Affinage

FGF4

Fibroblast growth factor 4 · UniProt P08620

Length
206 aa
Mass
22.0 kDa
Annotated
2026-06-09
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGF4 is a secreted, heparin-binding growth factor (~18 kDa) that drives autocrine and paracrine mitogenic and survival signaling by engaging extracellular FGF receptors, and it functions as a master regulator of progenitor maintenance and lineage decisions across early development (PMID:2978866, PMID:1990270). Its activity is gated by heparan sulfate: FGF4 requires a tissue-specific HS sulfation pattern distinct from FGF2, and FGFR2-IIIc binds FGF4/HS complexes broadly while FGFR1-IIIc largely does not, providing context-dependent receptor engagement (PMID:11724824). FGF4 expression is itself restricted to pluripotent/undifferentiated cells through a 3' distal enhancer bound cooperatively by Sox2 and Oct-3/4, where only the Sox2/Oct-3 ternary complex activates transcription and PARP1-mediated PARylation of Sox2 tunes enhancer occupancy (PMID:7590241, PMID:2188089, PMID:1723621, PMID:19531481). In the early embryo FGF4 maintains trophoblast stem cell self-renewal and supports inner cell mass proliferation, and it directs ICM lineage restriction toward epiblast versus primitive endoderm via ERK signaling, with a FRS2α→ERK→Cdx2→Bmp4 paracrine axis relaying the signal between trophectoderm and ICM (PMID:9851926, PMID:7809630, PMID:23193166, PMID:19890878). In the developing limb FGF4 acts as an AER-derived signal redundant with FGF8 — single Fgf4 loss is dispensable, but combined Fgf4/Fgf8 loss abolishes limb mesenchyme survival, and FGF4 can fully substitute for FGF8 — while also promoting mesenchymal proliferation, chemotaxis, and somitogenesis/axial elongation by maintaining presomitic mesoderm and WNT activity (PMID:10802662, PMID:15328019, PMID:8421496, PMID:10395792, PMID:21368122, PMID:22954964). In adult physiology FGF4 signals through FGFR4 to control hepatic bile acid homeostasis via an FXR→FGF4→FGFR4–LRH-1 axis repressing Cyp7a1/Cyp8b1, and protects the liver in NAFLD/NASH through a Ca2+/CaMKKβ–AMPK–Caspase 6 pathway (PMID:39393353, PMID:35152446). Ectopic FGF4 expression from a canine retrogene causes chondrodystrophy and intervertebral disc disease, linking FGF4 dosage to skeletal dysplasia (PMID:29073074).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1988 High

    Established the basic biochemical identity of FGF4 as a secreted mitogen, answering what kind of molecule the hst-1 transforming gene encodes.

    Evidence Baculovirus expression, heparin-affinity purification, mitogenesis and soft-agar assays

    PMID:2978866

    Open questions at the time
    • Receptor identity not defined
    • No physiological source tissue identified
  2. 1991 High

    Showed FGF4 transforms cells specifically through secretion and extracellular receptor engagement, distinguishing an autocrine extracellular mechanism from intracellular action.

    Evidence Signal-peptide deletion and KDEL retention mutants, neutralizing antibody reversal in soft-agar assays; receptor binding/suramin in NIH3T3

    PMID:1990270 PMID:2553749

    Open questions at the time
    • Specific FGFR engaged not resolved
    • HS dependence not yet defined
  3. 1995 High

    Defined the transcriptional logic restricting FGF4 to pluripotent cells, identifying Sox2/Oct-3 cooperative enhancer binding as the activating mechanism.

    Evidence EMSA, reporter assays and mutagenesis in EC cells; earlier 3' enhancer mapping and Oct4 binding studies

    PMID:1723621 PMID:2188089 PMID:7590241

    Open questions at the time
    • Did not address post-translational modulation of the complex
    • Did not connect to downstream signaling outcomes
  4. 1995 High

    Established FGF4 as essential for postimplantation development by genetic ablation, showing it is required for ICM proliferation.

    Evidence Knockout mouse with embryo culture and FGF4 protein rescue

    PMID:7809630

    Open questions at the time
    • Receptor and downstream pathway in ICM not defined
    • Lineage-specification role not yet separated from proliferation
  5. 1998 High

    Identified FGF4 as the required niche signal sustaining trophoblast stem cell self-renewal, answering what maintains the undifferentiated TS state.

    Evidence TS cell culture with/without FGF4 plus in vivo chimera assay

    PMID:9851926

    Open questions at the time
    • Intracellular signaling cascade not mapped
    • Source/receptor topology not defined
  6. 2004 High

    Resolved FGF4/FGF8 redundancy in the limb, showing FGF4 can fully substitute for FGF8 and that combined AER-FGF activity is required for mesenchyme survival.

    Evidence Conditional allele swap and double conditional knockout with skeletal/molecular analysis; earlier conditional Fgf4 KO showing dispensability alone

    PMID:10802662 PMID:15328019

    Open questions at the time
    • Quantitative contribution of each FGF not separated
    • Receptor usage in mesenchyme not defined
  7. 2010 High

    Mapped the paracrine signaling order from FGF4 to Bmp4, establishing FGF4→FRS2α→ERK→Cdx2→Bmp4 as the trophectoderm-to-ICM relay.

    Evidence FRS2α KO cells, ERK assays, Cdx2 ChIP on Bmp4 promoter, Bmp4 rescue of Frs2α-null ICM

    PMID:19890878

    Open questions at the time
    • Receptor identity upstream of FRS2α not specified
    • Generalizability beyond TS/ICM not tested
  8. 2012 High

    Clarified that FGF4/ERK controls lineage bias acquisition rather than initial marker activation in the ICM, refining its role in EPI vs PrE segregation.

    Evidence Zygotic and maternal/zygotic Fgf4 conditional KO with NANOG/GATA6 immunofluorescence and FGF rescue; parallel PSM and axial-elongation double-KO studies

    PMID:21368122 PMID:22954964 PMID:23193166

    Open questions at the time
    • Single-cell dynamics of salt-and-pepper resolution not fully resolved
    • FGF4 vs FGF8 contributions in PSM not individually dissected
  9. 2013 High

    Connected enhancer regulation to PARP1, showing PARylation of Sox2 tunes FGF4 expression and reprogramming efficiency.

    Evidence ChIP, in vitro PARylation, Artd1-/- reprogramming with FGF4 rescue

    PMID:19531481 PMID:23939864

    Open questions at the time
    • Stoichiometry/sites of Sox2 PARylation in vivo not fully defined
    • Whether this applies to all FGF4-expressing contexts unknown
  10. 2024 High

    Defined an adult metabolic role for FGF4 in the liver, establishing an FXR→FGF4→FGFR4–LRH-1 checkpoint for bile acid homeostasis and an AMPK-dependent hepatoprotective axis.

    Evidence Hepatic Fgf4 conditional KO, FXR ChIP, FGFR4 inhibition, Cyp7a1/Cyp8b1 assays, cholestasis and NAFLD/NASH models

    PMID:35152446 PMID:39393353

    Open questions at the time
    • Crosstalk with peripheral FGF15/19 quantitatively unresolved
    • Human relevance of hepatic FGF4 axis not established in timeline

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single ligand achieves its many distinct outcomes — the precise FGFR/HS combinations and receptor-proximal signaling that distinguish proliferation, survival, chemotaxis, lineage bias, and metabolic checkpoint functions in each tissue — remains unresolved.
  • No unified receptor-output map across tissues
  • Structural basis of HS-pattern selectivity not determined
  • Human disease relevance largely inferred from model organisms and canine retrogene

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2
Partners
FGFR1FGFR2FGFR3FGFR4FRS2LRH-1

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 FGF4 promotes proliferation of trophoblast stem cells; in the absence of FGF4, trophoblast stem cell lines differentiate to other trophoblast subtypes in vitro, establishing FGF4 as a required maintenance signal for trophoblast stem cell self-renewal. Trophoblast stem cell culture with/without FGF4; in vivo chimera assay Science High 9851926
1995 FGF-4 gene expression requires synergistic action of Sox2 and Oct-3 binding to adjacent sites on the FGF-4 enhancer; Sox2 forms a ternary complex with either Oct-1 or Oct-3 on the enhancer DNA, but only the Sox2/Oct-3 complex drives transcriptional activation, identifying FGF4 as the first known target gene for Oct-3 and Sox factors. cDNA cloning, gel-shift (EMSA), transcriptional reporter assays, transfection into EC cells Genes & Development High 7590241
1995 FGF-4 is required for postimplantation mouse development; Fgf4-null embryos fail to proliferate the inner cell mass after implantation, and this proliferative defect is rescued by exogenous FGF-4 protein in culture. Gene targeting (knockout mouse), embryo culture with FGF-4 rescue Science High 7809630
1993 FGF-4 protein stimulates proliferation of limb bud mesenchyme (pro-outgrowth), while BMP-2 inhibits limb growth; the extent of limb outgrowth can be modulated by mixing the two signals, demonstrating that limb growth is regulated by a balance of AER-derived stimulatory (FGF-4) and inhibitory (BMP-2) signals. In vitro limb bud culture system with FGF-4 and BMP-2 protein addition Nature High 8421496
1999 FGF4 signaling from the posterior AER maintains the polarizing region (SHH/FGF4 feedback loop); the BMP antagonist Gremlin relays the SHH signal from the polarizing region to the AER to induce Fgf4 expression; Gremlin-expressing cell grafts rescue Fgf4 expression and restore the feedback loop in limb deformity mutants. Genetic analysis of Shh-null and limb deformity mutant embryos; cell grafting experiments; in situ hybridization Nature High 10524628
2000 Conditional inactivation of Fgf4 alone in mouse limbs does not disrupt Shh expression or limb formation, contradicting the SHH/FGF4 feedback loop model; instead, Fgf9 and Fgf17 (but not Fgf8) expression in the AER is dependent on Shh, indicating that combined AER-FGF activities—not FGF4 alone—maintain the feedback loop with Shh. Conditional gene targeting (Cre/lox) of Fgf4 in AER; in situ hybridization of downstream targets Nature Genetics High 10802662
2004 FGF4 can functionally replace FGF8 in limb skeletal development; when Fgf4 is expressed in place of Fgf8 via conditional allele swap, all skeletal defects caused by Fgf8 loss are rescued. Simultaneous loss of both Fgf4 and Fgf8 in the AER causes failure of limb bud mesenchyme survival, with nearly abolished Shh and Fgf10 expression. Conditional Cre-mediated allele swap (Fgf4 gain-of-function + Fgf8 loss-of-function); double conditional knockout; skeletal analysis Developmental Biology High 15328019
2012 FGF4 is required for lineage restriction of primitive endoderm (PrE) in the blastocyst ICM; Fgf4-null ICMs initiate co-expression of EPI and PrE markers but fail to achieve salt-and-pepper segregation and exclusive NANOG or GATA6 expression, establishing FGF4/ERK signaling as the mechanism for lineage bias acquisition rather than initial lineage marker activation. Zygotic and maternal/zygotic Fgf4 conditional knockout; immunofluorescence for NANOG/GATA6; exogenous FGF rescue experiments Development High 23193166
2011 FGF4 and FGF8 together constitute the wavefront signal that maintains presomitic mesoderm (PSM) in an undifferentiated state during somitogenesis; double deletion of Fgf4 and Fgf8 in the PSM abolishes expression of cycling genes, WNT pathway genes, and PSM progenitor markers, causing premature differentiation of the entire PSM. FGF signaling maintains WNT signaling and operates independently of WNT in parallel. Double conditional Fgf4/Fgf8 knockout in PSM; in situ hybridization; WNT pathway rescue experiments PNAS High 21368122
2012 FGF4 and FGF8 signaling are required for axial elongation after gastrulation; combined loss of Fgf8 and Fgf4 during late gastrulation causes severe vertebral phenotype and failure to maintain epiblast progenitors that generate paraxial mesoderm, with reduced Wnt3a, Brachyury, and NOTCH pathway gene expression. Double conditional knockout; skeletal analysis; gene expression analysis Developmental Biology High 22954964
1988 The hst-1 (FGF4) transforming protein, expressed in insect cells, is a secreted heparin-binding growth factor of ~18 kDa that stimulates DNA synthesis in NIH3T3 cells and endothelial cell proliferation, and induces anchorage-independent growth. Baculovirus expression in BmN cells; heparin-affinity purification; mitogenesis assay; soft agar assay Oncogene High 2978866
1991 K-fgf/hst transformation of NIH 3T3 cells occurs via an autocrine mechanism requiring extracellular receptor activation; deletion of the signal peptide or retention of K-FGF in the ER/Golgi markedly reduces focus-forming ability, and anti-K-FGF neutralizing antibodies reverse the transformed phenotype, demonstrating that secretion and extracellular receptor engagement are required. Signal peptide deletion mutants; KDEL retention mutant; neutralizing antibody reversal; soft agar growth assay Molecular and Cellular Biology High 1990270
1989 NIH 3T3 cells transformed by hst/K-fgf show downregulation of FGF receptors, and this transformation is reversed by suramin (which blocks FGF-receptor interaction), indicating that K-FGF transforms cells through autocrine activation of its receptor and that K-FGF and bFGF may share the same receptor. 125I-bFGF receptor binding assay; suramin treatment; focus formation and transformation assays Journal of Cell Biology High 2553749
2001 FGF-4 binds heparan sulfate (HS) in a tissue-specific manner requiring a distinct HS sulfation pattern different from FGF-2; FGF-4 fails to bind HS or activate signaling in vascular tissues. FGFR2-IIIc binds all FGF-4/HS complexes, but FGFR1-IIIc fails to bind FGF-4/HS in most tissues, establishing that tissue-specific HS sulfation patterns differentially control FGF-4 signaling. FGF-4 and FGFR ectodomain probing of embryonic tissue sections; BaF3 cell proliferation assays with FR1c or FR2c Journal of Cell Biology High 11724824
2009 PARP1 binds the FGF4 enhancer, positively regulates FGF4 expression, and poly(ADP-ribosyl)ates Sox2, promoting dissociation/degradation of inhibitory Sox2 from the FGF4 enhancer; inhibition of PARP1 increases Sox2 occupancy at the FGF4 enhancer and reduces FGF4 expression, while Sox2 knockdown abrogates the inhibitory effect of PARP1 inhibitors on FGF4. ChIP on FGF4 enhancer; Co-IP of PARP1 with Oct4/Sox2; in vitro poly(ADP-ribosyl)ation assay; siRNA knockdown; PARP1 inhibitor treatment Journal of Biological Chemistry High 19531481
2013 PARP1/ARTD1-mediated poly(ADP-ribosyl)ation (PARylation) of Sox2 promotes Sox2 binding to the Fgf4 enhancer and activates Fgf4 expression during early reprogramming; Artd1-deficient fibroblasts show strongly decreased reprogramming capacity, and exogenous FGF4 (days 2–4) restores reprogramming efficiency in Artd1-null cells. Artd1-/- fibroblast reprogramming; Fgf4 reporter assays; FGF4 rescue experiment; ChIP Stem Cells High 23939864
1993 FGF-4 can induce Evx-1 (a homeobox gene normally regulated by AER signals) expression in limb bud mesenchyme; this induction is indirect (blocked by protein synthesis inhibitor) and is modulated by BMP-2, positioning Evx-1 as a downstream target in the FGF-4 signal transduction pathway in the limb. In vitro limb bud culture; cycloheximide (protein synthesis inhibitor) block; BMP-2 co-treatment Development Medium 7506139
1994 FGF-4 protein can substitute for the AER to allow virtually normal limb outgrowth and patterning after AER removal in chick limb; FGF-4 stimulates proliferation of limb mesenchyme and maintains polarizing region activity. AER removal + FGF-4 protein bead implant in ovo; DiI cell labeling; skeletal analysis Molecular Reproduction and Development Medium 7999365
1999 FGF-4 acts as a potent chemoattractive agent for limb bud mesenchymal cells in a dose-dependent manner; this chemotactic activity is independent of FGF-4's ability to induce Shh expression. The AER exerts chemoattractive function on subapical cells during limb outgrowth, partly mediated by FGF-4 production. DiI cell labeling + FGF-4 bead implantation; partial AER removal; cell migration tracking Developmental Biology Medium 10395792
2001 FGFR2-IIIb acts upstream of Shh and Fgf4 in the limb; Fgfr2-IIIb knockout mice lack Shh and Fgf4 expression in limb buds despite normal Fgf8, Fgf10, Bmp4, and Msx1, placing Shh and Fgf4 induction as downstream targets of FGFR2-IIIb signaling. Fgfr2-IIIb knockout mouse; in situ hybridization for downstream targets Developmental Biology High 11180951
2002 FGF4 is a direct transcriptional target of LEF1/Wnt signaling; FGF4 beads fully rescue developmental arrest of Lef1-null tooth germs, and FGF4 induces Fgf3 in dental mesenchyme and subsequently Shh in epithelium, establishing an FGF4-dependent signal relay cascade in tooth development. LEF1 knockout analysis; FGF4 protein bead rescue in Lef1-/- tooth germs; LEF1 ChIP/reporter assay; in situ hybridization for downstream targets Genes & Development High 12502739
2010 FGF4 signaling through FRS2α activates ERK and enhances Cdx2 expression in trophoblast stem cells; Cdx2 then binds an FGF4-responsive enhancer in the Bmp4 promoter to drive Bmp4 production; exogenous Bmp4 rescues defective growth of Frs2α-null ICM, establishing an FGF4→FRS2α→ERK→Cdx2→Bmp4 paracrine axis between trophectoderm and ICM. FRS2α knockout ESC/TS cells; ERK activation assay; Cdx2 ChIP on Bmp4 promoter; Bmp4 rescue of Frs2α-null ICM Stem Cells High 19890878
2002 Fgf4 expressed in muscle positively regulates scleraxis and tenascin expression in chick limb tendons; in muscleless and aneural limbs, these tendon markers are down-regulated, and exogenous FGF4 bead implantation induces scleraxis and tenascin but not Fgf8 in normal, aneural, and muscleless limbs. Muscleless/aneural limb preparation; FGF4 bead implantation; in situ hybridization for tendon markers Developmental Biology Medium 12086472
2001 Misexpression of Fgf-4 in chick limb inhibits myogenesis by downregulating Frek (an FGF receptor expressed in myoblasts) expression; retroviral overexpression of Fgf-4 reduces muscle cell number and inhibits terminal myogenic differentiation in vivo. RCAS retroviral overexpression of Fgf-4; quail/chick transplantation; in situ hybridization for Frek and muscle markers Developmental Biology Medium 11319857
1994 FGF-4 produced by undifferentiated ICM cells promotes differentiation and migration of parietal endoderm from ICM outgrowths (increasing 92 kDa gelatinase and tPA secretion), and FGFR-3 and FGFR-4 are expressed in blastocyst cells as receptors for FGF-4. Immunosurgical ICM isolation; ICM culture with recombinant FGF-4; gelatinase/tPA secretion assay; receptor expression analysis Development Medium 7925026
1997 FGF-4 does not act as an autocrine growth factor for ES cells in culture; FGF-4-/- ES cells proliferate normally and form complex teratomas. However, FGF-4 is required for the growth/survival of specific differentiated lineages (particularly parietal extraembryonic endoderm) derived from ES cells in vitro. Homologous recombination to generate FGF-4-/- ES cells; proliferation assay; retinoic acid differentiation; FGF-4 rescue Developmental Biology Medium 9441693
2009 Fgf4 is required for left-right (LR) patterning of visceral organs in zebrafish; Fgf4 knockdown randomizes organ laterality and is required for cilia formation in Kupffer's vesicle and for expression of lefty1 in the posterior notochord, establishing a role for Fgf4 in LR axis establishment distinct from Fgf8. Morpholino antisense knockdown of Fgf4 in zebrafish; in situ hybridization for laterality markers (lefty1, lefty2, southpaw, pitx2); cilia analysis in Kupffer's vesicle Developmental Biology Medium 19481538
1996 FGF-4 (hst/HST-1) causes dose-dependent prolactin secretion from rat pituitary cells and increases prolactin transcriptional activity via the rPRL promoter; stable hst transfection of GH4 cells causes enhanced basal PRL secretion, faster proliferation, and more aggressive tumor growth in vivo. Recombinant FGF-4 treatment of pituitary cell cultures; stable transfection of hst; PRL reporter luciferase assay; subcutaneous tumor injection Journal of Clinical Investigation Medium 8550832
2017 O-GlcNAcylation of PKCζ at its phosphorylation site inhibits PKCζ phosphorylation (activation), thereby inhibiting the FGF4-PKCζ-MEK-ERK1/2 signaling pathway in mouse ESCs and maintaining the undifferentiated state. O-GlcNAc site mapping on PKCζ; phosphorylation assays; MEK/ERK1/2 activity measurements; OGT inhibition and overexpression in ESCs Stem Cell Reports Medium 29249667
1994 Adenovirus-mediated HST-1 (FGF4) gene transfer in nude mice specifically increases peripheral platelet count and megakaryocyte numbers in bone marrow, with no other major hematological changes. Adenovirus-mediated gene delivery in vivo; complete blood counts; bone marrow histology PNAS Medium 7809043
1994 HST-1 (FGF4) protein has potent in vivo angiogenic activity demonstrated in the chick chorioallantoic membrane assay and rat cornea assay; NIH3T3 transformants expressing hst-1 form highly vascularized tumors in nude mice. E. coli-expressed recombinant hst-1 protein; CAM angiogenesis assay; rat cornea assay; xenograft tumor model Cancer Letters Medium 7520355
2022 FGF4 protects the liver from NAFLD/NASH by activating hepatic FGFR4, which triggers a Ca2+/CaMKKβ-dependent AMPK-Caspase 6 signaling axis, leading to enhanced fatty acid oxidation and reduced hepatocellular apoptosis. Hepatic Fgf4 knockout and recombinant FGF4 pharmacological administration in mouse NAFLD/NASH models; FGFR4-specific inhibition; AMPK and Caspase 6 activity assays Hepatology Medium 35152446
2024 Hepatic FXR directly targets Fgf4 as a paracrine regulator of bile acid homeostasis; FGF4 signals through FGFR4 to activate an intracellular FGFR4-LRH-1 node that downregulates Cyp7a1 and Cyp8b1, acting as a first-line checkpoint for intrahepatic BA flux upstream of the peripheral FXR-FGF15/19 pathway. Hepatic Fgf4 conditional knockout; FXR ChIP on Fgf4 promoter; FGFR4 inhibition; Cyp7a1/Cyp8b1 expression assays; cholestasis mouse models Cell Metabolism High 39393353
2004 HST-1/FGF-4 protects male germ cells from heat-stress-induced apoptosis; adenoviral FGF-4 overexpression reduces germ cell TUNEL staining, prevents testicular weight loss and sperm count reduction, activates MAPK survival signaling in germ cells, and stimulates lactate production in Sertoli cells. Adenoviral HST-1/FGF-4 delivery to mouse testis; hyperthermia model; TUNEL assay; MAPK pathway analysis; lactate production assay Experimental Cell Research Medium 14980503
1995 Hst-1/FGF-4 antisense oligonucleotides block mouse limb development in an organ culture system, while sense and scrambled oligonucleotides have no effect, demonstrating that Hst-1/FGF-4 is required for limb outgrowth. Antisense oligodeoxynucleotide treatment of mouse limb bud explants in organ culture; limb morphology analysis Journal of Cell Biology Medium 7642715
2006 FGF-4 regulates proliferation and neuronal differentiation of neural progenitor cells; recombinant FGF-4 promotes formation of large neurospheres with multipotent differentiation ability and significantly promotes neuronal differentiation in clonal neurosphere culture. Fgf-4 mRNA is expressed in postnatal mouse hippocampus, SVZ, and rostral migratory stream. In vitro neurosphere assay with recombinant FGF-4; in situ hybridization of Fgf-4 in brain; clonal neurosphere differentiation assay FASEB Journal Medium 16723380
1990 EC cell-specific expression of K-fgf/FGF4 is controlled by enhancer-like elements in the 3' noncoding region of exon 3 (downstream of the coding sequence), not by upstream promoter sequences; these elements promote expression in undifferentiated EC cells but not in differentiated or non-EC cells. CAT reporter transfections with 3' and 5' K-fgf regulatory element constructs; transfection into undifferentiated vs. differentiated F9 EC cells Molecular and Cellular Biology Medium 2188089
1991 The FGF4 gene (kFGF) is a target for positive transcriptional regulation by Oct4 via an octamer sequence in its distal enhancer; Oct4 but not Oct1 is bound in undifferentiated EC cells, while only Oct1 is present after differentiation. EMSA with nuclear extracts from undifferentiated and differentiated EC cells; reporter assays Mechanisms of Development Medium 1723621
2017 A highly expressed FGF4 retrogene on canine chromosome 12 (CFA12) is responsible for chondrodystrophy (shortened limbs) and intervertebral disc disease in dogs, with an odds ratio of 51.23 for IVDD, demonstrating that ectopic FGF4 expression causes skeletal dysplasia through FGF signaling pathway abnormalities. Genome-wide association study + whole genome sequencing; segregation analysis; copy number analysis; retrogene expression analysis PNAS Medium 29073074

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Promotion of trophoblast stem cell proliferation by FGF4. Science (New York, N.Y.) 1139 9851926
1992 Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. Development (Cambridge, England) 621 1618140
1995 Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes & development 611 7590241
1995 Requirement of FGF-4 for postimplantation mouse development. Science (New York, N.Y.) 606 7809630
1999 Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds. Nature 378 10524628
1993 FGF-4 and BMP-2 have opposite effects on limb growth. Nature 358 8421496
1989 Characterization of the HST-related FGF.6 gene, a new member of the fibroblast growth factor gene family. Oncogene 318 2649847
1987 Genomic sequence of hst, a transforming gene encoding a protein homologous to fibroblast growth factors and the int-2-encoded protein. Proceedings of the National Academy of Sciences of the United States of America 297 2959959
2000 Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development. Nature genetics 242 10802662
2012 FGF4 is required for lineage restriction and salt-and-pepper distribution of primitive endoderm factors but not their initial expression in the mouse. Development (Cambridge, England) 220 23193166
2001 Fibroblast growth factor receptor 2-IIIb acts upstream of Shh and Fgf4 and is required for limb bud maintenance but not for the induction of Fgf8, Fgf10, Msx1, or Bmp4. Developmental biology 215 11180951
2002 FGF4, a direct target of LEF1 and Wnt signaling, can rescue the arrest of tooth organogenesis in Lef1(-/-) mice. Genes & development 206 12502739
1999 Sequential roles for Fgf4, En1 and Fgf8 in specification and regionalisation of the midbrain. Development (Cambridge, England) 181 9927596
1991 Expression of the hst-1 and c-kit protooncogenes in human testicular germ cell tumors. Cancer research 179 1706218
1989 High incidence of coamplification of hst-1 and int-2 genes in human esophageal carcinomas. Cancer research 178 2529025
1989 The mouse homolog of the hst/k-FGF gene is adjacent to int-2 and is activated by proviral insertion in some virally induced mammary tumors. Proceedings of the National Academy of Sciences of the United States of America 173 2548184
2004 The roles of Fgf4 and Fgf8 in limb bud initiation and outgrowth. Developmental biology 159 15328019
1989 Mesoderm-inducing properties of INT-2 and kFGF: two oncogene-encoded growth factors related to FGF. Development (Cambridge, England) 156 2483371
1994 Expression and function of FGF-4 in peri-implantation development in mouse embryos. Development (Cambridge, England) 153 7925026
2002 Fgf4 positively regulates scleraxis and tenascin expression in chick limb tendons. Developmental biology 146 12086472
1989 Transformation of NIH 3T3 cells with basic fibroblast growth factor or the hst/K-fgf oncogene causes downregulation of the fibroblast growth factor receptor: reversal of morphological transformation and restoration of receptor number by suramin. The Journal of cell biology 144 2553749
2011 FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis. Proceedings of the National Academy of Sciences of the United States of America 143 21368122
1993 Mouse mammary tumor virus infection accelerates mammary carcinogenesis in Wnt-1 transgenic mice by insertional activation of int-2/Fgf-3 and hst/Fgf-4. Proceedings of the National Academy of Sciences of the United States of America 130 8380647
2013 FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma. Hepatology (Baltimore, Md.) 127 22890726
2002 Early embryonic expression of FGF4/6/9 gene and its role in the induction of mesenchyme and notochord in Ciona savignyi embryos. Development (Cambridge, England) 126 11923208
2001 Role of heparan sulfate as a tissue-specific regulator of FGF-4 and FGF receptor recognition. The Journal of cell biology 124 11724824
2017 FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs. Proceedings of the National Academy of Sciences of the United States of America 114 29073074
2020 In vitro generation of functional murine heart organoids via FGF4 and extracellular matrix. Nature communications 108 32883967
1997 Inactivation of the FGF-4 gene in embryonic stem cells alters the growth and/or the survival of their early differentiated progeny. Developmental biology 105 9441693
2012 Signaling by FGF4 and FGF8 is required for axial elongation of the mouse embryo. Developmental biology 96 22954964
2009 FGF4 and retinoic acid direct differentiation of hESCs into PDX1-expressing foregut endoderm in a time- and concentration-dependent manner. PloS one 86 19277121
1999 Cell migration and chick limb development: chemotactic action of FGF-4 and the AER. Developmental biology 86 10395792
1990 Expression of the K-fgf proto-oncogene is controlled by 3' regulatory elements which are specific for embryonal carcinoma cells. Molecular and cellular biology 86 2188089
2005 Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function. Development (Cambridge, England) 81 16308330
1989 Transformation by basic fibroblast growth factor requires high levels of expression: comparison with transformation by hst/K-fgf. Oncogene research 79 2608276
1988 Coamplification of the hst-1 and int-2 genes in human cancers. Japanese journal of cancer research : Gann 79 3133332
1988 Co-amplification of integrated hepatitis B virus DNA and transforming gene hst-1 in a hepatocellular carcinoma. Oncogene 75 2856253
2022 Exosomes from mmu_circ_0001052-modified adipose-derived stem cells promote angiogenesis of DFU via miR-106a-5p and FGF4/p38MAPK pathway. Stem cell research & therapy 72 35870977
1992 Inhibition by 5-fluorouracil of cis-diamminedichloroplatinum(II)-induced DNA interstrand cross-link removal in a HST-1 human squamous carcinoma cell line. Cancer research 72 1423296
1989 Expression of the K-fgf protooncogene is repressed during differentiation of F9 cells. Oncogene research 69 2780052
1999 Expression of Fgf4 during early development of the chick embryo. Mechanisms of development 67 10415361
2006 FGF-4 signaling is involved in mir-206 expression in developing somites of chicken embryos. Developmental dynamics : an official publication of the American Association of Anatomists 65 16804893
1993 FGF-4 regulates expression of Evx-1 in the developing mouse limb. Development (Cambridge, England) 64 7506139
2005 Heparan 2-O-sulfotransferase, hst-2, is essential for normal cell migration in Caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 63 15671174
2009 PARP1 poly(ADP-ribosyl)ates Sox2 to control Sox2 protein levels and FGF4 expression during embryonic stem cell differentiation. The Journal of biological chemistry 62 19531481
2022 FGF4 protects the liver from nonalcoholic fatty liver disease by activating the AMP-activated protein kinase-Caspase 6 signal axis. Hepatology (Baltimore, Md.) 55 35152446
2011 FGF4-dependent stem cells derived from rat blastocysts differentiate along the trophoblast lineage. Developmental biology 55 21215265
2004 Immunolocalization of BMP-2/-4, FGF-4, and WNT10b in the developing mouse first lower molar. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 55 14688221
2014 Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity. Laboratory investigation; a journal of technical methods and pathology 54 25329002
1990 Hst-3: an X-linked hybrid sterility gene. Genetical research 54 2272506
1995 Inhibition of cis-diamminedichloroplatinum (II)-induced DNA interstrand cross-link removal by 7-ethyl-10-hydroxy-camptothecin in HST-1 human squamous-carcinoma cells. International journal of cancer 53 7601570
1989 The mouse homologue of hst/k-FGF: sequence, genome organization and location relative to int-2. Nucleic acids research 53 2740210
2024 Hepatic FXR-FGF4 is required for bile acid homeostasis via an FGFR4-LRH-1 signal node under cholestatic stress. Cell metabolism 52 39393353
2014 Paracrine effects of embryo-derived FGF4 and BMP4 during pig trophoblast elongation. Developmental biology 52 24445281
2006 FGF-4 regulates neural progenitor cell proliferation and neuronal differentiation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 51 16723380
1991 The K-fgf/hst oncogene induces transformation through an autocrine mechanism that requires extracellular stimulation of the mitogenic pathway. Molecular and cellular biology 50 1990270
1996 Heparin-binding secretory transforming gene (hst) facilitates rat lactotrope cell tumorigenesis and induces prolactin gene transcription. The Journal of clinical investigation 49 8550832
1991 Octamer-dependent regulation of the kFGF gene in embryonal carcinoma and embryonic stem cells. Mechanisms of development 48 1723621
1988 Amplification of the hst-1 gene in human esophageal carcinomas. Japanese journal of cancer research : Gann 48 3136110
2010 An FGF4-FRS2alpha-Cdx2 axis in trophoblast stem cells induces Bmp4 to regulate proper growth of early mouse embryos. Stem cells (Dayton, Ohio) 46 19890878
2001 Misexpression of Fgf-4 in the chick limb inhibits myogenesis by down-regulating Frek expression. Developmental biology 46 11319857
1989 Expression and developmental regulation of the k-FGF oncogene in human and murine embryonal carcinoma cells. In vitro cellular & developmental biology : journal of the Tissue Culture Association 46 2481673
1988 hst-1 transforming protein: expression in silkworm cells and characterization as a novel heparin-binding growth factor. Oncogene 45 2978866
2016 FGF4 induces epithelial-mesenchymal transition by inducing store-operated calcium entry in lung adenocarcinoma. Oncotarget 44 27677589
2009 Pleiotropic function of FGF-4: its role in development and stem cells. Developmental dynamics : an official publication of the American Association of Anatomists 43 18792115
1988 Cloned hst gene from normal human leukocyte DNA transforms NIH3T3 cells. Biochemical and biophysical research communications 43 2895649
2011 TGF-β1, EGF and FGF4 synergistically induce differentiation of the seminoma cell line TCam-2 into a cell type resembling mixed non-seminoma. International journal of andrology 42 21649665
2007 FGF-4 increases in vitro expansion rate of human adult bone marrow-derived mesenchymal stem cells. Growth factors (Chur, Switzerland) 41 17852409
1992 In vivo comparative therapeutic study of optimal administration of 5-fluorouracil and cisplatin using a newly established HST-1 human squamous-carcinoma cell line. Cancer chemotherapy and pharmacology 41 1537072
1994 Function of FGF-4 in limb development. Molecular reproduction and development 38 7999365
2001 Modified FGF4 signal peptide inhibits entry of herpes simplex virus type 1. Journal of virology 36 11222686
1998 Effects of differentiation on the transcriptional regulation of the FGF-4 gene: critical roles played by a distal enhancer. Molecular reproduction and development 36 9740330
2014 Establishment of a primed pluripotent epiblast stem cell in FGF4-based conditions. Scientific reports 35 25515008
1996 Schedule-dependent reversion of acquired cisplatin resistance by 5-fluorouracil in a newly established cisplatin-resistant HST-1 human squamous carcinoma cell line. International journal of cancer 35 8621231
2009 Fgf4 is required for left-right patterning of visceral organs in zebrafish. Developmental biology 34 19481538
1998 Prolactinomas express human heparin-binding secretory transforming gene (hst) protein product: marker of tumour invasiveness. Clinical endocrinology 34 9509064
1996 Effects of fibroblast growth factor-4 (k-FGF) on long-term cultures of human bone marrow cells. Blood 33 8608216
1988 The FGF-related oncogene, K-FGF, maps to human chromosome region 11q13, possibly near int-2. Oncogene research 32 3060803
2023 FGF4 improves hepatocytes ferroptosis in autoimmune hepatitis mice via activation of CISD3. International immunopharmacology 31 36702076
2021 Cell-cell communication through FGF4 generates and maintains robust proportions of differentiated cell types in embryonic stem cells. Development (Cambridge, England) 31 34651174
2015 Mesenchymal Stem Cells Pretreated with HGF and FGF4 Can Reduce Liver Fibrosis in Mice. Stem cells international 31 25685159
1994 Angiogenic activity of the recombinant hst-1 protein. Cancer letters 31 7520355
2013 Artd1/Parp1 regulates reprogramming by transcriptional regulation of Fgf4 via Sox2 ADP-ribosylation. Stem cells (Dayton, Ohio) 29 23939864
1994 Adenovirus-mediated transfer of the HST-1 (FGF4) gene induces increased levels of platelet count in vivo. Proceedings of the National Academy of Sciences of the United States of America 29 7809043
2014 FGF4 and HGF promote differentiation of mouse bone marrow mesenchymal stem cells into hepatocytes via the MAPK pathway. Genetics and molecular research : GMR 28 24535868
1998 FGF-3 and FGF-4 elicit distinct oncogenic properties in mouse mammary myoepithelial cells. Oncogene 28 9798677
1995 Sequence-dependent modulation of anticancer drug activities by 7-ethyl-10-hydroxycamptothecin in an HST-1 human squamous carcinoma cell line. Anticancer research 28 7763013
1992 Human hst-2 (FGF-6) oncogene: cDNA cloning and characterization. Oncogene 28 1549352
2004 HST-1/FGF-4 protects male germ cells from apoptosis under heat-stress condition. Experimental cell research 27 14980503
1998 FGF4 dissociates anti-tumorigenic from differentiation signals of retinoic acid in human embryonal carcinomas. Oncogene 27 9715278
1995 Effective prevention of thrombocytopenia in mice using adenovirus-mediated transfer of HST-1 (FGF-4) gene. The Journal of clinical investigation 27 7635948
2019 Gain of FGF4 is a frequent event in KIT/PDGFRA/SDH/RAS-P WT GIST. Genes, chromosomes & cancer 26 30887595
2015 Intestinal Commitment and Maturation of Human Pluripotent Stem Cells Is Independent of Exogenous FGF4 and R-spondin1. PloS one 26 26230325
2000 FGF4 and INT2 oncogenes are amplified and expressed in Kaposi's sarcoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 26 10786811
1995 Hst-1 (FGF-4) antisense oligonucleotides block murine limb development. The Journal of cell biology 26 7642715
2009 FGF4 independent derivation of trophoblast stem cells from the common vole. PloS one 25 19777059
2001 Predominant expression of fibroblast growth factor (FGF) 8, FGF4, and FGF receptor 1 in nonseminomatous and highly proliferative components of testicular germ cell tumors. Virchows Archiv : an international journal of pathology 25 11764380
2017 O-GlcNAc on PKCζ Inhibits the FGF4-PKCζ-MEK-ERK1/2 Pathway via Inhibition of PKCζ Phosphorylation in Mouse Embryonic Stem Cells. Stem cell reports 23 29249667
2002 HST-1/FGF-4 gene activation induces spermatogenesis and prevents adriamycin-induced testicular toxicity. Oncogene 23 11840335
1994 All-trans-retinoic acid and hexamethylene bisacetamide (HMBA) regulate TGF-alpha and Hst-1/kFGF expression in differentiation sensitive but not in resistant human teratocarcinomas. Differentiation; research in biological diversity 22 8143931

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