Affinage

RASGRP3

Ras guanyl-releasing protein 3 · UniProt Q8IV61

Length
690 aa
Mass
78.3 kDa
Annotated
2026-06-10
38 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RASGRP3 (CalDAG-GEFIII) is a diacylglycerol/phorbol-ester-regulated guanine nucleotide exchange factor that couples receptor-driven lipid second-messenger signaling to small-GTPase activation, exchanging GDP for GTP on Ha-Ras, R-Ras and Rap1 with broader substrate specificity than its CalDAG-GEF relatives (PMID:10835426). Its C1 domain binds phorbol esters in an anionic-phospholipid-dependent manner, and ligand binding both stimulates exchange activity and redistributes RASGRP3 to plasma and intracellular membranes, defining it as a PKC-independent phorbol-ester receptor that links DAG to Ras-ERK activation (PMID:11221888, PMID:15657361). RASGRP3 is subject to dual regulation: in addition to DAG-driven membrane recruitment, PKC phosphorylates it specifically on Thr133 to achieve full Ras-activating capacity, a step required downstream of PLC-gamma2/BCR signaling in B cells and mediated by PKC isoforms including PKC-theta, PKC-beta2 and PKC-delta (PMID:12730099, PMID:15657177, PMID:15545601, PMID:15213298); a parallel input occurs via c-Src-dependent tyrosine phosphorylation downstream of the EGF receptor, routing signaling through Rap2B to PLC-epsilon (PMID:15143162). Genetic loss-of-function establishes RASGRP3 as essential for BCR-induced B cell proliferation and humoral immunity (PMID:16301621), for DAG-dependent endothelial morphogenesis and endothelin-1-driven endothelial migration (PMID:15572660, PMID:21474816), and as the critical node activating Ras downstream of oncogenic GNAQ/GNA11 in uveal melanoma, where it is engaged both by PKC-delta/epsilon phosphorylation and by DAG-mediated recruitment (PMID:28486107, PMID:29490280). Through activation of Rap1/RAP1B, RASGRP3 also restrains inflammatory signaling, limiting TLR-induced IL-6 production in macrophages and suppressing NF-kappaB activation in endothelial cells (PMID:25118589, PMID:41689678). Its subcellular localization is shaped by interactions with dynein light chain 1 (DLC1), which anchors it via its C-terminal region, and with Arp3, which links it to actin-dependent glioma cell migration (PMID:17012239, PMID:25682201); RASGRP3 protein levels are additionally controlled by ubiquitin-dependent degradation involving the E3 ligase family members MID1 and UHRF1 (PMID:36826998, PMID:41689678).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 High

    Established the core biochemical identity of RASGRP3 as a GEF, answering which GTPases it acts on and distinguishing it from related family members.

    Evidence In vitro GEF assay with multiple GTPase substrates plus PC12 differentiation and Rat1A transformation assays

    PMID:10835426

    Open questions at the time
    • Structural basis of substrate selectivity unresolved
    • Physiological receptor inputs not yet defined
  2. 2001 High

    Defined how RASGRP3 senses lipid second messengers, showing C1-domain phorbol ester binding activates exchange activity and drives membrane redistribution.

    Evidence Phorbol ester binding assay, Ras-GTP pull-down, GFP-RASGRP3 live-cell imaging in HEK-293 cells

    PMID:11221888

    Open questions at the time
    • Identity of physiological DAG-generating receptors not addressed
    • Quantitative coupling of membrane recruitment to exchange rate unclear
  3. 2003 High

    Revealed a second layer of regulation beyond membrane recruitment, showing PKC phosphorylates RASGRP3 coincident with Ras activation.

    Evidence In vitro kinase assay with PKC-theta/PKC-beta2, co-IP, pharmacological PKC inhibition and fractionation in B cells

    PMID:12730099

    Open questions at the time
    • Specific phosphosite not yet mapped
    • Relative contribution of phosphorylation vs recruitment not quantified
  4. 2004 High

    Pinpointed Thr133 as the PKC phosphosite functionally linking PKC to Ras activation downstream of the BCR, converting a correlative observation into a defined mechanistic step.

    Evidence MS phosphosite mapping, Thr133Ala mutagenesis, phospho-specific antibody, PLC-gamma2 deletion and PKC inhibition in B cells

    PMID:15545601 PMID:15657177

    Open questions at the time
    • Whether other sites contribute to full activation unknown
    • Structural consequence of Thr133 phosphorylation undefined
  5. 2004 High

    Expanded the regulatory kinase repertoire by showing PKC-delta physically associates with and phosphorylates RASGRP3, modulating localization and ERK output.

    Evidence Co-IP, in vitro kinase assay, PKC-delta kinase-dead mutant, rottlerin inhibition, colocalization

    PMID:15213298

    Open questions at the time
    • Serine sites phosphorylated by PKC-delta not mapped
    • Functional interplay with Thr133 phosphorylation unresolved
  6. 2004 Medium

    Identified a tyrosine-phosphorylation activation input, placing RASGRP3 in an EGFR-c-Src-Rap2B-PLC-epsilon axis distinct from the DAG/PKC route.

    Evidence Reciprocal co-IP, dominant-negative Rap2B, c-Src inhibition, GTP-loading and Ca2+ measurement in HEK-293 cells

    PMID:15143162

    Open questions at the time
    • c-Src tyrosine target site on RASGRP3 not mapped
    • Single-lab finding without genetic validation
  7. 2005 High

    Defined RASGRP3's physiological role in adaptive immunity, showing it sustains basal Ras-GTP and is required for BCR-induced proliferation and humoral responses.

    Evidence Rasgrp1/Rasgrp3 single and double knockout mice, Ras-GTP pull-down, proliferation and in vivo immunization assays

    PMID:16301621

    Open questions at the time
    • Molecular basis of redundancy with RASGRP1 not dissected
    • Downstream effector pathway in B cells not fully mapped
  8. 2005 Medium

    Clarified that RASGRP3 translocation tracks ligand localization and supports a PKC-independent output (exocytosis), broadening its functional scope beyond Ras-ERK.

    Evidence Live-cell imaging with fluorescent phorbol esters/GFP fusions in CHO cells; exocytosis assay with PKC/MEK inhibition in endocrine cells

    PMID:15657361 PMID:15737652

    Open questions at the time
    • Molecular mechanism coupling RASGRP3 GEF activity to exocytosis not identified
    • Exocytosis finding is low-confidence single functional assay
  9. 2006 Medium

    Identified DLC1 as an anchoring partner controlling RASGRP3 subcellular distribution via its C-terminus, explaining a determinant of localization independent of ligand binding.

    Evidence Yeast two-hybrid screen, in vitro pull-down, co-IP, C-terminal truncation mutagenesis, fluorescence localization

    PMID:17012239

    Open questions at the time
    • Functional consequence of DLC1 anchoring for GEF activity not measured
    • Single-lab interaction
  10. 2011 Medium

    Established RASGRP3 in endothelial pathophysiology, placing it in an endothelin-1-Ras/MEK/ERK axis required for migration and for diabetes-induced vascular defects.

    Evidence Rasgrp3 loss-of-function embryos from diabetic mothers, activated RASGRP3 overexpression in primary endothelial cells, migration and signaling assays

    PMID:15572660 PMID:21474816

    Open questions at the time
    • Receptor-proximal coupling of endothelin-1 to RASGRP3 not detailed
    • Single-lab models
  11. 2014 High

    Showed RASGRP3 sets an anti-inflammatory threshold via Rap1, distinguishing its Rap1 output from ERK and revealing a restraining role in innate immune signaling.

    Evidence CRISPR-Cas9 RASGRP3 knockout in RAW264.7 cells, Rap1-GTP pull-down, IL-6 measurement, in vivo colitis/arthritis models

    PMID:25118589

    Open questions at the time
    • How Rap1 mechanistically dampens TLR-ERK/IL-6 not fully resolved
    • Receptor-proximal activation of RASGRP3 by TLRs unclear
  12. 2015 Medium

    Linked RASGRP3 to the actin machinery through Arp3, providing a mechanism for its role in glioma migration and invasion beyond GTPase exchange.

    Evidence Pull-down/MS, co-IP, immunofluorescence, Arp3 siRNA, migration/invasion assays in glioma cells

    PMID:25682201

    Open questions at the time
    • Whether RASGRP3-Arp3 interaction is direct or scaffolded unclear
    • Single-lab finding
  13. 2018 High

    Identified RASGRP3 as the essential node coupling oncogenic GNAQ/GNA11 to Ras-MAPK in uveal melanoma, integrating both PKC-dependent and DAG-dependent activation modes.

    Evidence siRNA/shRNA knockdown, PKC inhibition, Ras-GTP pull-down in UM cell lines, GNA11Q209L mouse model, transcriptome and xenograft analyses

    PMID:28486107 PMID:29490280

    Open questions at the time
    • Mechanism of GNAQ/11-driven RASGRP3 overexpression not fully defined
    • Therapeutic exploitability of dual activation modes not resolved
  14. 2018 Medium

    Demonstrated that the RASGRP3 C1 domain is pharmacologically targetable with selectivity over PKC, establishing a chemical-biology entry point.

    Evidence In vitro C1-domain competitive binding assay and cell-based Ras-GTP/PKC-delta phosphorylation selectivity with DAG-lactone compound 96

    PMID:29860841

    Open questions at the time
    • In vivo efficacy and pharmacology of the ligand untested
    • Single-lab in vitro selectivity data
  15. 2023 Medium

    Revealed post-translational control of RASGRP3 abundance, showing ubiquitin-dependent degradation modulated by the E3 ligase MID1 governs RASGRP3 stability in NPM1-mutant AML.

    Evidence Co-IP, cycloheximide chase, proliferation assays in NPM1-mutated AML cells

    PMID:36826998

    Open questions at the time
    • Direct ubiquitination of RASGRP3 by MID1 not demonstrated
    • Single-lab finding
  16. 2026 Medium

    Reinforced the anti-inflammatory Rap1B output in vascular disease and identified a second E3-ligase-family regulator (UHRF1) controlling RASGRP3 protein turnover.

    Evidence Endothelial overexpression, Rap1 activity and NF-kappaB assays, endothelial-specific ApoE-/- transgenic mice, co-IP and ubiquitination assay

    PMID:41689678

    Open questions at the time
    • Whether UHRF1 directly ubiquitinates RASGRP3 not fully established
    • Single-lab recent finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple activation inputs (DAG recruitment, Thr133/Ser PKC phosphorylation, c-Src tyrosine phosphorylation) and degradation pathways are integrated to bias RASGRP3 toward Ras versus Rap1 outputs in a given cell type remains unresolved.
  • No structural model integrating C1, GEF and regulatory phosphosites
  • No unified quantitative model of Ras-vs-Rap1 output selection
  • Mechanism directing substrate choice across cell types unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 2 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2
Partners
ARP3DLC1MID1PRKCDPRKCQSRCUHRF1

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 CalDAG-GEFIII (RasGRP3) is a guanine nucleotide exchange factor that promotes GDP-to-GTP exchange on Ha-Ras, R-Ras, and Rap1 both in intact cells and in vitro, exhibiting broader substrate specificity than related family members CalDAG-GEFI and CalDAG-GEFII. Expression of RasGRP3 activates ERK/MAPK, and co-activation of Rap1 by RasGRP3 attenuates Ras-MAPK-dependent neuronal differentiation and cellular transformation. In vitro GEF assay (GTP/GDP ratio measurement), transfection in 293T cells, PC12 neuronal differentiation assay, Rat1A anchorage-independent growth assay The Journal of biological chemistry High 10835426
2001 RasGRP3 binds phorbol esters with high affinity via its C1 domain in an anionic phospholipid-dependent manner, and phorbol ester binding activates RasGRP3 exchange activity (increasing Ras-GTP and ERK phosphorylation) and causes redistribution of RasGRP3 to the plasma membrane and/or perinuclear area, identifying RasGRP3 as a PKC-independent phorbol ester receptor linking DAG/phorbol ester signaling to Ras activation. Phorbol ester binding assay, Ras-GTP pull-down, ERK phosphorylation (Western blot), GFP-RasGRP3 live-cell imaging/redistribution in HEK-293 cells Cancer research High 11221888
2003 RasGRP3 is phosphorylated coincident with Ras activation after PMA stimulation of B cells; PKC inhibitors attenuate both Ras activation and RasGRP3 phosphorylation. PKC-theta and PKC-beta2 phosphorylate RasGRP3 in vitro, and a dominant-active PKC-theta mutant co-expressed with RasGRP3 in HEK-293 cells enhances Ras-ERK signaling. PMA also induces membrane association of RasGRP3, indicating dual regulation by DAG-mediated membrane recruitment and PKC-dependent phosphorylation. In vitro kinase assay with PKC-theta and PKC-beta2, co-immunoprecipitation, Ras-GTP pull-down, pharmacological PKC inhibition, subcellular fractionation Blood High 12730099
2004 PKC phosphorylates RasGRP3 specifically on threonine 133 (identified by mass spectrometry in vitro). A Thr133Ala substitution renders RasGRP3 a poor PKC substrate in vitro and a poor Ras activator in vivo. Anti-phospho-Thr133 antibodies detect phosphorylated RasGRP3 in B cells after BCR stimulation or DAG analog treatment; PKC inhibitors block both Thr133 phosphorylation and Ras-ERK signaling. This defines Thr133 phosphorylation as a mechanistic link between PKC and Ras activation downstream of BCR signaling. In vitro kinase assay with mass spectrometry (Thr133 identification), site-directed mutagenesis (Thr133Ala), anti-phosphopeptide antibody, pharmacological PKC inhibition, Ras-GTP pull-down in B cells Blood High 15545601 15657177
2004 RasGRP3 Thr133 is phosphorylated upon BCR cross-linking; deletion of PLC-gamma2 or pharmacological inhibition of conventional PKCs markedly reduces both Thr133 phosphorylation and Ras activation. Thr133Ala mutation severely impairs RasGRP3-mediated Ras activation in BCR signaling, indicating that PKC (activated by DAG downstream of PLC-gamma2) phosphorylates RasGRP3 at Thr133 to achieve full activation. BCR cross-linking, pharmacological PKC inhibition, Thr133Ala mutagenesis, Ras activation assay in B cell lines Proceedings of the National Academy of Sciences of the United States of America High 15545601
2004 PKCdelta physically associates with RasGRP3 upon PMA stimulation, as shown by co-immunoprecipitation and co-localization in the perinuclear region. PKCdelta phosphorylates RasGRP3 in vitro (on serine residues). A PKCdelta kinase-dead mutant blocks the PMA-induced mobility shift of RasGRP3. Co-expression of PKCdelta and RasGRP3 modulates Erk1/2 activation compared with either alone. Co-immunoprecipitation, in vitro kinase assay, kinase-dead mutant expression, pharmacological inhibition (rottlerin), immunofluorescence colocalization Molecular pharmacology High 15213298
2004 EGF receptor activates Rap2B-dependent stimulation of PLC-epsilon through RasGRP3: EGF induces tyrosine phosphorylation of RasGRP3 (but not RasGRP1) by c-Src; inhibition of c-Src blocks EGF-induced Rap2B-GTP loading and PLC-epsilon stimulation. RasGRP3 overexpression enhances GTP loading of Rap2B and PLC/Ca2+ signaling by EGF receptor, establishing a pathway: EGF receptor → c-Src → RasGRP3 (Tyr phosphorylation) → Rap2B → PLC-epsilon. Co-immunoprecipitation (Rap2B-PLC-epsilon), dominant-negative Rap2B expression, c-Src pharmacological inhibition, RasGRP3 overexpression, Ca2+ signaling measurement, GTP-loading assay in HEK-293 cells Molecular and cellular biology Medium 15143162
2004 RasGRP3 is expressed in embryonic blood vessels, downregulated in mature vessels, and re-expressed in angiogenic vessels during pregnancy and tumorigenesis. RasGRP3 is upregulated downstream of VEGF stimulation in HUVECs. In ES cell-derived vascular models, loss of RasGRP3 abolishes phorbol ester (PMA)-induced aberrant endothelial morphogenesis (formation of large sheets rather than branched vessels), establishing RasGRP3 as a required endothelial phorbol ester receptor mediating DAG-dependent angiogenic responses. Gene trap loss-of-function mouse model, ES cell vascular differentiation assay, PMA treatment, RT-PCR/in situ hybridization for expression pattern Molecular and cellular biology Medium 15572660
2005 RasGRP1 and RasGRP3 both contribute to BCR-induced Ras-GTP generation in B cells, with RasGRP3 alone responsible for maintaining basal Ras-GTP levels in unstimulated B cells. Double-null mutant mice show no defect in B cell development, but loss of RasGRP3 leads to humoral deficiencies (hypogammaglobulinemia, isotype-specific Ab induction defects) and loss of BCR-induced B cell proliferation. RasGRP-independent pathways support LPS-induced proliferation. Single and double Rasgrp1/Rasgrp3 knock-out mice, Ras-GTP pull-down, B cell proliferation assay, in vivo immunization, serum Ig measurement Journal of immunology High 16301621
2005 Fluorescent phorbol esters and complementary GFP-RasGRP3 fusion constructs showed that RasGRP3 co-localizes with and translocates to intracellular membranes upon phorbol ester treatment, with translocation pattern following ligand localization. The rate of phorbol ester uptake influences the pattern of RasGRP3 translocation. Live-cell fluorescence imaging with fluorescently labeled phorbol esters and GFP/DsRed fusion constructs for RasGRP3 in CHO cells Molecular cancer therapeutics Medium 15657361
2005 RasGRP3 is expressed in endocrine tissues and mediates phorbol ester-induced exocytosis in a PKC-independent manner; this effect was partially blocked by PKC inhibitors but not MEK inhibitor, despite MEK inhibitor blocking phorbol ester-induced ERK1/2 phosphorylation. Exocytosis assay in endocrine cells, pharmacological inhibition of PKC and MEK, ERK1/2 phosphorylation (Western blot) Biochemical and biophysical research communications Low 15737652
2006 Dynein light chain 1 (DLC1) is a novel RasGRP3-interacting protein identified by yeast two-hybrid screening of a human brain cDNA library and confirmed by in vitro pull-down and co-immunoprecipitation. The interaction requires the C-terminal 127 amino acids of RasGRP3. A truncated RasGRP3 lacking this C-terminal domain cannot interact with DLC1 and displays dramatically altered subcellular localization (strong reticular distribution with perinuclear and nuclear accumulation), suggesting DLC1 acts as an anchoring protein regulating RasGRP3 subcellular localization. Yeast two-hybrid screen, in vitro pull-down, co-immunoprecipitation, C-terminal truncation mutagenesis, subcellular localization by fluorescence microscopy The Journal of biological chemistry Medium 17012239
2010 In prostate cancer cell lines, RasGRP3 maintains Ras-GTP formation; siRNA knockdown reduces Ras-GTP, AKT phosphorylation, and ERK1/2 phosphorylation, inhibits proliferation, migration, and anchorage-independent growth, and induces apoptosis and sensitizes cells to carboplatin. Ectopic RasGRP3 expression in LNCaP cells elevates Ras-GTP and stimulates proliferation, defining RasGRP3 as an upstream activator of both AKT and ERK pathways in prostate cancer. siRNA knockdown, Ras-GTP pull-down, AKT/ERK phosphorylation (Western blot), proliferation assay, migration assay, soft-agar colony formation, xenograft mouse model Cancer research Medium 20876802
2011 RasGRP3 mediates diabetes-induced vascular developmental defects: embryos lacking Rasgrp3 function show dramatically attenuated diabetes-induced developmental defects. Endothelial cells expressing activated RasGRP3 have elevated Ras-ERK signaling and perturbed migration; cells lacking Rasgrp3 have attenuated Ras-ERK signaling and fail to migrate in response to endothelin-1. This establishes RasGRP3 in a pathway: endothelin-1 (upstream input) → RasGRP3 → Ras/MEK/ERK → endothelial migration. Rasgrp3 loss-of-function mouse embryos from diabetic mothers, activated RasGRP3 overexpression in primary endothelial cells, endothelin-1 stimulation, Ras-ERK signaling (Western blot), endothelial migration assay Circulation research Medium 21474816
2014 RasGRP3 activates Rap1 in macrophages downstream of TLR3/4/9 stimulation. In RasGRP3-deficient RAW264.7 cells (generated by CRISPR-Cas9), TLR-induced Rap1 activation is inhibited while ERK1/2 activation is enhanced. RasGRP3 thus limits IL-6 production in macrophages exposed to low levels of TLR agonists by activating Rap1, setting a threshold for inflammatory responses. CRISPR-Cas9 knockout of RasGRP3 in RAW264.7 cells, Rap1-GTP pull-down, ERK1/2 phosphorylation (Western blot), IL-6 cytokine measurement, in vivo colitis and arthritis models Nature communications High 25118589
2015 RasGRP3 interacts with Arp3 (actin-related protein 3) in glioma cells, identified by pull-down/mass spectrometry and validated by co-immunoprecipitation and immunofluorescence. PMA-induced translocation of RasGRP3 to the perinuclear region increases its association with Arp3. Silencing Arp3 partially abrogates RasGRP3-induced glioma cell migration and invasion, linking RasGRP3 to actin polymerization-dependent cell motility. Pull-down assay with mass spectrometry, co-immunoprecipitation, immunofluorescence, siRNA knockdown, cell migration/invasion assay Oncotarget Medium 25682201
2017 In GNAQ/GNA11 mutant uveal melanoma, MAPK activation requires Ras and is caused by RasGRP3, which is selectively overexpressed in response to GNAQ/11 mutation. PKCδ and PKCε are required and sufficient for MAPK activation upstream of RasGRP3. RasGRP3 is activated by two mechanisms: PKCδ/ε-dependent phosphorylation and PKC-independent DAG-mediated membrane recruitment, explaining the limited durability of PKC inhibitor effects on MAPK suppression. siRNA/shRNA knockdown, pharmacological PKC inhibition, Ras-GTP pull-down, ERK phosphorylation (Western blot), reconstitution of signaling in cell lines, expression analysis in human UM samples Cancer cell High 28486107
2018 In a GNA11Q209L mouse model of uveal melanoma, RasGRP3 is specifically expressed in GNAQ/GNA11-driven melanomas (identified by integrative transcriptome analysis). In human UM cell lines and murine models, RasGRP3 is specifically required for GNAQ/GNA11-driven Ras activation and tumorigenesis, confirming RasGRP3 as an essential node in the Gαq/11 → Ras signaling axis. GNA11Q209L knock-in mouse model, transcriptome analysis (human and murine melanomas), siRNA/shRNA knockdown in human UM cell lines, Ras-GTP pull-down, xenograft tumorigenesis assay Cell reports High 29490280
2018 DAG-lactone compound 96 shows 73-fold selectivity for RasGRP3 versus PKCα and 45-fold versus PKCε in C1-domain binding assays in vitro, and in intact cells induces Ras activation (downstream of RasGRP) with 8–29-fold selectivity relative to PKCδ phosphorylation, establishing that selective RasGRP3 C1-domain targeting is achievable with this ligand scaffold. In vitro C1-domain competitive binding assay, cell-based Ras-GTP and PKCδ phosphorylation assay Journal of medicinal chemistry Medium 29860841
2023 In NPM1-mutated AML, mislocalized NPM1-mA in the cytoplasm binds E3 ubiquitin ligase MID1 to block ubiquitin-dependent degradation of RasGRP3, thereby stabilizing RasGRP3 protein. Elevated RasGRP3 then activates the EGFR-STAT3 axis to promote AML cell proliferation and autophagy. Co-immunoprecipitation, Western blot, cycloheximide chase assay (protein stability), CCK8/EdU proliferation assay, immunofluorescence Journal of leukocyte biology Medium 36826998
2023 In colorectal cancer, the lncRNA AC092894.1 acts as a scaffold to mediate USP3-dependent de-ubiquitination and stabilization of the androgen receptor (AR), which then transcriptionally activates RASGRP3 expression, sustaining MAPK signaling and sensitizing cells to oxaliplatin. RASGRP3 thus functions downstream of an AR transcriptional program whose activity is regulated by protein ubiquitination. RNA pull-down, RIP assay, co-immunoprecipitation, gain/loss-of-function experiments BMC medicine Low 37013584
2026 In endothelial cells, RasGRP3 overexpression activates RAP1B and inhibits NF-κB pathway activation and pro-inflammatory cytokine production; endothelial-specific RasGRP3 overexpression in ApoE-/- mice reduces atherosclerotic plaque formation. UHRF1, an E3 ubiquitin ligase family member, is identified as a RasGRP3-binding protein; UHRF1 knockdown inhibits ubiquitination and degradation of RasGRP3, promoting its protein expression. Overexpression in endothelial cells, Rap1 activity assay, NF-κB pathway assay, endothelial-specific transgenic ApoE-/- mouse model, co-immunoprecipitation (UHRF1-RasGRP3 interaction), ubiquitination assay Inflammation Medium 41689678

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma. Cancer cell 131 28486107
2000 CalDAG-GEFIII activation of Ras, R-ras, and Rap1. The Journal of biological chemistry 125 10835426
2005 RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling. Journal of immunology (Baltimore, Md. : 1950) 112 16301621
2003 Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3. Blood 104 12730099
2001 Phorbol esters modulate the Ras exchange factor RasGRP3. Cancer research 90 11221888
2005 Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells. Blood 86 15657177
2018 GNA11 Q209L Mouse Model Reveals RasGRP3 as an Essential Signaling Node in Uveal Melanoma. Cell reports 71 29490280
2016 GRP-3 and KAPP, encoding interactors of WAK1, negatively affect defense responses induced by oligogalacturonides and local response to wounding. Journal of experimental botany 65 26748394
2004 Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated Ras activation. Proceedings of the National Academy of Sciences of the United States of America 65 15545601
2014 RasGRP3 limits Toll-like receptor-triggered inflammatory response in macrophages by activating Rap1 small GTPase. Nature communications 50 25118589
2004 Rap2B-dependent stimulation of phospholipase C-epsilon by epidermal growth factor receptor mediated by c-Src phosphorylation of RasGRP3. Molecular and cellular biology 44 15143162
2004 A vascular gene trap screen defines RasGRP3 as an angiogenesis-regulated gene required for the endothelial response to phorbol esters. Molecular and cellular biology 42 15572660
2010 RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype. Cancer research 41 20876802
2004 PKCdelta associates with and is involved in the phosphorylation of RasGRP3 in response to phorbol esters. Molecular pharmacology 39 15213298
2011 RasGRP3, a Ras activator, contributes to signaling and the tumorigenic phenotype in human melanoma. Oncogene 33 21602881
2023 Downregulation of AC092894.1 promotes oxaliplatin resistance in colorectal cancer via the USP3/AR/RASGRP3 axis. BMC medicine 28 37013584
2005 Role of phorbol ester localization in determining protein kinase C or RasGRP3 translocation: real-time analysis using fluorescent ligands and proteins. Molecular cancer therapeutics 27 15657361
2014 Function of RasGRP3 in the formation and progression of human breast cancer. Molecular cancer 25 24779681
1995 The nodule-specific VfENOD-GRP3 gene encoding a glycine-rich early nodulin is located on chromosome I of Vicia faba L. and is predominantly expressed in the interzone II-III of root nodules. Plant molecular biology 20 7632912
2015 Dysregulation of RasGRP1 in rheumatoid arthritis and modulation of RasGRP3 as a biomarker of TNFα inhibitors. Arthritis research & therapy 18 26714738
2006 The exchange factor and diacylglycerol receptor RasGRP3 interacts with dynein light chain 1 through its C-terminal domain. The Journal of biological chemistry 18 17012239
2011 The Ras activator RasGRP3 mediates diabetes-induced embryonic defects and affects endothelial cell migration. Circulation research 17 21474816
2015 RasGRP3 regulates the migration of glioma cells via interaction with Arp3. Oncotarget 16 25682201
2017 RasGRP3 controls cell proliferation and migration in papillary thyroid cancer by regulating the Akt-MDM2 pathway. Gene 15 28864115
2014 Upregulation of RASGRP3 expression in prostate cancer correlates with aggressive capabilities and predicts biochemical recurrence after radical prostatectomy. Prostate cancer and prostatic diseases 14 24418912
2013 RasGRP1, but not RasGRP3, is required for efficient thymic β-selection and ERK activation downstream of CXCR4. PloS one 13 23308188
2016 RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors. Journal of immunology (Baltimore, Md. : 1950) 12 27465532
2005 RasGRP3 mediates phorbol ester-induced, protein kinase C-independent exocytosis. Biochemical and biophysical research communications 10 15737652
2018 A somatic mutation of RasGRP3 decreases Na+/I- symporter expression in metastases of radioactive iodine-refractory thyroid cancer by stimulating the Akt signaling pathway. American journal of cancer research 9 30323976
2018 α-Arylidene Diacylglycerol-Lactones (DAG-Lactones) as Selective Ras Guanine-Releasing Protein 3 (RasGRP3) Ligands. Journal of medicinal chemistry 7 29860841
2023 Mutant NPM1 maintains RASGRP3 protein stability via interaction with MID1 to promote acute myeloid leukemia cell proliferation and autophagy. Journal of leukocyte biology 6 36826998
2023 Citri Reticulatae Pericarpium Limits TLR-4-Triggered Inflammatory Response in Raw264.7 Macrophages by Activating RasGRP3. International journal of molecular sciences 5 37762079
2018 RasGRP3, a Ras guanyl releasing protein 3 that contributes to malignant proliferation and aggressiveness in human esophageal squamous cell carcinoma. Clinical and experimental pharmacology & physiology 5 29461644
2017 The Effects of Low Doses of Gamma-Radiation on Growth and Membrane Activity of Pseudomonas aeruginosa GRP3 and Escherichia coli M17. Cell biochemistry and biophysics 5 29039057
2019 RasGRP3 in peripheral blood mononuclear cells is associated with disease activity and implicated in the development of systemic lupus erythematosus. American journal of translational research 4 30972203
2017 Novel transduction of nutrient stress to Notch pathway by RasGRP3 promotes malignant aggressiveness in human esophageal squamous cell carcinoma. Oncology reports 3 29048643
2026 RasGRP3 Promotes RAP1B Activity to Inhibit Endothelial Inflammation and Alleviate Atherosclerosis in High-Fat Diet-Fed ApoE-/- Mice. Inflammation 0 41689678
2026 RASGRP3 orchestrates trophoblast morphogenesis of placental cotyledons via RAP1-dependent signaling in goat (Capra hircus). Theriogenology 0 42134179

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