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A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia...

ABSTRACT: 3xFLAG-IPs from HEK293T cell lysates expressing 3xFLAG-bait or 3xFLAG-control. Trypsin Digestion

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Tony Pawson

PROVIDER: MSV000079100 | MassIVE | Thu Apr 09 06:07:00 BST 2015

REPOSITORIES: MassIVE

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Publications

A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis.

Abraham Sabu S Scarcia Margherita M Bagshaw Richard D RD McMahon Kathryn K Grant Gary G Harvey Tracey T Yeo Maggie M Esteves Filomena O G FOG Thygesen Helene H HH Jones Pamela F PF Speirs Valerie V Hanby Andrew M AM Selby Peter J PJ Lorger Mihaela M Dear T Neil TN Pawson Tony T Marshall Christopher J CJ Mavria Georgia G

Nature communications 20150701

During angiogenesis, Rho-GTPases influence endothelial cell migration and cell-cell adhesion; however it is not known whether they control formation of vessel lumens, which are essential for blood flow. Here, using an organotypic system that recapitulates distinct stages of VEGF-dependent angiogenesis, we show that lumen formation requires early cytoskeletal remodelling and lateral cell-cell contacts, mediated through the RAC1 guanine nucleotide exchange factor (GEF) DOCK4 (dedicator of cytokine ...[more]

PMID: 26129894

Similar Datasets

A Rac/Cdc42 exchange factor complex promotes formation of lateral filopodia and blood vessel lumen morphogenesis.

Project description:During angiogenesis, Rho-GTPases influence endothelial cell migration and cell-cell adhesion; however it is not known whether they control formation of vessel lumens, which are essential for blood flow. Here, using an organotypic system that recapitulates distinct stages of VEGF-dependent angiogenesis, we show that lumen formation requires early cytoskeletal remodelling and lateral cell-cell contacts, mediated through the RAC1 guanine nucleotide exchange factor (GEF) DOCK4 (dedicator of cytokinesis 4). DOCK4 signalling is necessary for lateral filopodial protrusions and tubule remodelling prior to lumen formation, whereas proximal, tip filopodia persist in the absence of DOCK4. VEGF-dependent Rac activation via DOCK4 is necessary for CDC42 activation to signal filopodia formation and depends on the activation of RHOG through the RHOG GEF, SGEF. VEGF promotes interaction of DOCK4 with the CDC42 GEF DOCK9. These studies identify a novel Rho-family GTPase activation cascade for the formation of endothelial cell filopodial protrusions necessary for tubule remodelling, thereby influencing subsequent stages of lumen morphogenesis.

| S-EPMC4507007 | biostudies-other

The guanine nucleotide exchange factor Arhgef7/?Pix promotes axon formation upstream of TC10.

Project description:The characteristic six layers of the mammalian neocortex develop sequentially as neurons are generated by neural progenitors and subsequently migrate past older neurons to their final position in the cortical plate. One of the earliest steps of neuronal differentiation is the formation of an axon. Small GTPases play essential roles during this process by regulating cytoskeletal dynamics and intracellular trafficking. While the function of GTPases has been studied extensively in cultured neurons and in vivo much less is known about their upstream regulators. Here we show that Arhgef7 (also called ?Pix or Cool1) is essential for axon formation during cortical development. The loss of Arhgef7 results in an extensive loss of axons in cultured neurons and in the developing cortex. Arhgef7 is a guanine-nucleotide exchange factor (GEF) for Cdc42, a GTPase that has a central role in directing the formation of axons during brain development. However, active Cdc42 was not able to rescue the knockdown of Arhgef7. We show that Arhgef7 interacts with the GTPase TC10 that is closely related to Cdc42. Expression of active TC10 can restore the ability to extend axons in Arhgef7-deficient neurons. Our results identify an essential role of Arhgef7 during neuronal development that promotes axon formation upstream of TC10.

| S-EPMC5995858 | biostudies-literature

Extra-hematopoietic immunomodulatory role of the guanine exchange factor DOCK-2 [MethylCap-Seq]

Project description:The molecular basis of stromal immunomodulation is still unresolved. Here, we show a novel function for dedicator of cytokinesis 2 (DOCK2) in regulating extra-hematopoietic immune function of three independent stromal cell sources: induced pluripotent stem cells (iPSC)-derived mesodermal stromal cell (iPS-MSC), severe combined immunodeficiency (SCID) patient-derived fibroblasts and CRISPR/Cas9 knockout cells (iPS-MSCDOCK2KO). We first reprogrammed human mesenchymal stromal cells (MSC) into iPSC before differentiating the iPSCs back into MSC. Immature iPS-MSCs lacked immunosuppressive potential. Successive phenotypic maturation facilitated immunomodulatory function, while maintaining clonogenicity, comparable to parental MSCs. Sequential RNA-seq displayed time-dependent immune-related gene expression eventually resembling parental MSCs. SCID patient-derived fibroblasts harboring bi-allelic DOCK2 mutations also showed significantly reduced immunomodulatory capacity compared to non-mutated fibroblasts. CRISPR/Cas9-mediated DOCK2 knockout in healthy iPSCs resulted in significantly reduced immunomodulatory capacity, reduced F-actin stress-fibers, and a disturbed subcellular localization of CDC42 activation. We provide first evidence for extra-hematopoietic immunomodulation by the guanin exchange factor DOCK2. This suggests that persisting immune disease after successful blood stem cell transplantation in SCID patients could in part be due to loss-of-function DOCK2 mutations.

2022-11-11 | GSE189896 | GEO

Extra-hematopoietic immunomodulatory role of the guanine exchange factor DOCK-2 [RNA-Seq]

2022-11-11 | GSE189895 | GEO

HSP70 binds RNA and regulates transcription by RNA Polymerase III [ChIP-seq]

Project description:We examined the RNA binding ability of the 70-kDa heat shock protein (HSP70) family member HSPA1A and identified the RNA species bound to HSP70 in vivo. We used a UV-crosslinkiung and immunoprecipitation based approach named FLASH-seq (Aktaş et al., 2017) using 3xFLAG-Histidine-Biotin tagged ectopically expressed protein in HEK293T cells.

2024-01-17 | GSE191243 | GEO

HSP70 binds RNA and regulates transcription by RNA Polymerase III [RNA-seq]

2024-01-17 | GSE191244 | GEO

HSP70 binds RNA and regulates transcription by RNA Polymerase III [FLASH-seq]

Project description:We examined the RNA binding ability of the 70-kDa heat shock protein (HSP70) family member HSPA1A and HSP8 and identified the RNA species bound to HSP70 or HSP8 in vivo. We used a UV-crosslinkiung and immunoprecipitation based approach named FLASH-seq (Akta? et al., 2017) using 3xFLAG-Histidine-Biotin tagged ectopically expressed protein in HEK293T cells.

2024-01-17 | GSE191242 | GEO

METTL3 and N6-methyladenosine Promotes Homologous Recombination Mediated Repair of DSBs by Facilitating R-loop Formation [other]

Project description:Examination of R-loop formation at I-PpoI cutting site (28S rDNA and DAB1) and other uncut genome in NC or siMETTL3 transferred HEK293T with or without I-PpoI cutting

2020-04-14 | GSE148571 | GEO

Dynamic studies of H-Ras•GTP?S interactions with nucleotide exchange factor Sos reveal a transient ternary complex formation in solution.

Project description:The cycling between GDP- and GTP- bound forms of the Ras protein is partly regulated by the binding of Sos. The structural/dynamic behavior of the complex formed between activated Sos and Ras at the point of the functional cycle where the nucleotide exchange is completed has not been described to date. Here we show that solution NMR spectra of H-Ras?GTP?S mixed with a functional fragment of Sos (Sos(Cat)) at a 2:1 ratio are consistent with the formation of a rather dynamic assembly. H-Ras?GTP?S binding was in fast exchange on the NMR timescale and retained a significant degree of molecular tumbling independent of Sos(Cat), while Sos(Cat) also tumbled largely independently of H-Ras. Estimates of apparent molecular weight from both NMR data and SEC-MALS revealed that, at most, only one H-Ras?GTP?S molecule appears stably bound to Sos. The weak transient interaction between Sos and the second H-Ras?GTP?S may provide a necessary mechanism for complex dissociation upon the completion of the native GDP???GTP exchange reaction, but also explains measurable GTP???GTP exchange activity of Sos routinely observed in in vitro assays that use fluorescently-labelled analogs of GTP. Overall, the data presents the first dynamic snapshot of Ras functional cycle as controlled by Sos.

| S-EPMC4944212 | biostudies-literature

Multi-omic analyses reveal minimal impact of the CRISPR-Cas9 nuclease on the host

Project description:Transcriptomics strategies were applied to explore the cellular feedback after incorporating the Cas9. HEK293T cell lysates were collected after 24h transfected with PX330-GFP-cas9-6T, PX330-GFP-cas9-luciferase, PX330-GFP-noCas9-6T, PX330-GFP-noCas9-luciferase. RNA-seq data were generated from deep sequence. We found the impact caused by Cas9 is very minor

2021-03-20 | GSE112076 | GEO

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