Affinage

DDR1

Epithelial discoidin domain-containing receptor 1 · UniProt Q08345

Length
913 aa
Mass
101.1 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DDR1 is a collagen-activated receptor tyrosine kinase that transduces extracellular matrix signals into diverse cellular responses including adhesion, migration, ECM remodeling, epithelial differentiation, and mechanotransduction. DDR1 exists as disulfide-linked dimers mediated by stalk-region cysteines (Cys303, Cys348); collagen binding to surface loops of the discoidin domain induces lateral association of pre-formed dimers, clustering, and trans-phosphorylation dependent on the transmembrane leucine zipper, followed by dynamin-mediated endocytosis (PMID:16774916, PMID:18065762, PMID:28590245, PMID:19007791). Downstream, DDR1 signals through phosphotyrosine-dependent recruitment of Shp-2 (at Y740), Nck2, and BCR, and activates NF-κB–NRF2, STAT3, Src–FAK, and Hippo–YAP pathways—the latter via liquid–liquid phase separation that sequesters LATS1 from MOB1 (PMID:16337946, PMID:29438985, PMID:36475898, PMID:36198801). The DDR1 extracellular domain independently organizes collagen fiber alignment to exclude T cell infiltration in tumors, while kinase-dependent signaling drives vascular remodeling after injury, kidney fibrosis, and intestinal barrier regulation (PMID:34732895, PMID:11254672, PMID:34941574, PMID:35905891).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2001 High

    Establishing DDR1 as a physiologically relevant collagen receptor in vivo: DDR1-null mice showed reduced neointimal thickening after vascular injury, demonstrating that DDR1 mediates smooth muscle cell adhesion, migration, MMP production, and collagen deposition during wound repair.

    Evidence DDR1-knockout mouse carotid artery injury model with in vitro SMC assays

    PMID:11254672

    Open questions at the time
    • Downstream signaling intermediates not identified
    • Relative contribution of kinase activity vs. ECD-mediated collagen organization unknown
  2. 2001 Medium

    Identifying a non-canonical co-factor requirement: Wnt-5a was shown to be necessary for collagen-induced DDR1 phosphorylation in mammary epithelial cells, operating independently of β-catenin, suggesting DDR1 activation is context-dependent.

    Evidence Antisense repression and overexpression of Wnt-5a with DDR1 phosphorylation and cell migration assays

    PMID:11493640

    Open questions at the time
    • Mechanism by which Wnt-5a facilitates DDR1 phosphorylation not defined
    • Not replicated in other cell types
    • Direct physical interaction between Wnt-5a and DDR1 not demonstrated
  3. 2004 High

    Mapping the collagen-binding interface: alanine-scanning mutagenesis identified four surface-exposed loops of the discoidin domain essential for collagen binding, providing the first structural map of DDR1 ligand recognition.

    Evidence GST-fusion discoidin domain mutagenesis with solid-phase collagen-binding assays and homology modeling

    PMID:15136580

    Open questions at the time
    • No atomic-resolution structure of the DDR1–collagen complex
    • Collagen-type selectivity determinants not fully resolved
  4. 2005 High

    Identifying first proximal signaling effectors: phosphopeptide mapping revealed Nck2 and Shp-2 as collagen-dependent DDR1-binding partners, with Shp-2 binding mapped to Tyr-740 in an ITIM motif, and DDR1-null mammary glands showed mislocalized Nck2.

    Evidence Phosphopeptide mapping, mutagenesis, SH2 pull-downs, co-IP, DDR1-null mouse mammary analysis

    PMID:16337946

    Open questions at the time
    • Functional consequence of Shp-2 recruitment to Y740 on downstream pathways not determined
    • Additional phosphotyrosine-dependent effectors likely exist
  5. 2006 High

    Resolving the dimerization mechanism: DDR1 forms ligand-independent dimers in the biosynthetic pathway, and the transmembrane leucine zipper—not the GXXXG motif—is specifically required for collagen-induced kinase activation while being dispensable for dimerization per se.

    Evidence Chemical cross-linking, co-IP of differentially tagged constructs, TOXCAT assay, site-directed mutagenesis

    PMID:16774916

    Open questions at the time
    • Structure of the transmembrane leucine zipper dimer not solved
    • Mechanism coupling TM conformational change to kinase activation unclear
  6. 2007 High

    Identifying disulfide bonds that stabilize the dimer: Cys303 and Cys348 in the extracellular stalk were shown to be required for disulfide-linked dimerization, collagen binding, and kinase activation, placing the stalk as a critical structural element.

    Evidence Non-reducing SDS-PAGE, cysteine mutagenesis, collagen binding and kinase activity assays

    PMID:18065762

    Open questions at the time
    • Stalk conformation and its role in transmitting collagen-binding signal to TM domain not structurally resolved
  7. 2008 High

    Visualizing ligand-induced receptor dynamics: live-cell FRET showed DDR1 dimers exist constitutively, and collagen triggers rapid clustering into aggregates followed by internalization into early endosomes, preceding full kinase activation.

    Evidence CFP/YFP-tagged DDR1 FRET microscopy with internalization kinetics in live cells

    PMID:19007791

    Open questions at the time
    • Whether clustering is necessary for or merely accompanies activation not formally separated
  8. 2011 High

    Connecting DDR1 to cell–cell adhesion: DDR1 stabilizes E-cadherin at the plasma membrane by inactivating Cdc42, linking collagen sensing to epithelial differentiation and polarity beyond the classical cell–matrix signaling framework.

    Evidence FRAP/photoconversion of Eos-E-cadherin, dominant-negative Cdc42 rescue, DDR1 overexpression/knockdown

    PMID:21289093

    Open questions at the time
    • Kinase-dependence of E-cadherin stabilization not fully tested
    • Whether Cdc42 inactivation is direct or through an intermediary not defined
  9. 2017 High

    Establishing the trans-phosphorylation activation model: collagen induces lateral association of pre-formed DDR1 dimers, and kinase-active 'donor' dimers trans-phosphorylate kinase-dead 'receiver' dimers in a TM-domain-dependent manner, definitively resolving the activation mechanism.

    Evidence Co-expression of engineered donor/receiver DDR1 mutants, enforced dimerization constructs, fluorescence clustering assays

    PMID:28590245

    Open questions at the time
    • Stoichiometry of the higher-order signaling cluster not determined
    • Whether specific dimer–dimer interfaces exist beyond TM contacts is unknown
  10. 2018 High

    Identifying BCR as a DDR1 substrate: phosphoproteomics revealed DDR1 phosphorylates BCR at Tyr177, maintaining β-catenin transcriptional activity required for colorectal cancer invasion.

    Evidence Quantitative phosphoproteomics with nilotinib treatment, co-IP, β-catenin reporter, invasion assays

    PMID:29438985

    Open questions at the time
    • Whether BCR is a direct kinase substrate or requires an intermediate kinase not formally shown by in vitro kinase assay
  11. 2020 Medium

    Expanding the co-receptor repertoire: LRP-1 was shown to interact with DDR1 at the plasma membrane and regulate DDR1 surface levels through endocytosis, linking DDR1 turnover to cell cycle progression.

    Evidence Co-IP, LRP-1 knockdown, DDR1 surface expression quantification, 3D collagen proliferation assays

    PMID:32582700

    Open questions at the time
    • Single co-IP without reciprocal or domain-mapping validation
    • Whether LRP-1 acts as a clearance receptor or signaling partner not resolved
  12. 2021 High

    Separating kinase-dependent from ECD-dependent functions in vivo: the DDR1 extracellular domain alone—independent of kinase activity—promotes collagen fiber alignment that physically excludes T cells from tumors, establishing a non-catalytic structural role.

    Evidence DDR1-KO tumor models with domain-specific rescue constructs and ECD-neutralizing antibodies in immunocompetent hosts

    PMID:34732895

    Open questions at the time
    • Molecular mechanism by which ECD aligns collagen fibers not defined
    • Whether ECD oligomerization state affects fiber alignment unknown
  13. 2021 Medium

    Linking DDR1 to mammary stem cell fate: DDR1 instructs basal differentiation of breast epithelial stem cells, which in turn drives luminal progenitor differentiation via Notch, establishing a DDR1→ECM→stem cell hierarchy.

    Evidence 3D biomimetic breast tissue model with DDR1 inhibition/knockdown and Notch pathway epistasis

    PMID:34893587

    Open questions at the time
    • Whether kinase activity or ECD collagen binding drives stem cell differentiation not separated
    • Relevance to in vivo human mammary development not confirmed
  14. 2022 High

    Revealing DDR1 as a mechanosensor via phase separation: matrix stiffness and collagen trigger DDR1 liquid–liquid phase separation through its TM domain; DDR1 condensates sequester LATS1 from MOB1, suppressing Hippo signaling and activating YAP in vascular smooth muscle cells.

    Evidence In vitro LLPS reconstitution with purified DDR1 domains, point mutagenesis (H745P, H902P), SMC-specific Ddr1-KO mice, YAP activity assays

    PMID:36475898

    Open questions at the time
    • Whether LLPS occurs under physiological DDR1 expression levels not shown
    • Contribution of phase separation vs. conventional signaling complexes to YAP activation in vivo not quantified
  15. 2022 High

    Defining collagen-quality-dependent signaling: MMP-cleaved collagen I activates DDR1→NF-κB→p62→NRF2 signaling promoting pancreatic cancer, whereas intact collagen I triggers DDR1 degradation, revealing that the collagen modification state determines DDR1 signaling outcome.

    Evidence Genetic mouse models with MMP-resistant collagen I, DDR1 KO/inhibition, NF-κB inhibition, epistasis analysis

    PMID:36198801

    Open questions at the time
    • Structural basis for differential DDR1 response to cleaved vs. intact collagen not known
    • Whether other collagen modifications elicit distinct DDR1 outputs not tested
  16. 2022 High

    Extending DDR1–BCR–β-catenin axis to kidney fibrosis: DDR1 phosphorylates BCR and activates STAT3 in renal proximal tubule cells, with BCR acting as a negative regulator whose phosphorylation by DDR1 de-represses MCP-1 production and TGF-β secretion.

    Evidence Ddr1-null mouse ischemia/reperfusion model, co-IP, siRNA, β-catenin reporter

    PMID:34941574

    Open questions at the time
    • How BCR phosphorylation converts it from inhibitor to activator of MCP-1 mechanistically unclear
  17. 2023 High

    Structural basis for therapeutic antibody targeting: a 3.15-Å crystal structure of DDR1-ECD bound to PRTH-101 Fab revealed binding to the DS-like domain (not the collagen-binding DS domain), explaining how the antibody inhibits DDR1 phosphorylation and shedding without directly competing for collagen binding.

    Evidence X-ray crystallography, DDR1 phosphorylation/shedding/cell-attachment assays, in vivo tumor collagen fiber alignment

    PMID:37328286

    Open questions at the time
    • Full-length DDR1 dimer structure still lacking
    • Whether allosteric inhibition mechanism generalizes to other DDR1 antibodies unknown
  18. 2023 Medium

    Identifying CD44 as a DDR1 co-receptor in Hippo suppression: CD44 amplifies collagen-induced DDR1 signaling and facilitates recruitment of PP2AA to MST1 for dephosphorylation, linking DDR1 to YAP activation and cancer stemness in hepatocellular carcinoma.

    Evidence Co-IP of DDR1–CD44 and PP2AA–MST1, combined DDR1/YAP inhibition in vitro and in vivo

    PMID:37117273

    Open questions at the time
    • Direct vs. bridged interaction between DDR1 and CD44 not resolved
    • Whether CD44–DDR1 crosstalk operates in non-cancer contexts unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions: no full-length DDR1 dimer structure exists; the mechanism by which the ECD organizes collagen fibers independently of kinase activity is unknown; the relative contributions of phase separation versus classical signaling complexes to DDR1-mediated YAP activation in vivo remain unquantified; and how collagen modification state (intact vs. cleaved) differentially engages DDR1 at a structural level is unresolved.
  • Full-length DDR1 dimer structure
  • Mechanism of ECD-mediated collagen fiber alignment
  • In vivo significance of DDR1 LLPS
  • Structural basis of cleaved vs. intact collagen discrimination

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 4 R-HSA-1474244 Extracellular matrix organization 3 R-HSA-1500931 Cell-Cell communication 1
Partners
BCRCD44IGF1RLATS1LRP1NCK2SHP2TM4SF1

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 DDR1 forms ligand-independent dimers in the biosynthetic pathway and on the cell surface; the transmembrane leucine zipper (but not the GXXXG motif) is required for collagen-induced signaling, as leucine-zipper mutations abolish kinase activation while still permitting dimerization. Both extracellular and cytoplasmic domains are individually dispensable for dimerization. Chemical cross-linking, co-immunoprecipitation of differentially tagged DDR1 constructs, TOXCAT bacterial membrane reporter assay, site-directed mutagenesis The Journal of biological chemistry High 16774916
2007 DDR1 exists as a disulfide-linked dimer; cysteines 303 and 348 in the stalk region of the extracellular domain are necessary for dimerization, collagen binding, and kinase activation. Deletion of the discoidin domain does not prevent dimerization, whereas deletion of the stalk region abolishes it. Non-reducing SDS-PAGE, deletion and point mutagenesis of extracellular domain, collagen-binding and kinase activity assays The Journal of biological chemistry High 18065762
2017 Collagen activates DDR1 through lateral association of pre-formed DDR1 dimers and trans-phosphorylation between dimers. Receiver dimers (kinase-dead) are phosphorylated by donor DDR1 in a collagen-dependent manner requiring donor kinase activity but not receiver kinase activity; transmembrane domain mutation abolishes trans-phosphorylation, and collagen-binding-deficient DDR1 is recruited into DDR1 signaling clusters. Co-expression of signalling-incompetent ('receiver') and functional ('donor') DDR1 mutants, enforced covalent dimerization constructs, mutagenesis of transmembrane domain, fluorescence-based clustering assay eLife High 28590245
2004 The DDR1 collagen-binding site maps to four surface-exposed loops of the discoidin domain: residues Ser52–Thr57 (loop 1), Arg105–Lys112 (loop 3), and Ser175 (loop 4) are critically required for collagen binding, as determined by alanine-scanning and deletion mutagenesis of GST-fusion discoidin domain proteins in solid-phase collagen-binding assays. GST-fusion protein expression in insect cells, solid-phase collagen-binding assay, ELISA-based collagen binding, alanine-scanning and deletion mutagenesis, 3D homology modeling The Journal of biological chemistry High 15136580
2008 Collagen stimulation induces rapid aggregation and internalization of DDR1 dimers into early endosomes, preceding receptor activation. Significant FRET signal indicating DDR1 dimerization is present even without collagen; collagen causes clustering and sharp FRET increase in aggregated receptor regions. FRET microscopy with CFP- and YFP-tagged DDR1 in live cells, internalization kinetics imaging Journal of molecular biology High 19007791
2005 Collagen-induced DDR1 activation leads to phosphorylation of multiple tyrosine residues; Nck2 and Shp-2 bind DDR1 in a collagen-dependent manner. The Shp-2 binding site was mapped to Tyr-740 within an ITIM-consensus sequence. DDR1 ablation in mouse mammary gland causes delocalized Nck2 expression, linking DDR1-Nck2 interaction to alveologenesis defects. Phosphopeptide mapping, site-directed mutagenesis, SH2 domain pull-down, co-immunoprecipitation, DDR1-null mouse mammary gland analysis FEBS letters High 16337946
2001 DDR1 regulates smooth muscle cell attachment to collagen, chemotaxis, proliferation, and MMP production. DDR1-null mice show significantly reduced neointimal thickening and collagen deposition after carotid artery injury, establishing DDR1 as a collagen receptor mediating vascular wound repair. DDR1-knockout mouse model, carotid artery injury model, in vitro smooth muscle cell assays (migration, proliferation, MMP production) The Journal of clinical investigation High 11254672
2001 Wnt-5a is a co-factor necessary for collagen-induced DDR1 phosphorylation in mammary epithelial cells. Repression of Wnt-5a abolishes DDR1 phosphorylation, impairs cell-collagen interaction, and enhances motility; conversely, Wnt-5a overexpression enables DDR1 phosphorylation in non-Wnt-5a-producing cells. This effect is independent of β-catenin/canonical Wnt signaling. Antisense repression and overexpression of Wnt-5a, DDR1 phosphorylation assays, collagen binding assays, cell migration assays, β-catenin pathway inhibition Journal of cell science Medium 11493640
2011 DDR1 promotes E-cadherin-mediated cell-cell adhesion and epithelial differentiation by stabilizing E-cadherin at the plasma membrane through inactivation of Cdc42. DDR1 overexpression reduces E-cadherin degradation rate and increases its membrane stability (shown by FRAP/photoconversion); dominant-negative DDR1 has opposite effects. DDR1 overexpression and knockdown, photobleaching (FRAP) and photoconversion of Eos-E-cadherin, pull-down assays, constitutively active/dominant-negative Cdc42 constructs Molecular biology of the cell High 21289093
2018 DDR1 identifies BCR as a substrate: nilotinib inhibits DDR1 kinase activity and prevents DDR1-mediated BCR phosphorylation at Tyr177, which is required to maintain β-catenin transcriptional activity necessary for colorectal cancer cell invasion. Quantitative phosphoproteomics, nilotinib treatment, co-immunoprecipitation, β-catenin reporter assays, invasion assays EMBO molecular medicine High 29438985
2022 DDR1 promotes kidney inflammation and fibrosis via phosphorylation of BCR in renal proximal tubule cells, which increases β-catenin activity and MCP-1 production. DDR1 also activates STAT3 to stimulate TGF-β secretion. DDR1-induced BCR phosphorylation or BCR downregulation both increase MCP-1, indicating BCR acts as a negative regulator downstream of DDR1. Ddr1-null mouse ischemia/reperfusion model, co-immunoprecipitation, phosphorylation assays, β-catenin reporter, siRNA knockdown JCI insight High 34941574
2021 DDR1 extracellular domain (ECD), but not its intracellular kinase domain, is required for immune exclusion in triple-negative breast cancer. DDR1-ECD binding to collagen enforces aligned collagen fibers that obstruct T cell infiltration. Membrane-untethered DDR1-ECD is sufficient to rescue tumor growth in immunocompetent hosts. Ddr1 knockout mouse tumor models, domain-specific rescue constructs (ECD vs. kinase-dead), ECD-neutralizing antibodies, collagen fiber alignment imaging, T cell infiltration quantification Nature High 34732895
2022 Matrix-metalloprotease-cleaved collagen I (cCol I) activates DDR1-NF-κB-p62-NRF2 signaling to promote pancreatic cancer growth; intact collagen I (iCol I) triggers DDR1 degradation and restrains growth. Inhibition of NF-κB or mitochondrial biogenesis downstream of DDR1 blocks tumorigenesis in wild-type but not MMP-resistant collagen I-expressing mice. Genetic mouse models with MMP-resistant collagen I, DDR1 knockout/inhibition, NF-κB inhibition, in vivo tumor assays, western blotting for NRF2/p62 pathway Nature High 36198801
2022 DDR1 undergoes stiffness/collagen-stimulated liquid-liquid phase separation (LLPS), co-condensing with LATS1 to competitively inhibit MOB1 binding to LATS1 and thereby suppress LATS1 phosphorylation, leading to YAP activation. The transmembrane domain drives DDR1 droplet formation; the C-terminus is required for co-condensation with LATS1. Single-point C-terminus mutants (H745P, H902P) abolish co-condensation. VSMCs on polyacrylamide gels of varying stiffness, LLPS assays with purified DDR1 domains, mutagenesis, co-immunoprecipitation/co-condensation assays, SMC-specific Ddr1-KO mice with LATS1 inhibition, YAP activity assays Circulation research High 36475898
2022 ECM stiffness induces DDR1 phosphorylation, oligomerization, and endocytosis in a collagen-independent manner in vascular smooth muscle cells, leading to ERK and p53 pathway activation that represses DNMT1 expression, resulting in a proinflammatory phenotype. VSMCs on PA gels of varying stiffness, DDR1 phosphorylation/oligomerization/endocytosis assays, ERK and p53 pathway inhibition, DNMT1 expression assays, DDR1 inhibitor treatment in vivo Bioactive materials Medium 35386458
2015 DDR1 constitutively associates with IGF-IR; IGF-I stimulation enhances this interaction and promotes rapid DDR1 tyrosine phosphorylation and co-internalization with IGF-IR into early endosomes. DDR1 is critical for IGF-IR endocytosis, trafficking, and protein expression, as well as IGF-I-induced signaling and biological responses. Reciprocally, IGF-IR is required for collagen-dependent DDR1 phosphorylation. Co-immunoprecipitation, DDR1 silencing and overexpression, IGF-IR endocytosis/trafficking assays, co-transfection in mouse fibroblasts Oncotarget Medium 25840417
2019 DDR1 drives glioblastoma therapy resistance by associating with a YWHA/14-3-3–BECN1–AKT1 multiprotein complex that promotes pro-survival AKT-MTOR signaling and suppresses autophagy. DDR1 inhibition sensitizes glioblastoma cells to radio- and chemotherapy by inducing autophagic cell death. Co-immunoprecipitation of multiprotein complex, DDR1 inhibition/knockdown, autophagy flux assays, clonogenic survival after irradiation/chemotherapy Autophagy Medium 31117874
2013 Oligomers of recombinant DDR1-Fc extracellular domain bind collagen with higher affinity than dimeric DDR1-Fc alone. DDR1-Fc oligomerizes upon in vitro collagen binding as shown by AFM. Inhibition of dynamin-mediated endocytosis blocks ligand-induced internalization of DDR1 but does not affect oligomerization. Solid-phase binding assays, atomic force microscopy, dynamin inhibition, live-cell internalization assays Journal of structural biology Medium 23810922
2017 TM4SF1 colocalizes with and co-immunoprecipitates with DDR1 in pancreatic cancer cells; TM4SF1 silencing reduces DDR1 expression and invadopodia formation, and DDR1 overexpression rescues the inhibitory effects of TM4SF1 silencing on migration, invasion, and MMP2/9 expression. Co-immunoprecipitation, double immunofluorescence, siRNA knockdown, DDR1 rescue overexpression, invadopodia functional assays Scientific reports Medium 28368050
2020 Periostin signals through DDR1 to promote cartilage degeneration: genetic deficiency or pharmacological inhibition of DDR1 in mouse chondrocytes blocks periostin-induced MMP-13 expression and collagen/proteoglycan degradation downstream of AKT/β-catenin. DDR1-knockout mouse chondrocytes, DDR1 pharmacological inhibitor, periostin stimulation assays, MMP-13 expression readout PloS one Medium 32330138
2020 LRP-1 interacts with DDR1 at the plasma membrane in colon cancer cells and regulates DDR1 cell-surface levels through endocytosis. LRP-1-mediated DDR1 endocytosis promotes cell cycle progression and decreases apoptosis. Co-immunoprecipitation, LRP-1 knockdown, DDR1 surface expression quantification, 3D collagen matrix proliferation/apoptosis assays Frontiers in cell and developmental biology Medium 32582700
2022 DDR1 promotes YAP/TAZ nuclear localization and transcriptional activity in VSMCs; YAP/TAZ knockdown attenuates DDR1 expression, and YAP/TAZ bind to the Ddr1 promoter in response to collagen or increased substrate stiffness, establishing a DDR1-YAP/TAZ positive feedback loop for DDR1 auto-regulation. DDR1-KO and WT VSMCs on varied-stiffness substrates, YAP/TAZ nuclear localization assays, ChIP at Ddr1 promoter, YAP/TAZ siRNA knockdown, collagen stimulation Matrix biology Medium 35562016
2023 DDR1 interacts with CD44 as a co-receptor that amplifies collagen I-induced DDR1 signaling. Collagen I–DDR1 activation antagonizes Hippo signaling by facilitating PP2AA recruitment to MST1, leading to MST1 dephosphorylation and exaggerated YAP activation, promoting HCC cancer stem cell properties. Co-immunoprecipitation (DDR1–CD44 and PP2AA–MST1 interactions), in vitro and in vivo DDR1 activation assays, combined DDR1/YAP inhibition experiments Cell death and differentiation Medium 37117273
2022 DDR1 promotes intestinal barrier disruption in ulcerative colitis via the NF-κB p65-MLCK-p-MLC2 pathway, leading to tight junction protein degradation and epithelial apoptosis. DDR1 knockout mice show alleviated barrier injury, upregulated tight junction proteins, and reduced proinflammatory cytokines after DSS-induced colitis. DDR1-knockout and WT mice (DSS colitis model), DDR1 overexpression and shRNA in epithelial cell monolayers, NF-κB p65 inhibition (JSH-23), tight junction protein assays Pharmacological research Medium 35905891
2024 DDR1 directly interacts with the PAS domain of HIF-1α, suppresses HIF-1α ubiquitination and degradation, and strengthens HIF-1α transcriptional regulation of angiogenesis. DDR1 also promotes actin cytoskeleton reorganization via HIF-1α/RhoA/ROCK1 signaling to enhance gastric cancer metastasis. Co-immunoprecipitation (DDR1–HIF-1α PAS domain), ubiquitination assays, RhoA/ROCK1 pathway assays, PDX and organoid models with DDR1 inhibition Advanced science Medium 39024501
2022 DDR1 promotes migration and invasion of breast cancer cells by binding to Src and FAK (co-immunoprecipitation) and activating Src-FAK signaling; inhibition of FAK and Src attenuates DDR1-enhanced migration. Co-immunoprecipitation of DDR1 with Src and FAK, DDR1 knockdown/overexpression, Src and FAK inhibitor treatment, migration/invasion assays Neoplasma Low 35818965
2021 DDR1 instructs breast epithelial stem cell differentiation into basal cells, which in turn stimulate luminal progenitor differentiation via Notch signaling to form lobules in a 3D biomimetic breast tissue model. This establishes DDR1 as the receptor linking ECM collagen signals to multi-lineage stem cell differentiation. 3D biomimetic human breast tissue engineering, DDR1 inhibition/knockdown, Notch pathway inhibition, lineage differentiation assays Nature communications Medium 34893587
2023 A humanized DDR1 antibody (PRTH-101) binds the discoidin-like (DS-like) domain (not the collagen-binding DS domain) of DDR1 ECD as revealed by 3.15-Å crystal structure of the DDR1-ECD/Fab complex. Mechanistically, PRTH-101 inhibits DDR1 phosphorylation, decreases collagen-mediated cell attachment, and blocks DDR1 shedding from the cell surface. Crystal structure at 3.15 Å resolution, DDR1 phosphorylation assays, cell attachment assays, DDR1 shedding assays, in vivo tumor model with collagen fiber alignment imaging Journal for immunotherapy of cancer High 37328286

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Deep learning enables rapid identification of potent DDR1 kinase inhibitors. Nature biotechnology 707 31477924
1997 Mammalian membrane metallopeptidases: NEP, ECE, KELL, and PEX. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 344 9141502
2001 The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function. BioEssays : news and reviews in molecular, cellular and developmental biology 333 11223883
2021 Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion. Nature 285 34732895
2002 Beta-amyloid catabolism: roles for neprilysin (NEP) and other metallopeptidases? Journal of neurochemistry 207 12067222
2001 The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair. The Journal of clinical investigation 174 11254672
2022 Collagenolysis-dependent DDR1 signalling dictates pancreatic cancer outcome. Nature 153 36198801
2016 Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nature medicine 150 26855149
2002 Properties of a fetal multipotent neural stem cell (NEP cell). Developmental biology 149 12435354
2012 Emerging roles for the influenza A virus nuclear export protein (NEP). PLoS pathogens 131 23236273
2013 Neprilysin and Aβ Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer's Disease. Frontiers in aging neuroscience 124 24391587
2006 A transmembrane leucine zipper is required for activation of the dimeric receptor tyrosine kinase DDR1. The Journal of biological chemistry 101 16774916
2010 Loss of collagen-receptor DDR1 delays renal fibrosis in hereditary type IV collagen disease. Matrix biology : journal of the International Society for Matrix Biology 98 20307660
2018 Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer. EMBO molecular medicine 92 29438985
2018 DNA-Encoded Library-Derived DDR1 Inhibitor Prevents Fibrosis and Renal Function Loss in a Genetic Mouse Model of Alport Syndrome. ACS chemical biology 92 30452219
2019 Placental Syncytiotrophoblast-Derived Extracellular Vesicles Carry Active NEP (Neprilysin) and Are Increased in Preeclampsia. Hypertension (Dallas, Tex. : 1979) 91 30929513
2001 Repression of Wnt-5a impairs DDR1 phosphorylation and modifies adhesion and migration of mammary cells. Journal of cell science 86 11493640
2019 NSD2 circular RNA promotes metastasis of colorectal cancer by targeting miR-199b-5p-mediated DDR1 and JAG1 signalling. The Journal of pathology 82 30666650
2008 Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease. Neurobiology of aging 75 19019493
2019 DDR1 role in fibrosis and its pharmacological targeting. Biochimica et biophysica acta. Molecular cell research 73 30954571
2008 Mapping of DDR1 distribution and oligomerization on the cell surface by FRET microscopy. Journal of molecular biology 73 19007791
2016 IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. Oncotarget 71 26655502
2021 The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer. International journal of molecular sciences 70 34207360
2014 Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery. Drug discovery today 69 25284748
2019 MicroRNA-486-3p functions as a tumor suppressor in oral cancer by targeting DDR1. Journal of experimental & clinical cancer research : CR 65 31253192
1993 NEP: a novel receptor-like tyrosine kinase expressed in proliferating neuroepithelia. Oncogene 64 8397369
2015 Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer. Breast cancer research and treatment 62 25667101
2018 Discoidin domain receptor 1 (DDR1) ablation promotes tissue fibrosis and hypoxia to induce aggressive basal-like breast cancers. Genes & development 60 29483153
2004 Exploring the collagen-binding site of the DDR1 tyrosine kinase receptor. The Journal of biological chemistry 58 15136580
2011 DDR1 triggers epithelial cell differentiation by promoting cell adhesion through stabilization of E-cadherin. Molecular biology of the cell 56 21289093
1994 CD10/NEP in non-small cell lung carcinomas. Relationship to cellular proliferation. The Journal of clinical investigation 56 7962523
2015 Novel cross talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses. Oncotarget 55 25840417
2017 Collagen induces activation of DDR1 through lateral dimer association and phosphorylation between dimers. eLife 54 28590245
2019 Dichotomy of the function of DDR1 in cells and disease progression. Biochimica et biophysica acta. Molecular cell research 51 30954568
2023 Collagen I-DDR1 signaling promotes hepatocellular carcinoma cell stemness via Hippo signaling repression. Cell death and differentiation 50 37117273
2022 Identification of novel discoidin domain receptor 1 (DDR1) inhibitors using E-pharmacophore modeling, structure-based virtual screening, molecular dynamics simulation and MM-GBSA approaches. Computers in biology and medicine 50 35032738
2022 Matrix stiffness exacerbates the proinflammatory responses of vascular smooth muscle cell through the DDR1-DNMT1 mechanotransduction axis. Bioactive materials 48 35386458
2015 Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors. ACS medicinal chemistry letters 48 26191369
2001 Influenza A virus NEP (NS2 protein) downregulates RNA synthesis of model template RNAs. Journal of virology 48 11312364
2017 TM4SF1 Promotes Metastasis of Pancreatic Cancer via Regulating the Expression of DDR1. Scientific reports 47 28368050
2007 Inner ear defects and hearing loss in mice lacking the collagen receptor DDR1. Laboratory investigation; a journal of technical methods and pathology 47 18026164
2022 lncRNA XIST induces Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in Alzheimer's disease. Journal of neurogenetics 46 35098860
2019 Collagen Induces a More Proliferative, Migratory and Chemoresistant Phenotype in Head and Neck Cancer via DDR1. Cancers 46 31717573
2008 Gene cloning and heterologous synthesis of a haloalkaliphilic extracellular protease of Natrialba magadii (Nep). Extremophiles : life under extreme conditions 46 18553052
2005 Inhibition of neutral endopeptidase (NEP) facilitates neurogenic inflammation. Experimental neurology 46 15963503
2022 Discoidin domain receptor 1(DDR1) promote intestinal barrier disruption in Ulcerative Colitis through tight junction proteins degradation and epithelium apoptosis. Pharmacological research 45 35905891
2022 DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3. JCI insight 44 34941574
2019 DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop. Endocrine-related cancer 44 30121624
2023 A highly selective humanized DDR1 mAb reverses immune exclusion by disrupting collagen fiber alignment in breast cancer. Journal for immunotherapy of cancer 43 37328286
2001 Effect of ACE/NEP inhibition on cardiac and vascular collagen in stroke-prone spontaneously hypertensive rats. American journal of hypertension 43 11710787
2016 Stimulatory actions of IGF-I are mediated by IGF-IR cross-talk with GPER and DDR1 in mesothelioma and lung cancer cells. Oncotarget 42 27384677
2022 Liquid-Liquid Phase Separation of DDR1 Counteracts the Hippo Pathway to Orchestrate Arterial Stiffening. Circulation research 41 36475898
2021 Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma. Signal transduction and targeted therapy 41 33976105
2016 DDR1 enhances invasion and metastasis of gastric cancer via epithelial-mesenchymal transition. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 40 27179963
2018 Inhibition of EP300 and DDR1 synergistically alleviates pulmonary fibrosis in vitro and in vivo. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 38 30119248
2017 E2F1 silencing inhibits migration and invasion of osteosarcoma cells via regulating DDR1 expression. International journal of oncology 38 29039472
2012 Study of CCN3 (NOV) and DDR1 in normal melanocytes and vitiligo skin. Experimental dermatology 38 22507556
2019 2-Amino-2,3-dihydro-1H-indene-5-carboxamide-Based Discoidin Domain Receptor 1 (DDR1) Inhibitors: Design, Synthesis, and in Vivo Antipancreatic Cancer Efficacy. Journal of medicinal chemistry 37 31310125
2018 A novel functional crosstalk between DDR1 and the IGF axis and its relevance for breast cancer. Cell adhesion & migration 37 29486622
2007 Identification of disulfide-linked dimers of the receptor tyrosine kinase DDR1. The Journal of biological chemistry 37 18065762
2005 Pinpointing phosphotyrosine-dependent interactions downstream of the collagen receptor DDR1. FEBS letters 37 16337946
2019 DDR1 (discoidin domain receptor tyrosine kinase 1) drives glioblastoma therapy resistance by modulating autophagy. Autophagy 35 31117874
2019 Targeting of DDR1 with antibody-drug conjugates has antitumor effects in a mouse model of colon carcinoma. Molecular oncology 32 31116512
2023 Multifaceted collagen-DDR1 signaling in cancer. Trends in cell biology 30 37709651
2020 Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding. International journal of molecular sciences 30 32668815
2020 miR-199b-5p-DDR1-ERK signalling axis suppresses prostate cancer metastasis via inhibiting epithelial-mesenchymal transition. British journal of cancer 30 33239676
2020 Periostin interaction with discoidin domain receptor-1 (DDR1) promotes cartilage degeneration. PloS one 29 32330138
2020 Discoidin Domain Receptor 1 (DDR1) Is Necessary for Tissue Homeostasis in Pancreatic Injury and Pathogenesis of Pancreatic Ductal Adenocarcinoma. The American journal of pathology 29 32339496
2019 Expression of DDR1 in the CNS and in myelinating oligodendrocytes. Biochimica et biophysica acta. Molecular cell research 28 31108116
2016 Discoidin domain receptor 1 (DDR1), a promising biomarker, induces epithelial to mesenchymal transition in renal cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 28 27020590
2007 Clinical relevance of neutral endopeptidase (NEP/CD10) in melanoma. Journal of translational medicine 26 17207277
2021 Design and Synthesis of DDR1 Inhibitors with a Desired Pharmacophore Using Deep Generative Models. ChemMedChem 25 33289306
2008 Human neprilysin-2 (NEP2) and NEP display distinct subcellular localisations and substrate preferences. FEBS letters 25 18539150
2024 DDR1 Drives Malignant Progression of Gastric Cancer by Suppressing HIF-1α Ubiquitination and Degradation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 39024501
2020 LRP-1 Promotes Colon Cancer Cell Proliferation in 3D Collagen Matrices by Mediating DDR1 Endocytosis. Frontiers in cell and developmental biology 24 32582700
2019 Discovery of VU6015929: A Selective Discoidin Domain Receptor 1/2 (DDR1/2) Inhibitor to Explore the Role of DDR1 in Antifibrotic Therapy. ACS medicinal chemistry letters 23 31938459
2022 DDR1 promotes migration and invasion of breast cancer by modulating the Src-FAK signaling. Neoplasma 22 35818965
2020 Discoidin Domain Receptor-1 (DDR1) is Involved in Angiolymphatic Invasion in Oral Cancer. Cancers 22 32244515
2020 Inhibition of DDR1 enhances in vivo chemosensitivity in KRAS-mutant lung adenocarcinoma. JCI insight 22 32759499
2022 Ginsenoside F1 Protects the Brain against Amyloid Beta-Induced Toxicity by Regulating IDE and NEP. Life (Basel, Switzerland) 21 35054451
2022 Stiffness-responsive feedback autoregulation of DDR1 expression is mediated by a DDR1-YAP/TAZ axis. Matrix biology : journal of the International Society for Matrix Biology 21 35562016
2020 The cross-talk between DDR1 and STAT3 promotes the development of hepatocellular carcinoma. Aging 21 32716315
2018 Selective pharmacological inhibition of DDR1 prevents experimentally-induced glomerulonephritis in prevention and therapeutic regime. Journal of translational medicine 21 29859097
2016 Identification of novel inhibitors of DDR1 against idiopathic pulmonary fibrosis by integrative transcriptome meta-analysis, computational and experimental screening. Molecular bioSystems 21 26956955
2010 NEP-like endopeptidases and Alzheimer's disease [corrected]. Current Alzheimer research 21 20088804
2022 New target DDR1: A "double-edged sword" in solid tumors. Biochimica et biophysica acta. Reviews on cancer 20 36356724
2020 Silencing of sinusoidal DDR1 reduces murine liver metastasis by colon carcinoma. Scientific reports 20 33110221
2016 Andrographolide promotes vincristine-induced SK-NEP-1 tumor cell death via PI3K-AKT-p53 signaling pathway. Drug design, development and therapy 20 27729773
2007 NHERFs, NEP, MAGUKs, and more: interactions that regulate PTEN. Journal of cellular biochemistry 20 17786934
2022 DDR1 activation in macrophage promotes IPF by regulating NLRP3 inflammasome and macrophage reaction. International immunopharmacology 19 36257259
2021 Nilotinib, a Discoidin domain receptor 1 (DDR1) inhibitor, induces apoptosis and inhibits migration in breast cancer. Neoplasma 19 34263649
2021 Curcumin derivative ST09 modulates the miR-199a-5p/DDR1 axis and regulates proliferation and migration in ovarian cancer cells. Scientific reports 19 34837026
2021 Breast tissue regeneration is driven by cell-matrix interactions coordinating multi-lineage stem cell differentiation through DDR1. Nature communications 19 34893587
2019 The synergistic effect of DZ‑NEP, panobinostat and temozolomide reduces clonogenicity and induces apoptosis in glioblastoma cells. International journal of oncology 19 31746375
2016 Compounds from Polyphaga plancyi and their inhibitory activities against JAK3 and DDR1 kinases. Fitoterapia 19 27642041
2023 Inhibition of discoidin domain receptor (DDR)-1 with nilotinib alters CSF miRNAs and is associated with reduced inflammation and vascular fibrosis in Alzheimer's disease. Journal of neuroinflammation 18 37194065
2021 Involvement of miR-199a-3p/DDR1 in vascular endothelial cell senescence in diabetes. European journal of pharmacology 18 34270989
2019 3D culture enhances chemoresistance of ALL Jurkat cell line by increasing DDR1 expression. Experimental and therapeutic medicine 18 30783426
2018 DDR1 and DDR2 in skin. Cell adhesion & migration 18 29952722
2013 Oligomerization of DDR1 ECD affects receptor-ligand binding. Journal of structural biology 18 23810922