Affinage

FGFR1

Fibroblast growth factor receptor 1 · UniProt P11362

Round 2 corrected
Length
822 aa
Mass
91.9 kDa
Annotated
2026-04-28
130 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGFR1 is a receptor tyrosine kinase that transduces FGF signals to govern cell proliferation, migration, and metabolic reprogramming across development and disease. Ligand binding (FGF1 being the universal activator of all splice variants) triggers formation of a 2:2:2 FGF–FGFR1–heparan sulfate ternary complex that dimerizes the receptor via direct D2–D2 contacts and heparin-bridged cross-links, leading to autophosphorylation and recruitment of FRS2α/β to activate Ras/MAPK and PI3K/Akt cascades; endocrine FGFs (FGF19, FGF21, FGF23) require the co-receptors Klotho or βKlotho to convert FGFR1 into a high-affinity receptor (PMID:10490103, PMID:11030354, PMID:17086194, PMID:15863030). During gastrulation, FGFR1 kinase activity is cell-autonomously required for epiblast cell movement through the primitive streak, and loss-of-function mutations cause Kallmann syndrome (defective olfactory/GnRH neuron migration) while a gain-of-function extracellular-domain mutation causes Pfeiffer syndrome (craniosynostosis) (PMID:9226454, PMID:12627230, PMID:7874169). Oncogenic FGFR1 amplification or FGFR1–TACC1 fusion constitutively activates kinase signaling—including direct phosphorylation of PKM2-Y105 to promote aerobic glycolysis—and drives tumor proliferation, aneuploidy, and endocrine therapy resistance in lung, breast, and brain cancers (PMID:19920251, PMID:21160078, PMID:22837387, PMID:20179196).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1994 High

    Demonstrating that a gain-of-function missense mutation in the FGFR1 extracellular domain causes Pfeiffer syndrome established the first direct link between altered FGFR1 signaling and a human developmental disorder (craniosynostosis).

    Evidence Sequencing of FGFR1 exon 5 in five unrelated Pfeiffer syndrome families

    PMID:7874169

    Open questions at the time
    • Structural basis of how the Pro→Arg substitution activates signaling was not resolved
    • Whether other craniosynostosis-causing FGFR1 mutations share the same mechanism was unknown
  2. 1996 High

    Systematic profiling of all FGF ligands against FGFR splice variants revealed FGF1 as the universal FGFR1 activator and defined the selectivity landscape for FGFR1b versus FGFR1c isoforms, answering which ligand–receptor pairs are functional.

    Evidence Mitogenic assays in BaF3 cells expressing individual FGFR splice variants

    PMID:8663044

    Open questions at the time
    • The structural determinants of splice-variant selectivity were not explained
    • Endocrine FGFs showed weak activity, and the basis for this deficiency was unresolved
  3. 1997 High

    Two key advances resolved how FGFR1 kinase is inhibited and how it functions in vivo: crystal structures of the kinase domain with ATP-competitive inhibitors defined the drug-binding pocket, while chimeric embryo analysis proved that FGFR1 kinase activity is cell-autonomously required for epiblast migration through the primitive streak during gastrulation.

    Evidence X-ray crystallography of FGFR1 kinase–inhibitor complexes; mouse chimera analysis with kinase-dead Fgfr1 allele

    PMID:9139660 PMID:9226454

    Open questions at the time
    • Full autophosphorylation site mapping and downstream docking protein identity remained incomplete
    • Why kinase-dead cells adopt ectopic neural fate was not mechanistically explained
  4. 1999 High

    The crystal structure of the FGF2–FGFR1(D2-D3) complex revealed the receptor dimerization interface, answering the longstanding question of how ligand binding induces receptor activation at atomic resolution.

    Evidence X-ray crystallography at 2.8 Å of the FGF2–FGFR1 dimer

    PMID:10490103

    Open questions at the time
    • Heparin's precise contacts were not resolved in this binary structure
    • How alternative ligands might employ different dimerization geometries was unknown
  5. 2000 High

    The ternary FGF–FGFR1–heparin crystal structure resolved heparin's dual role—augmenting ligand binding within each 1:1 complex and bridging to the adjacent receptor to stabilize the dimer—establishing that heparan sulfate is an integral component of the signaling complex, not merely a concentrating device.

    Evidence X-ray crystallography of 2:2:2 ternary complex at 3 Å with supporting biochemical assays

    PMID:11030354

    Open questions at the time
    • Whether endogenous HSPGs with defined sulfation patterns recapitulate these contacts in vivo was untested
    • Kinetics of complex assembly on the cell surface were not addressed
  6. 2003 High

    Identification of loss-of-function FGFR1 mutations as the cause of autosomal dominant Kallmann syndrome proved that FGFR1 is required for olfactory and GnRH neuron migration in humans, complementing the mouse gastrulation phenotype.

    Evidence Positional cloning and mutation analysis in multiple Kallmann syndrome families

    PMID:12627230

    Open questions at the time
    • The precise ligand and co-receptor triggering FGFR1 during GnRH neuron migration were unidentified
    • Anosmin-1's proposed role as an FGFR1 co-factor lacked direct biochemical validation
  7. 2005 High

    Comprehensive characterization of FGFR1 downstream signaling consolidated that FRS2α/β are the major docking proteins linking receptor autophosphorylation to Ras/MAPK and PI3K/Akt pathways, with built-in negative feedback loops regulating signal amplitude.

    Evidence Phosphorylation assays, co-immunoprecipitation, and cell-based signaling studies synthesized across multiple laboratories

    PMID:15863030

    Open questions at the time
    • Quantitative contributions of individual autophosphorylation sites to pathway branching were not dissected
    • Negative feedback mechanisms were not fully mapped at the molecular level
  8. 2006 High

    Discovery that Klotho and βKlotho serve as obligate co-receptors that convert FGFR1 into high-affinity receptors for endocrine FGFs (FGF23 and FGF19/21, respectively) resolved why these ligands showed negligible activity in standard assays and explained tissue-specific endocrine FGF responses.

    Evidence Binding assays, forced Klotho expression in cell lines, in vivo antibody blockade; co-IP and glucose-uptake assays for βKlotho

    PMID:17086194 PMID:17623664

    Open questions at the time
    • The structural basis of the Klotho–FGFR1–FGF23 ternary complex was not yet determined
    • Relative contributions of FGFR1 versus FGFR3/FGFR4 in Klotho-dependent signaling in different tissues remained unclear
  9. 2009 High

    Identification of PKM2-Y105 as a direct FGFR1 substrate linked receptor tyrosine kinase signaling to metabolic reprogramming, demonstrating that FGFR1 promotes aerobic glycolysis by inhibiting PKM2 tetramerization.

    Evidence Phosphoproteomics, in vitro kinase assay, Y105F mutagenesis, xenograft models, metabolic flux assays

    PMID:19920251

    Open questions at the time
    • Whether this metabolic rewiring operates in non-transformed, FGFR1-dependent tissues was untested
    • Other direct kinase substrates beyond FRS2 and PKM2 remained largely uncharacterized
  10. 2010 High

    Two studies established FGFR1 amplification as an actionable oncogenic driver: in squamous lung cancer, FGFR1 amplification creates a kinase dependency reversible by FGFR inhibitors, while in breast cancer, FGFR1 overexpression drives ligand-independent MAPK/AKT activation and endocrine therapy resistance.

    Evidence FISH for amplification, siRNA knockdown, resistant-mutant rescue (V561M), FGFR inhibitor treatment, tamoxifen sensitivity assays

    PMID:20179196 PMID:21160078

    Open questions at the time
    • Biomarkers distinguishing FGFR1-amplified tumors that are truly kinase-dependent from bystander amplifications were not defined
    • Mechanisms of acquired resistance to FGFR inhibitors were unexplored
  11. 2012 High

    Discovery of FGFR1-TACC1 fusion in glioblastoma revealed a novel oncogenic mechanism in which the fusion protein localizes to mitotic spindle poles, causes chromosomal missegregation and aneuploidy, and drives glioma formation—all reversible by FGFR kinase inhibition.

    Evidence RNA-seq fusion detection, kinase assay, immunofluorescence at spindle poles, aneuploidy measurement, intracranial mouse model, FGFR inhibitor treatment

    PMID:22837387

    Open questions at the time
    • Whether TACC1-mediated spindle-pole localization is the primary oncogenic mechanism or whether constitutive kinase activity alone suffices was not resolved
    • Prevalence and therapeutic response of FGFR1-TACC1 fusions in clinical cohorts was not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • A comprehensive catalog of direct FGFR1 kinase substrates beyond FRS2 and PKM2 remains incomplete, and the structural basis for co-receptor (Klotho/βKlotho) engagement with FGFR1 and endocrine FGFs is not fully resolved; acquired resistance mechanisms to clinical FGFR inhibitors also require systematic characterization.
  • Full substrate repertoire of FGFR1 kinase is unmapped
  • Structural details of Klotho–FGFR1–FGF ternary complex at atomic resolution are needed
  • Mechanisms of clinical resistance to FGFR-targeted therapies are poorly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 6 GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005576 extracellular region 2 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 1
Partners
FGF1FGF2FGF23FRS2KLKLBPKMTACC1
Complex memberships
FGF-FGFR1-heparin ternary complexKlotho-FGFR1 co-receptor complexβKlotho-FGFR1 co-receptor complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Crystal structures of the FGFR1 tyrosine kinase domain in complex with indolinone inhibitors revealed that the oxindole core occupies the ATP adenine-binding site, and the more specific inhibitor induces a conformational change in the nucleotide-binding loop, establishing the structural basis for ATP-competitive kinase inhibition of FGFR1. X-ray crystallography of FGFR1 kinase domain–inhibitor complexes combined with kinase activity assays Science High 9139660
1999 The crystal structure of FGF2 bound to FGFR1 immunoglobulin-like domains D2 and D3 revealed that two FGF2:FGFR1 complexes form a symmetric dimer stabilized by FGF2–D2 cross-contacts and a direct D2–D2 receptor–receptor interaction, establishing the structural mechanism of ligand-induced FGFR1 dimerization and a positively charged canyon as the heparin-binding site. X-ray crystallography at 2.8 Å resolution of FGF2–FGFR1(D2-D3) complex Cell High 10490103
2000 The crystal structure of a 2:2:2 FGF:FGFR:heparin ternary complex at 3 Å resolution showed that heparin plays a dual role: it augments FGF–FGFR binding by contacting both molecules within each 1:1 complex, and it simultaneously bridges to FGFR in the adjoining complex to promote receptor dimerization, with the 6-O-sulfate group of heparin being pivotal for both interactions. X-ray crystallography of ternary FGF–FGFR1–heparin complex plus supporting biochemical assays Molecular Cell High 11030354
1996 Systematic mitogenesis assays in engineered cell lines expressing major splice variants of all four FGF receptors demonstrated that FGF1 is the only FGF ligand capable of activating all FGFR splice variants including FGFR1, while other FGF family members show selective receptor binding, establishing the binding specificity matrix for FGFR1 and its isoforms. Mitogenic activity assays on BaF3 cells engineered to express individual FGFR splice variants Journal of Biological Chemistry High 8663044
2005 FGFR1 activation by FGF and heparan sulfate proteoglycan (HSPG) induces receptor dimerization and autophosphorylation of multiple cytoplasmic tyrosine residues; the docking proteins FRS2α and FRS2β are major substrates that mediate downstream activation of the Ras/MAPK and PI3K/Akt signaling pathways, as well as negative feedback loops regulating signal amplitude. Biochemical phosphorylation assays, co-immunoprecipitation, and cell-based signaling studies synthesized across multiple laboratories Cytokine & Growth Factor Reviews High 15863030
2006 Klotho, a single-pass transmembrane protein, physically binds FGF23 and directly converts FGFR1(IIIc) into a high-affinity FGF23 receptor; forced Klotho expression restored FGF23 responsiveness in a renal cell line, and anti-Klotho antibody injection abrogated endogenous FGF23 function in vivo, establishing that concerted Klotho–FGFR1(IIIc) interaction is required for FGF23 signaling. Renal homogenate binding assays, forced expression in cell lines, in vivo antibody blockade, co-immunoprecipitation Nature High 17086194
2006 Receptor specificity studies for the complete 22-member FGF family using BaF3 cell lines expressing individual FGFRs showed that FGF10 and FGF22 signal selectively through FGFR1b (IIIb) splice variant, while FGF19/21/23 subfamily members (endocrine FGFs) have reduced or absent activity at FGFR1 without co-receptors, defining the full specificity profile of FGFR1 isoforms. Mitogenic activity assays on BaF3 cells expressing FGFR1 splice variants with all FGF ligands Journal of Biological Chemistry High 16597617
2007 betaKlotho in combination with specific FGFR isoforms, including FGFR1, confers tissue-specific responsiveness to FGF19 and FGF21; both ligands signal through betaKlotho–FGFR1 complexes to increase glucose uptake in adipocytes, while only FGF19 efficiently signals through FGFR4 in hepatocytes to reduce CYP7A1 transcription. Co-immunoprecipitation, ligand-binding assays, cell-based glucose uptake assays, hepatocyte CYP7A1 reporter assays Journal of Biological Chemistry High 17623664
1997 Chimeric embryo analysis demonstrated that cells homozygous for a kinase-dead Fgfr1 allele (fgfr1-Δtmk) accumulate within the primitive streak and fail to populate anterior mesoderm and endodermal lineages, indicating that FGFR1 kinase activity is specifically required for the morphogenetic movement of epiblast cells through the primitive streak during gastrulation, and that cells arrested in the streak adopt ectopic neural fate. Mouse chimera analysis, embryonic histology, cell lineage tracing using mutant vs. wild-type cells Development High 9226454
2009 Oncogenic FGFR1 directly phosphorylates pyruvate kinase M2 (PKM2) at tyrosine 105, disrupting binding of the cofactor fructose-1,6-bisphosphate and inhibiting formation of active tetrameric PKM2, thereby promoting aerobic glycolysis (Warburg effect) and tumor growth; Y105F mutation reversed these metabolic and proliferative effects in cancer cells and xenografts. Phosphoproteomic mass spectrometry, in vitro kinase assay, site-directed mutagenesis (Y105F), xenograft tumor models, metabolic flux assays Science Signaling High 19920251
2010 Focal FGFR1 amplification in squamous cell lung cancer drives tumor cell proliferation and survival; FGFR1 knockdown and expression of the kinase-resistant allele FGFR1(V561M) specifically rescued FGFR1-amplified cells from FGFR inhibitor cytotoxicity, confirming that amplified FGFR1 kinase activity is the dependency driver in these tumors. FISH for gene amplification, FGFR1 siRNA knockdown, ectopic expression of resistant mutant FGFR1(V561M), FGFR inhibitor (PD173074) treatment, in vivo tumor shrinkage assay Science Translational Medicine High 21160078
2010 FGFR1 overexpression/amplification in breast cancer cell lines causes ligand-independent basal MAPK and PI3K-AKT pathway activation and confers resistance to 4-hydroxytamoxifen; siRNA silencing of FGFR1 reversed endocrine resistance, and FGFR1 signaling suppresses progesterone receptor expression. siRNA knockdown, Western blotting of signaling intermediates, anchorage-independent growth assay, tamoxifen sensitivity assay, PR expression analysis Cancer Research High 20179196
2012 In-frame chromosomal translocations fuse the FGFR1 kinase domain to TACC1 in a subset of GBMs; the FGFR1-TACC1 fusion protein localizes to mitotic spindle poles, has constitutive kinase activity, induces chromosomal segregation defects and aneuploidy, and drives oncogenesis in astrocytes and in mouse brain, which is reversed by FGFR kinase inhibition. RNA sequencing for fusion discovery, FGFR kinase assay, immunofluorescence localization to spindle poles, aneuploidy measurement, intracranial mouse glioma model, FGFR inhibitor treatment Science High 22837387
2003 Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome (KAL2), demonstrating that FGFR1 signaling is required for normal migration of olfactory/GnRH neurons; the extracellular matrix protein anosmin-1 (KAL1 product) is proposed to be involved in FGF signaling, explaining the dosage-sensitive sex difference in disease prevalence. Positional cloning, mutation analysis in Kallmann syndrome families, interstitial deletion mapping Nature Genetics High 12627230
1994 A specific Pro→Arg missense mutation in the extracellular domain (exon 5) of FGFR1 causes Pfeiffer syndrome (autosomal dominant craniosynostosis), demonstrating that gain-of-function FGFR1 mutations in the immunoglobulin-like domain lead to premature fusion of cranial sutures. Mutation analysis by sequencing in affected members of five unrelated Pfeiffer syndrome families Nature Genetics High 7874169
2019 In FGFR1-amplified lung cancer cells, miR-214-3p directly targets the FGFR1 3'-UTR to downregulate FGFR1 expression (validated by luciferase reporter assay), and FGFR1 signaling through ERK establishes a negative feedback loop that suppresses miR-214-3p; miR-214-3p inhibits EMT and Wnt/MAPK/AKT signaling by targeting FGFR1. Luciferase 3'-UTR reporter assay, qRT-PCR, Western blot, transwell migration/invasion assay, signaling pathway analysis Oncogenesis Medium 31492847
2020 In FGFR1-amplified lung squamous cell carcinoma cell lines, FGFR1 promotes epithelial-mesenchymal transition and metastatic behavior through AKT/MAPK signaling by transcriptionally or post-translationally targeting CCND1 (cyclin D1), which is co-overexpressed with FGFR1 and required for proliferation and invasion. qRT-PCR, Western blot, transwell migration/invasion assay, FGFR1 and CCND1 manipulation in FGFR1-amplified cell lines Cell Adhesion & Migration Low 32380883

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Cellular signaling by fibroblast growth factor receptors. Cytokine & growth factor reviews 1528 15863030
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 1447 17086194
1996 Receptor specificity of the fibroblast growth factor family. The Journal of biological chemistry 1425 8663044
1993 Structural and functional diversity in the FGF receptor multigene family. Advances in cancer research 1173 8417497
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2006 Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. The Journal of biological chemistry 974 16597617
2000 Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Molecular cell 958 11030354
1997 Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science (New York, N.Y.) 954 9139660
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2012 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 708 22939624
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2020 FGF/FGFR signaling in health and disease. Signal transduction and targeted therapy 678 32879300
2010 Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Science translational medicine 673 21160078
1990 Cloning and expression of two distinct high-affinity receptors cross-reacting with acidic and basic fibroblast growth factors. The EMBO journal 673 1697263
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2009 Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Science signaling 652 19920251
2007 Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. The Journal of biological chemistry 645 17623664
2012 Transforming fusions of FGFR and TACC genes in human glioblastoma. Science (New York, N.Y.) 640 22837387
2010 FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer research 585 20179196
2005 A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 568 16273093
2003 Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. Nature genetics 566 12627230
1991 FGFR-4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. The EMBO journal 553 1709094
1996 Nucleosome assembly by a complex of CAF-1 and acetylated histones H3/H4. Cell 543 8858152
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
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1994 A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nature genetics 504 7874169
1999 Structural basis for FGF receptor dimerization and activation. Cell 494 10490103
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2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2006 Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology 363 16530522
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2010 Partitioning of histone H3-H4 tetramers during DNA replication-dependent chromatin assembly. Science (New York, N.Y.) 278 20360108
1997 Chimeric analysis of fibroblast growth factor receptor-1 (Fgfr1) function: a role for FGFR1 in morphogenetic movement through the primitive streak. Development (Cambridge, England) 276 9226454
1978 Structure of chromatin containing extensively acetylated H3 and H4. Cell 268 657272
2006 Organismal differences in post-translational modifications in histones H3 and H4. The Journal of biological chemistry 244 17194708
1995 Amino acid substitutions in the structured domains of histones H3 and H4 partially relieve the requirement of the yeast SWI/SNF complex for transcription. Genes & development 230 7590252
1999 Virus infection leads to localized hyperacetylation of histones H3 and H4 at the IFN-beta promoter. Molecular cell 222 10024886
2002 Elongator is a histone H3 and H4 acetyltransferase important for normal histone acetylation levels in vivo. Proceedings of the National Academy of Sciences of the United States of America 221 11904415
2016 The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science (New York, N.Y.) 216 27229140
2012 DAXX envelops a histone H3.3-H4 dimer for H3.3-specific recognition. Nature 209 23075851
2010 The program for processing newly synthesized histones H3.1 and H4. Nature structural & molecular biology 204 20953179
2005 Insights into the role of histone H3 and histone H4 core modifiable residues in Saccharomyces cerevisiae. Molecular and cellular biology 204 16260619
2015 A unique binding mode enables MCM2 to chaperone histones H3-H4 at replication forks. Nature structural & molecular biology 194 26167883
2008 Probing nucleosome function: a highly versatile library of synthetic histone H3 and H4 mutants. Cell 179 18805098
2018 The Mcm2-Ctf4-Polα Axis Facilitates Parental Histone H3-H4 Transfer to Lagging Strands. Molecular cell 162 30244834
1982 Soluble acidic complexes containing histones H3 and H4 in nuclei of Xenopus laevis oocytes. Cell 151 6891289
2009 Fine tuning the immune response through B7-H3 and B7-H4. Immunological reviews 143 19426220
2009 Histone chaperone spt16 promotes redeposition of the original h3-h4 histones evicted by elongating RNA polymerase. Molecular cell 138 19683500
1991 Nucleosome positioning is determined by the (H3-H4)2 tetramer. Proceedings of the National Academy of Sciences of the United States of America 129 1961726
2001 Pathways mediating the nuclear import of histones H3 and H4 in yeast. The Journal of biological chemistry 121 11694505
2009 Histamine H3 and H4 receptors as novel drug targets. Expert opinion on investigational drugs 120 19758107
2009 Brd4 engagement from chromatin targeting to transcriptional regulation: selective contact with acetylated histone H3 and H4. F1000 biology reports 119 20495683
2011 Histamine H1, H3 and H4 receptors are involved in pruritus. Neuroscience 116 21689731
2008 The FACT Spt16 "peptidase" domain is a histone H3-H4 binding module. Proceedings of the National Academy of Sciences of the United States of America 116 18579787
2018 POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication. Molecular cell 111 30217558
1990 Nucleosome linking number change controlled by acetylation of histones H3 and H4. The Journal of biological chemistry 111 2123193
2015 EP400 Deposits H3.3 into Promoters and Enhancers during Gene Activation. Molecular cell 102 26669263
1997 Expression of fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3) in the developing head and face. Developmental dynamics : an official publication of the American Association of Anatomists 101 9286594
2012 Structure of the variant histone H3.3-H4 heterodimer in complex with its chaperone DAXX. Nature structural & molecular biology 94 23142979
2020 The histone H3-H4 tetramer is a copper reductase enzyme. Science (New York, N.Y.) 92 32631887
2012 Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106. Nature 92 22307274
2010 Systematic screen reveals new functional dynamics of histones H3 and H4 during gametogenesis. Genes & development 84 20713519
2007 The role of histamine in human mammary carcinogenesis: H3 and H4 receptors as potential therapeutic targets for breast cancer treatment. Cancer biology & therapy 80 17932461
2018 H3-H4 Histone Chaperone Pathways. Annual review of genetics 75 30183406
2000 Importance of histamine in the cytokine network in the lung through H2 and H3 receptors: stimulation of IL-10 production. Journal of immunology (Baltimore, Md. : 1950) 75 10706683
2007 Plasticity of fission yeast CENP-A chromatin driven by relative levels of histone H3 and H4. PLoS genetics 73 17677001
2013 Histone H3 and H4 N-terminal tails in nucleosome arrays at cellular concentrations probed by magic angle spinning NMR spectroscopy. Journal of the American Chemical Society 71 24088044
1997 The H3/H4 tetramer blocks transcript elongation by RNA polymerase II in vitro. The Journal of biological chemistry 68 9287358
2016 TGF-β1 promotes colorectal cancer immune escape by elevating B7-H3 and B7-H4 via the miR-155/miR-143 axis. Oncotarget 67 27626488
1983 Multiple, independently regulated, polyadenylated messages for histone H3 and H4 in Tetrahymena. Nucleic acids research 67 6135196
2010 Prion fibrillization is mediated by a native structural element that comprises helices H2 and H3. The Journal of biological chemistry 65 20375014
2005 The immunomodulatory proteins B7-DC, B7-H2, and B7-H3 are differentially expressed across gestation in the human placenta. The American journal of pathology 65 16049332
2002 Heritable chromatin structure: mapping "memory" in histones H3 and H4. Proceedings of the National Academy of Sciences of the United States of America 65 12196632
2015 Opposing roles of H3- and H4-acetylation in the regulation of nucleosome structure––a FRET study. Nucleic acids research 63 25589544
2007 Mutational analysis of H3 and H4 N termini reveals distinct roles in nuclear import. The Journal of biological chemistry 63 17507373
2013 A sequence in the Drosophila H3-H4 Promoter triggers histone locus body assembly and biosynthesis of replication-coupled histone mRNAs. Developmental cell 62 23537633
2012 Yeast CAF-1 assembles histone (H3-H4)2 tetramers prior to DNA deposition. Nucleic acids research 60 22941638
2011 Splitting of H3-H4 tetramers at transcriptionally active genes undergoing dynamic histone exchange. Proceedings of the National Academy of Sciences of the United States of America 60 21220302
1999 NF-Y associates with H3-H4 tetramers and octamers by multiple mechanisms. Molecular and cellular biology 59 10567583
2013 H3.3-H4 tetramer splitting events feature cell-type specific enhancers. PLoS genetics 56 23754967
1996 Expression and regulation of Cek-8, a cell to cell signalling receptor in developing chick limb buds. Development (Cambridge, England) 55 8620841
1996 Histamine inhibits tumor necrosis factor alpha release by mast cells through H2 and H3 receptors. American journal of respiratory cell and molecular biology 55 8652190
2000 The H3-H4 N-terminal tail domains are the primary mediators of transcription factor IIIA access to 5S DNA within a nucleosome. Molecular and cellular biology 54 10688663
2012 Structural plasticity of histones H3-H4 facilitates their allosteric exchange between RbAp48 and ASF1. Nature structural & molecular biology 53 23178455
2006 Compared pharmacology of human histamine H3 and H4 receptors: structure-activity relationships of histamine derivatives. British journal of pharmacology 53 16432504
2018 SIRT1-dependent epigenetic regulation of H3 and H4 histone acetylation in human breast cancer. Oncotarget 52 30093977
2016 The Cac1 subunit of histone chaperone CAF-1 organizes CAF-1-H3/H4 architecture and tetramerizes histones. eLife 52 27690308
2011 The replication-independent histone H3-H4 chaperones HIR, ASF1, and RTT106 co-operate to maintain promoter fidelity. The Journal of biological chemistry 50 22128187
2004 Folding mechanism of the (H3-H4)2 histone tetramer of the core nucleosome. Protein science : a publication of the Protein Society 49 15096635
2017 Insights into the molecular architecture and histone H3-H4 deposition mechanism of yeast Chromatin assembly factor 1. eLife 47 28315525
1993 Identification of endothelial H1, vascular H2 and cardiac presynaptic H3 receptors in the pithed rat. Naunyn-Schmiedeberg's archives of pharmacology 47 8383300
2018 Negative roles of B7-H3 and B7-H4 in the microenvironment of cervical cancer. Experimental cell research 46 30099052
1997 Amino termini of histones H3 and H4 are required for a1-alpha2 repression in yeast. Molecular and cellular biology 46 9343419
1993 Mutation of a tyrosine in the H3-H4 ectodomain of Na,K-ATPase alpha subunit confers ouabain resistance. The Journal of biological chemistry 46 8394348
2008 Role of histamine H3 and H4 receptors in mechanical hyperalgesia following peripheral nerve injury. Neuroimmunomodulation 45 18401194
2019 Reciprocal regulatory mechanism between miR-214-3p and FGFR1 in FGFR1-amplified lung cancer. Oncogenesis 44 31492847
1991 Associative behavior of the histone (H3-H4)2 tetramer: dependence on ionic environment. Biochemistry 44 1888742
2020 Acetylated histone H4 tail enhances histone H3 tail acetylation by altering their mutual dynamics in the nucleosome. Proceedings of the National Academy of Sciences of the United States of America 42 32747537
2018 Probing the Function of Metazoan Histones with a Systematic Library of H3 and H4 Mutants. Developmental cell 42 30595536
2014 Virulence patterns in a murine sepsis model of ST131 Escherichia coli clinical isolates belonging to serotypes O25b:H4 and O16:H5 are associated to specific virotypes. PloS one 42 24498015
2018 Evidence for the nuclear import of histones H3.1 and H4 as monomers. The EMBO journal 41 30177573
2015 Hematolymphoid neoplasms associated with rearrangements of PDGFRA, PDGFRB, and FGFR1. American journal of clinical pathology 41 26276769
2011 Comprehensive structural analysis of mutant nucleosomes containing lysine to glutamine (KQ) substitutions in the H3 and H4 histone-fold domains. Biochemistry 40 21812398
2003 Differential hyperacetylation of histones H3 and H4 upon promoter-specific recruitment of EBNA2 in Epstein-Barr virus chromatin. Journal of virology 40 12829856
1996 Functional domains for assembly of histones H3 and H4 into the chromatin of Xenopus embryos. Proceedings of the National Academy of Sciences of the United States of America 39 8917496
1982 H-2 effects on cell-cell interactions in the response to single non-H-2 alloantigens. V. Effects of H-2Kb mutations on presentation of H-4 and H-3 alloantigens. Journal of immunology (Baltimore, Md. : 1950) 39 6978909
1998 Evolution of histone H4 and H3 genes in different ciliate lineages. Journal of molecular evolution 38 9493359
2015 Structure-function studies of histone H3/H4 tetramer maintenance during transcription by chaperone Spt2. Genes & development 37 26109053
2024 A replisome-associated histone H3-H4 chaperone required for epigenetic inheritance. Cell 36 39094570
2020 FGFR1 regulates proliferation and metastasis by targeting CCND1 in FGFR1 amplified lung cancer. Cell adhesion & migration 36 32380883
2023 A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation. Acta neuropathologica 34 38066305
2016 Recognition Elements in the Histone H3 and H4 Tails for Seven Different Importins. The Journal of biological chemistry 34 27528606
1990 Conservative segregation of tetrameric units of H3 and H4 histones during nucleosome replication. Journal of biochemistry 34 2332416
2018 Homogeneous, Real-Time NanoBRET Binding Assays for the Histamine H3 and H4 Receptors on Living Cells. Molecular pharmacology 32 30249614
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1988 Polyadenylation of histone H3 and H4 mRNAs in dicotyledonous plants. Gene 32 2905689
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2014 DAXX co-folds with H3.3/H4 using high local stability conferred by the H3.3 variant recognition residues. Nucleic acids research 29 24493739
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2004 The histones H2A/H2B and H3/H4 are imported into the yeast nucleus by different mechanisms. European journal of cell biology 29 15679097
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2007 Acetylated histone H3 and H4 mark the upregulated LMP2A promoter of Epstein-Barr virus in lymphoid cells. Journal of virology 26 17898065
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