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Rho Guanine Nucleotide Exchange Factor ARHGEF10 is a putative tumor suppressor in pancreatic ductal adenocarcinoma

ABSTRACT: Rho Guanine Nucleotide Exchange Factor ARHGEF10 is a putative tumor suppressor in pancreatic ductal adenocarcinoma

PROVIDER: PRJNA545132 | ENA |

REPOSITORIES: ENA

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Extracellular Superoxide Dismutase Regulates the Expression of GTPase Guanine Nucleotide Exchange Factors (GEFs), GTPase-activating proteins (GAPs), and Rho Guanine nucleotide disassociation inhibitors (GDI)

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

Rho Guanine Nucleotide Exchange Factor ARHGEF10 is a putative tumor suppressor in pancreatic ductal adenocarcinoma

Project description:Our study has shown that ARHGEF10 is a putative tumor suppressor in pancreatic ductal adenocarcinoma. To determine its functional mechanism, we perfomed microarray gene expression analysis of two pancreatic cancer cell line models of ARHGEF10 expression : MiaPACA2 cells in which ARHGEF10 was stably overexpressed, and Hs766T cells in which ARHGEF10 expression had been stably knocked down by short hairpin RNAs.

2019-09-05 | GSE131859 | GEO

Identification of Rac guanine nucleotide exchange factors promoting Lgl1 phosphorylation in glioblastoma

Project description:The protein Lgl has key roles in the regulation of cell polarity. We have shown that Lgl is inactivated by hyperphosphorylation in glioblastoma as a consequence of PTEN loss and aberrant activation of the PI 3-kinase pathway; this contributes to glioblastoma pathogenesis both by promoting invasion and repressing glioblastoma cell differentiation. Lgl is phosphorylated by atypical protein kinase C in a complex with Par6 and either activated Cdc42 or activated Rac. Here we have investigated the role of specific Rac guanine nucleotide exchange factors in Lgl hyperphosphorylation in glioblastoma. We used CRISPR/Cas9 to knockout PREX1, a PI 3-kinase pathway-responsive Rac guanine nucleotide exchange factor that is overexpressed in glioblastoma. Knockout of PREX1 in patient-derived glioblastoma cells resulted in a reduction in Lgl phosphorylation and this could be reversed by re-expressing PREX1. PREX1 knockout cells showed reduced motility and altered phenotype suggestive of partial neuronal differentiation; consistent with this, RNA-seq analyses of these cells identified sets of PREX1-regulated genes with roles in promoting cell motility and repressing neuronal differentiation. Knockout of PREX1 in glioblastoma cells derived from a second patient did not affect Lgl phosphorylation. These cells overexpressed a short isoform of the Rac guanine nucleotide exchange factor TIAM1; knockdown of TIAM1 in PREX1-knockout cells from this patient reduced Lgl phosphorylation. These data show that PREX1 links aberrant PI 3-kinase to Lgl phosphorylation in glioblastoma, but that TIAM1 can also promote Lgl phosphorylation in a subset of patients. While this shows redundant mechanisms for Lgl phosphorylation, PREX1 appears to have a non-redundant role in glioblastoma cell motility, as this was impaired in PREX1 knockout cells from both patients.

2021-08-23 | GSE162783 | GEO

Identification of Rac guanine nucleotide exchange factors promoting Lgl1 phosphorylation in glioblastoma

Project description:Identification of Rac guanine nucleotide exchange factors promoting Lgl1 phosphorylation in glioblastoma

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Scambio, a novel guanine nucleotide exchange factor for Rho.

Project description: Not available

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Ota2015 - Positive regulation of Rho GTPase activity by RhoGDIs as a result of their direct interaction with GAPs (GDI integrated)

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.

2019-12-17 | BIOMD0000000899 | BioModels

The Rho Exchange Factors Vav2 and Vav3 Control a Lung Metastasis–Specific Transcriptional Program in Breast Cancer Cells

Project description:The guanosine triphosphatases of the Rho and Rac subfamilies regulate protumorigenic pathways and are activated by guanine nucleotide exchange factors (Rho GEFs), which could be potential targets for anticancer therapies. We report that two Rho GEFs, Vav2 and Vav3, play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and many of the steps involved in lung-specific metastasis. The involvement of Vav proteins in these processes did not correlate with Rac1 and RhoA activity or cell migration, implying the presence of additional biological programs. Microarray analyses revealed that Vav2 and Vav3 controlled a vast transcriptional program in breast cancer cells through mechanisms that were shared between the two proteins, isoform-specific or synergistic. Furthermore, the abundance of Vav regulated transcripts was modulated by Rac1-dependent and Rac1-independent pathways. This transcriptome encoded therapeutically targetable proteins that played non redundant roles in primary tumorigenesis and lung-specific metastasis, such as integrin-linked kinase (Ilk), the transforming growth factor–b family ligand inhibin bA, cyclooxygenase-2, and the epithelial cell adhesion molecule Tacstd2. It also contained gene signatures that predicted disease outcome in breast cancer patients. These results identify possible targets for treating breast cancer and lung metastases and provide a potential diagnostic tool for clinical use.

2012-10-03 | GSE33348 | GEO

Structure of the Rho-specific guanine nucleotide-exchange factor Xpln.

Project description: Not available

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Small-molecule inhibitors targeting G-protein-coupled Rho guanine nucleotide exchange factors.

Project description: Not available

| S-EPMC3581902 | biostudies-literature

Structure and function of heterotrimeric G protein-regulated Rho guanine nucleotide exchange factors.

Project description: Not available

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