Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA243869 | ENA |
REPOSITORIES: ENA
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Project description:This is a ordinary differential equation mathematical model describing the Rho GTPase cycle in which Rho GDP-dissociation inhibitors (RhoGDIs) inhibit the regulatory activities of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) by interacting with them directly as well as by sequestering the Rho GTPases. The model was constructed with the intent of analyzing the role of RhoGDIs in Rho GTPase signaling.
2024-09-02 | BIOMD0000000899 | BioModels
Project description:Extracellular superoxide dismutase (SOD3), which dismutases hydrogen peroxide to superoxide anion at cell membranes, mimics RAS oncogene action inducing primary cell immortalization at sustained low-level expression while high expression activates cancer barrier signaling through p53-p21 growth arrest pathway. We have previously demonstrated that the growth regulation of SOD3 occurs at the level of RAS and is mediated through non-transcriptional and transcriptional routes. Therefore, in the current work we assayed the growth suppressive mechanisms of SOD3 by characterizing the main signal transduction routes from the cell membrane into the nucleus. Based on our data robust over-expression of SOD3 in anaplastic thyroid cancer 8505c cells increased EGFR, RYK, ALK, FLT3, and EPHA10 tyrosine kinase receptor phosphorylation with consequent downstream SRC, FYN, YES, HCK, and LYN kinase activation. However, RAS pull-down experiment suggested lack of mitogen pathway stimulation that was confirmed by MEK1/2 and ERK1/2 Western blot. Interestingly, mRNA expression analysis indicated that SOD3 regulated in a dose dependent manner the expression of selected guanine nucleotide exchange factors (Rho GEF16, Ral GEF RGL1), GTPase activating proteins (ArfGAP ADAP2, Ras GAP RASAL1, RGS4), and Rho guanine nucleotide disassociation inhibitors (Rho GDI 2) therefore controlling the signal transduction through RAS GTPases to downstream signal transduction pathways. Our current data suggests a SOD3-induced activation of growth signal transduction is controlled in a dose dependent manner through GEF, GAP, and GDI.
2014-12-31 | GSE56546 | GEO
Project description:GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) function as negative and positive regulators of small GTPases, respectively, and play key roles in cell fate determination. The aberrant function of GAPs and GEFs has long been implicated in cancer development but their vast number and potential redundancy have hindered comprehensive understanding of their roles. Here we performed functional genetic screens of GAPs and GEFs in primary AML specimens to uncover an unexpected and selective role for ARHGAP45 in AML. Depletion of ARHGAP45 impedes AML growth without affecting normal human CD34+ cells in vivo. Epistasis screens revealed RhoA as the major substrate of ARHGAP45 and that depletion of the Rho GTPase CDC42 synergized with ARHGAP45 deletion. Consistent with this, pharmacologic CDC42 inhibition enhanced the effect of ARHGAP45 deletion. ARHGAP45 gives rise to a minor histocompatibility antigen (termed HA-1), which can be recognized by antigen-specific T cells. CDC42 inhibition not only sensitized AML cells to ARHGAP45 inhibition but also promoted the activity of HA-1 antigen-specific T cells by upregulating ARHGAP45-derived epitope in AML cells.
2024-07-26 | GSE273164 | GEO
Project description:Apigenin regulates multiple pathways related to microvesicle biogenesis without affecting the expression of small Rho GTPase activator guanine nucleotide exchange factors (GEFs). However, apigenin can primarily targets ARHGEF1 protein, a GEF of the small GTPases, thereby inhibiting the activity of small G proteins such as Cdc42, which is essential in regulating the signaling for the release of microvesicles from tumor cells. Targeting ARHGEF1, apigenin effectively prevents tumor cells from releasing microvesicles. This, in turn, inhibits tumor angiogenesis related to VEGF90K transport on microvesicles, ultimately impeding tumor progression.
2024-07-22 | GSE251817 | GEO
Project description:RASA3 (RAS p21 protein activator 3), also called GAPIII or IP4BP (inositol 1,3,4,5-tetrakisphosphate, IP4, binding protein), is a member of the GAP1 family of RAS-GTPase-activating proteins (GAPs). The RAS superfamily of small GTPases includes the subfamily RAP. Small GTPases act as molecular switches, cycling between active GTP-bound and inactive GDP-bound forms. They are activated by guanine nucleotide exchange factors (GEFs), which stimulate GTP loading, and inactivated by GAPs, which accelerate GTP hydrolysis. A major role of RASA3 in hematopoiesis was first identified upon positional cloning of the co-isogenic autosomal recessive mouse mutation, scat (severe combined anemia and thrombocytopenia. The scat phenotype, in addition to severe anemia and thrombocytopenia, includes significant leukopenia as well. The scat disease progresses episodically, with periods of severe crisis interspersed with one or two periods of remission. The RASA3 mutation (G125V) in scat causes mislocalization of RASA3 to the cytosol, abrogating RASA3 GAP activity and increasing active RAS levels in scat erythroid cells. As part of a broader study to analyze the role of RASA3 in hematopoiesis, we performed RNAseq studies to generate hypotheses regarding the progression of the scat disease from periods of crisis to partial remission.
2021-02-10 | GSE148821 | GEO
Project description:ARHGEF4 expression is associated with t(12;21) acute lymphoblastic leukaemia (ALL). Our study investigated the substrate specificity of ARHGEF4, a member of the diffuse B-cell lymphoma (DBL) family of guanine nucleotide exchange factors (GEFs), in t(12;21) ALL REH cells. ARHGEF4 was found to activate the small guanine nucleotide binding protein (GTPase) CDC42. In order to determine the function of CDC42 in t(12;21) ALL cells, we performed RNAseq analysis on REH cells treated for 24 hours with DMSO vehicle control in comparison to 25uM ML141, a CDC42 inhibitor.
2020-06-20 | GSE152836 | GEO
Project description:Ras proteins are GTPases that regulate a wide range of cellular processes. The activity of Ras is dependent on its nucleotide-binding status, which is modulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Previously, we demonstrated that mutation of lysine 104 to glutamine (K104Q) attenuates the transforming capacity of oncogenic K-Ras by interrupting GEF induced nucleotide exchange. To assess the effect of this mutation in vivo, we used CRISPR/Cas9 to generate mouse models carrying the K104Q point mutation in wild-type and conditional K- RasLSL-G12D alleles. Homozygous animals for K104Q were viable, fertile, and arose at Mendelian frequency, indicating that K104Q is not a complete loss of function mutation. Consistent with our previous findings from in vitro studies, however, the oncogenic activity of K-RasG12D was significantly attenuated by mutation at K104. These data demonstrate that lysine at position 104 is critical for the full oncogenic activity of mutant K-Ras and suggest that modification at K104, for example acetylation, may also regulate its activity. Using biochemical and structural analysis, we found that the G12D and K104Q mutations cooperate to suppress GEF-mediated nucleotide exchange, explaining the preferential effect of K104Q on oncogenic K-Ras. Furthermore, we found that K104 site forms allosteric network with three residues (M72, R73 and G75) on 2 helix at switch II. Intriguingly, point mutation at glutamine 75 to alanine (G75A) showed strong negative regulatory effect on K-RasG12D. Collectively, modulating these sites may provide a unique therapeutic approach in cancer expressing mutant K-Ras.
2023-06-01 | GSE233945 | GEO
Project description:T cell recirculation and organ entry involve diapedesis through cytoskeleton remodeling. Part of this process is controlled by guanosine exchange factors (GEFs) and GTPase activating proteins (GAPs) that promote active and inactive forms of Rho family of GTPases. Among GAPs, we identified the ARHGAP45, also known as HMHA1 (human minor histocompatibility antigen 1) and determined its interactome by affinity purification coupled to quantitative mass spectrometry (AP-MS) in Jurkat cells. This dataset contains results of AP-MS of Jurkat cells expressing One-Strep-tagged (OST) ARHGAP45 prior to and after TCR stimulation. Each AP-MS purification of OST- protein is associated with a corresponding control (WT Jurkat) at the same time point of stimulation. For each time point, three independent biological replicates were performed and each biological replicate was analyzed in duplicate by mass spectrometry.
2021-02-04 | PXD018016 | Pride
Project description:GTPase-activating proteins (GAPs) and guanine exchange factors (GEFs) play essential roles in regulating the activity of small GTPases. Several GAPs and GEFs have been shown to be present at the postsynaptic density (PSD) within excitatory glutamatergic neurons and regulate the activity of glutamate receptors. However, it is not known how synaptic GAP and GEF proteins are organized within the PSD signaling machinery, if they have overlapping interaction networks, or if they associate with proteins implicated in contributing to psychiatric disease. Here, we determine the interactomes of three interacting GAP/GEF proteins at the PSD, including the RasGAP Syngap1, the ArfGAP Agap2, and the RhoGEF Kalirin. We describe the functional properties of each interactome and show that these GAP/GEF proteins are highly associated with and cluster other proteins directly involved in GTPase signaling mechanisms. We also utilize Agap2 as an example of GAP/GEFs localized within multiple neuronal compartments and determine additional interactions involving Agap2 outside of the PSD. Functional analysis of PSD and non-PSD interactomes illustrates both common and unique functions of Agap2 determined by its subcellular location.
2022-02-22 | PXD006326 | Pride
Project description:The T lymphoma invasion and metastasis inducing protein 1 (TIAM1) is a guanine nucleotide exchange factor (GEF) that activates the small GTPase RAC1. We have shown that nuclear TIAM1 promotes the migration of NSCLC cells and regulates the expression of adhesion genes as part of a repressive complex. To further investigate this, we performed ChIP-Seq analysis to determine the enrichment of TIAM1, TRIM28 and H3K9me3 to chromatin in H441 cells.
2023-09-12 | GSE219029 | GEO