CDC25HD) in the C-terminal catalytic domain name exhibits GEF activity for Ras-like GTPases [9]. (researchensemble.com)
Survival1
In African-Americans, ESCC is the predominant subtype, and the survival rate is worse than in patients of other ethnic groups [ 5 ]. (biomedcentral.com)
Genetic1
Validation of R-Ras and R-Ras2 action and R-Ras regulated networks was performed using genetic and/or pharmacologic approaches. (biomedcentral.com)
Cancer2
In addition we analyse the role of these GTPases in cancer progression and metastatic dissemination. (biomedcentral.com)
Among them, colorectal adenocarcinoma is the main histological subtype of colorectal cancer. (biomedcentral.com)
Present1
R-Ras2 was uniformly expressed in MPNST cells, with R-Ras present in a major subset. (biomedcentral.com)
Role1
A common theme of these processes is a dynamic reorganization of actin cytoskeleton which has now emerged as a major switch control mainly carried out by Rho and Rac GTPase subfamilies, playing an acknowledged role in adaptation of cell motility to the microenvironment. (biomedcentral.com)
Levels1
Conversely, in amoeboid movement cells have a rounded morphology, the movement is independent from proteases but requires high Rho GTPase to drive elevated levels of actomyosin contractility. (biomedcentral.com)
Results1
To facilitate communication between research groups and comparison of results, a consensus in nomenclature needed to be established based on the type of isolation procedure used to purify EVs and the techniques used to distinguish between EV subtypes according to their biogenesis or release. (encyclopedia.pub)
Cells1
Both R-Ras and R-Ras2 are expressed in MPNST cells and activated. (biomedcentral.com)