Affinage

FGD3

FYVE, RhoGEF and PH domain-containing protein 3 · UniProt Q5JSP0

Length
725 aa
Mass
79.4 kDa
Annotated
2026-06-09
5 papers in source corpus 5 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGD3 is a Cdc42-specific guanine nucleotide exchange factor that remodels the actin cytoskeleton through its adjacent RhoGEF and pleckstrin homology domains (PMID:10721717, PMID:18363964). By elevating GTP-bound Cdc42, it drives actin-based protrusions—filopodia in fibroblasts and broad sheet-like protrusions in HeLa cells—and, unlike its homolog FGD1, suppresses rather than promotes cell migration (PMID:10721717, PMID:18363964). FGD3 protein abundance is restrained by SCF(FWD1/β-TrCP)-mediated proteasomal degradation following phosphorylation of serine residues in a conserved DSGIDS degron motif (PMID:18363964). Loss of its Cdc42-GEF activity is linked to skeletal dysplasia and growth plate cartilage defects in cattle (PMID:26306008). Beyond its cytoskeletal role, FGD3 binds the transcription factor HSF4 to restrain HSF4 nuclear translocation and canonical NF-κB (p65/RelA) signaling (PMID:34975151), and at the plasma membrane it couples cell swelling to membrane rupture and lytic cell death through a Cdc42–ARP2/3 actin reorganization axis, enhancing DAMP release and NK cell-mediated killing (PMID:41225536).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2000 Medium

    Established that FGD3 is a RhoGEF acting on Cdc42, answering whether this protein could regulate the actin cytoskeleton.

    Evidence Microinjection of Fgd3 into fibroblasts with filopodia readout and domain architecture analysis

    PMID:10721717

    Open questions at the time
    • Direct biochemical GEF activity not measured in this study
    • Endogenous function not addressed
  2. 2008 Medium

    Demonstrated FGD3 directly elevates active Cdc42 and produces a distinct protrusion morphology from FGD1, while opposing it in migration—showing homologous GEFs have divergent outputs.

    Evidence Inducible expression in HeLa Tet-Off cells with GTP-Cdc42 pulldown, morphological analysis, and migration assays

    PMID:18363964

    Open questions at the time
    • Mechanism distinguishing FGD3 from FGD1 outputs not resolved
    • Migration effect studied only by overexpression
  3. 2008 Medium

    Identified how FGD3 levels are controlled, showing SCF(FWD1/β-TrCP) degrades phosphorylated FGD3 via a DSGIDS degron.

    Evidence Degron mutagenesis, co-IP with SCF components, and proteasome inhibitor rescue

    PMID:18363964

    Open questions at the time
    • Upstream kinase phosphorylating the degron not identified
    • Physiological trigger for degradation unknown
  4. 2015 Medium

    Linked FGD3 Cdc42-GEF activity to organismal phenotype, showing a variant with reduced GEF activity causes skeletal dysplasia.

    Evidence Positional cloning in cattle, in vitro GEF activity comparison of wild-type vs mutant, and growth plate expression analysis

    PMID:26306008

    Open questions at the time
    • Cell-type mechanism in chondrocytes not defined
    • Human disease relevance not established
  5. 2022 Medium

    Revealed a non-cytoskeletal role, showing FGD3 binds HSF4 to suppress NF-κB signaling in pancreatic cancer cells.

    Evidence Co-IP for FGD3–HSF4 binding and siRNA knockdown with fractionation/IF for HSF4 and p65

    PMID:34975151

    Open questions at the time
    • Whether GEF activity is required for HSF4 binding unknown
    • Direct binding interface not mapped
  6. 2025 High

    Established FGD3 as a driver of plasma membrane rupture and immunogenic lytic cell death via the Cdc42–ARP2/3 axis.

    Evidence Genome-wide CRISPR screen, organoids, orthotopic xenografts, and NK-cell cytotoxicity assays

    PMID:41225536

    Open questions at the time
    • Molecular link between swelling sensing and FGD3 activation unclear
    • How actin reorganization mechanically drives rupture not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FGD3's distinct activities—cytoskeletal GEF function, HSF4/NF-κB regulation, and membrane rupture—are integrated and contextually selected remains unresolved.
  • No structural model of FGD3 domain function
  • Upstream signals selecting between filopodia, lamellipodia, and lytic death pathways unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 1
Pathway
GO:0140110 transcription regulator activity 1 R-HSA-5357801 Programmed Cell Death 1
Partners
ARPCBTRCCDC42HSF4

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Mouse Fgd3 encodes a RhoGEF protein that activates Cdc42, leading to filopodia formation in fibroblasts upon microinjection; the protein contains adjacent RhoGEF and pleckstrin homology (PH) domains, a second carboxy-terminal PH domain, and a FYVE domain. Microinjection of Fgd3 into fibroblasts with actin cytoskeleton readout; domain architecture analysis Gene Medium 10721717
2008 FGD3 functions as a GEF for Cdc42 (elevating GTP-bound Cdc42 levels) and induces broad sheet-like protrusions (rather than the finger-like protrusions induced by FGD1) in HeLa Tet-Off cells upon inducible expression. Inducible expression in HeLa Tet-Off cells; GTP-bound Cdc42 pulldown assay; morphological analysis Genes to cells : devoted to molecular & cellular mechanisms Medium 18363964
2008 FGD3 inhibits cell migration when inducibly expressed in HeLa Tet-Off cells, in contrast to FGD1 which stimulates migration, establishing that these highly homologous GEFs have opposing effects on motility. Inducible expression in HeLa Tet-Off cells; cell migration assay Genes to cells : devoted to molecular & cellular mechanisms Medium 18363964
2008 FGD3 protein is targeted for proteasomal degradation by the SCF(FWD1/β-TrCP) ubiquitin ligase upon phosphorylation of serine residues in its conserved DSGIDS motif, analogous to the destruction of FGD1. Phosphorylation site mutagenesis; co-immunoprecipitation with SCF(FWD1/β-TrCP) components; proteasome inhibitor rescue experiments Genes to cells : devoted to molecular & cellular mechanisms Medium 18363964
2015 A non-synonymous variant of FGD3 identified in Japanese Black cattle produces a mutant protein with reduced GEF activity toward Cdc42, linking loss of FGD3 Cdc42-GEF activity to skeletal dysplasia and growth plate cartilage defects. Positional cloning; GEF activity assay of wild-type vs. mutant FGD3 protein; expression analysis in growth plate cartilage PLoS genetics Medium 26306008
2022 FGD3 binds with the transcription factor HSF4; FGD3 silencing promotes HSF4 nuclear translocation and increases p65 (RelA) expression, thereby activating canonical NF-κB signaling in pancreatic cancer cells. Co-immunoprecipitation (FGD3–HSF4 interaction); siRNA knockdown of FGD3 with immunoblotting and subcellular fractionation/immunofluorescence for HSF4 and p65 Oncogene Medium 34975151
2025 FGD3 mediates plasma membrane rupture (PMR) and lytic cell death (necrosis, necroptosis, pyroptosis) in breast cancer cells by controlling actin reorganization via the Cdc42–ARP2/3 axis; FGD3 also increases DAMP release and immunogenic calreticulin surface exposure, enhancing NK cell-mediated killing. Genome-wide CRISPR screen selecting against lytic cell death; 2D cell culture and patient-derived organoid experiments; orthotopic mouse xenografts; immunoblotting; immunofluorescence; NK-cell cytotoxicity assays Journal of experimental & clinical cancer research : CR High 41225536

Source papers

Stage 0 corpus · 5 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Novel insights into FGD3, a putative GEF for Cdc42, that undergoes SCF(FWD1/beta-TrCP)-mediated proteasomal degradation analogous to that of its homologue FGD1 but regulates cell morphology and motility differently from FGD1. Genes to cells : devoted to molecular & cellular mechanisms 46 18363964
2000 Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue. Gene 35 10721717
2015 Non-synonymous FGD3 Variant as Positional Candidate for Disproportional Tall Stature Accounting for a Carcass Weight QTL (CW-3) and Skeletal Dysplasia in Japanese Black Cattle. PLoS genetics 26 26306008
2022 FGD3 binds with HSF4 to suppress p65 expression and inhibit pancreatic cancer progression. Oncogene 13 34975151
2025 FGD3 mediates lytic cell death, enhancing efficacy and immunogenicity of chemotherapy agents in breast cancer. Journal of experimental & clinical cancer research : CR 0 41225536

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