Affinage

DDR2

Discoidin domain-containing receptor 2 · UniProt Q16832

Length
855 aa
Mass
96.7 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DDR2 is a collagen-activated receptor tyrosine kinase that couples extracellular matrix sensing to intracellular signaling controlling cell proliferation, ECM remodeling, skeletal development, and cancer metastasis (PMID:11696582, PMID:11375938). Its surface discoidin domain is sufficient for high-affinity collagen I binding and transmembrane signaling, recognizing collagen through three adjacent surface loops that engage the triple-helical GVMGFO motif; single triple-helical peptides containing this motif activate the receptor, so fibrillar assembly is not required, and collagen X engages the receptor through regions beyond the discoidin domain (PMID:12611880, PMID:18201965, PMID:16806867). Ligand engagement is reinforced by the cytoplasmic JM2 juxtamembrane region, which drives receptor dimerization and efficient collagen binding (PMID:24740739), and triggers kinase-dependent autophosphorylation that recruits SHP-2 and engages SRC, JAK2 and ERK/p38 MAPK cascades (PMID:23822953, PMID:26390252, PMID:21335558). Through these effectors DDR2 phosphorylates and activates Runx2 to drive osteoblast differentiation, induces MMPs and stabilizes SNAIL1 to promote invasion and EMT, and converges on transcription programs through AP-1/CYR61, STAT3, β-catenin and SRF (PMID:20734453, PMID:26362312, PMID:27653023, PMID:38969205, PMID:36471363, PMID:32412792). In bone, ATF4/C/EBPβ transcriptionally induce DDR2, and DDR2 additionally suppresses osteoclastogenesis by forming a Nrp1–PlexinA1 complex that blocks PlexinA1 engagement of TREM2/DAP12 (PMID:20564243, PMID:25805889). In the tumor stroma, DDR2 in cancer-associated fibroblasts reorganizes collagen and controls tumor stiffness through Rap1-mediated Talin1/Kindlin2 recruitment and integrin activation to promote metastasis (PMID:31144616). DDR2 protein levels are set by HSP47, which binds the ectodomain to maintain stability and surface localization, and by Cbl-b-mediated proteasomal degradation (PMID:31570520, PMID:26826182). Beyond its kinase function, the DDR2 extracellular domain acts kinase-independently to inhibit collagen fibrillogenesis and to support fibroblast spreading and tumor cell invasion (PMID:18996394, PMID:34477203, PMID:23131558). Activating kinase-domain mutations confer oncogenic, dasatinib-sensitive transformation in squamous lung cancer, whereas loss-of-function mutations that impair kinase activity, ER export, or collagen binding cause the skeletal disorder SMED-SL, and gain-of-function ligand-independent variants cause Warburg–Cinotti syndrome (PMID:22328973, PMID:19110212, PMID:20223752, PMID:30449416).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2001 High

    Establishing that DDR2 kinase activity is functionally required answered whether the receptor is a driver of proliferation and ECM-invasive behavior rather than a passive collagen binder.

    Evidence DDR2 knockout mice with kinase-dead rescue, and overexpression of wild-type vs kinase-dead DDR2 in hepatic stellate cells with MMP-2 and invasion readouts

    PMID:11375938 PMID:11696582

    Open questions at the time
    • Did not define the collagen recognition site
    • Downstream effectors of kinase activity not yet mapped
  2. 2008 High

    Defining the molecular collagen recognition determinants established how DDR2 senses matrix at the structural level and which collagen features are required for activation.

    Evidence Recombinant discoidin domain binding and loop-exchange mutagenesis, plus Toolkit peptide screening identifying the triple-helical GVMGFO motif and the collagen II D2 period

    PMID:12611880 PMID:15544808 PMID:16806867 PMID:18201965

    Open questions at the time
    • Structural basis of dimerization not resolved
    • How distinct collagens (e.g. collagen X) produce differential activation not fully explained
  3. 2008 Medium

    Identifying kinase-independent actions of the DDR2 ectodomain answered whether the receptor influences matrix and cell behavior outside of canonical phospho-signaling.

    Evidence Membrane-anchored and secreted kinase-dead DDR2 ECD expressed in osteoblasts with TEM, hydroxyproline assays, and fibroblast migration/spreading assays

    PMID:18996394 PMID:19900459 PMID:23131558

    Open questions at the time
    • Molecular mechanism of fibrillogenesis inhibition not defined
    • Kinase-independent migration partners unidentified
  4. 2010 High

    Placing DDR2 in an ERK/p38-Runx2 axis and identifying its transcriptional induction by ATF4 established its mechanistic role in osteoblast differentiation and skeletal development.

    Evidence shRNA knockdown, constitutively active DDR2, ERK/p38 inhibitors, Runx2 phospho-mutant epistasis, and DDR2 promoter mapping with ATF4/C/EBPβ dissection

    PMID:20564243 PMID:20734453

    Open questions at the time
    • Direct DDR2-to-ERK coupling step not resolved
    • In vivo contribution of each MAPK branch not separated
  5. 2011 High

    Discovery of recurrent activating kinase-domain mutations established DDR2 as a targetable oncogenic driver in squamous lung cancer.

    Evidence Tyrosine kinome sequencing, RNAi, transformation and xenograft assays, and dasatinib sensitivity testing

    PMID:22328973

    Open questions at the time
    • Mechanism by which mutations elevate activity not structurally defined
    • Resistance mechanisms not yet known
  6. 2008 High

    Loss-of-function genetics linked DDR2 to a Mendelian skeletal disorder, defining the consequences of receptor inactivation in humans.

    Evidence Homozygosity mapping and sequencing identifying SMED-SL kinase-domain mutations, followed by trafficking and ligand-binding characterization of mutant classes

    PMID:19110212 PMID:20223752 PMID:24725993

    Open questions at the time
    • Tissue-specific signaling deficits underlying skeletal phenotype not delineated
    • Whether residual kinase-independent functions persist in ER-retained mutants unknown
  7. 2013 Medium

    Identifying SHP-2 as a kinase-dependent phospho-substrate and mapping dasatinib resistance routes built the proximal signaling and pharmacology of DDR2.

    Evidence Temporal phosphoproteomics with mutant-panel validation, and exome sequencing of resistant cell lines identifying the T654I gatekeeper mutation and NF1-loss RAS-ERK bypass

    PMID:23822953 PMID:24296828

    Open questions at the time
    • Full proximal interactome beyond SHP-2 incomplete
    • Clinical generalizability of resistance mechanisms untested
  8. 2015 High

    Characterizing DDR2 protein partners established mechanisms regulating its stability, localization, and divergent roles in bone homeostasis.

    Evidence Co-IP and functional assays identifying SRC, Nrp1 (stabilizing DDR2 half-life and forming a Nrp1–PlexinA1 complex), in osteoblast and osteoclast models and DDR2-mutant lung cancer cells

    PMID:25805889 PMID:25924845 PMID:26390252

    Open questions at the time
    • Stoichiometry and structural basis of the Nrp1-PlexinA1 complex unresolved
    • How DDR2 toggles between pro-osteoblast and anti-osteoclast outputs unclear
  9. 2016 Medium

    Defining downstream transcriptional loops connected DDR2 to invasion, EMT, and inflammatory matrix programs across disease contexts.

    Evidence Pathway dissection in HCC (ERK2-SNAIL1 stabilization), RA synoviocytes (AP-1-CYR61-ETS1-MMP1), and lung fibroblasts (DDR2-JAK2-ERK-PEA3 inducing DDR1) using inhibitors, ChIP, and promoter reporters

    PMID:21335558 PMID:26362312 PMID:27653023

    Open questions at the time
    • Cross-talk between parallel transcriptional loops not integrated
    • Direct vs indirect target relationships partly inferred
  10. 2016 Medium

    Cbl-b-mediated degradation established a ubiquitin-dependent route controlling DDR2 abundance and a cancer-associated mutation altering it.

    Evidence Co-IP with Cbl-b, proteasome inhibitor rescue of the E655K mutant, and collagen-induced p38-dependent growth suppression assays

    PMID:26826182

    Open questions at the time
    • Ubiquitination sites not mapped
    • Physiological signals triggering Cbl-b recruitment unknown
  11. 2018 Medium

    Identifying ligand-independent activating variants and an allosteric ectodomain inhibitor expanded the disease and pharmacological landscape of DDR2.

    Evidence Family sequencing and patient-fibroblast phosphorylation for Warburg-Cinotti variants, and screening/characterization of the WRG-28 allosteric ECD inhibitor with invasion assays

    PMID:30061414 PMID:30449416

    Open questions at the time
    • Structural basis of autoinhibition release not defined
    • WRG-28 in vivo therapeutic window untested
  12. 2019 High

    Defining stromal DDR2 mechanotransduction established how fibroblast DDR2 shapes the tumor microenvironment to drive metastasis, and that HSP47 maintains DDR2 stability.

    Evidence DDR2 depletion in CAFs with collagen imaging and Rap1-Talin1-Kindlin2 integrin-activation studies in vivo, and Co-IP/TIRF imaging of HSP47-DDR2 ectodomain interaction

    PMID:31144616 PMID:31570520

    Open questions at the time
    • How DDR2 signaling activates Rap1 mechanistically unclear
    • HSP47-DDR2 stoichiometry and chaperone cycle undefined
  13. 2021 Medium

    Demonstrating kinase-independent contributions to metastasis and drug resistance reframed DDR2 as functioning beyond its catalytic activity in tumor progression.

    Evidence Kinase-dead DDR2 rescue in invasion and metastasis models with paracrine co-culture, and DDR1/DDR2 clustering driving a NIK/IKKα/NF-κB2 ECM-resistance pathway in melanoma

    PMID:34477203 PMID:34957688

    Open questions at the time
    • Kinase-independent effector mechanism unidentified
    • Relative contribution of kinase-dependent vs independent functions in patients unknown
  14. 2023 Medium

    Linking DDR2 to fibroblast metabolic reprogramming established a role in regulating collagen production and matrix-supportive metabolism via SNAI1.

    Evidence DDR2 depletion in CAFs with arginase/metabolomics and ChIP for SNAI1 at the arginase-1 promoter, and glycolytic enzyme/LOXL2 rescue experiments in vivo

    PMID:37527178 PMID:37996700

    Open questions at the time
    • How DDR2 signaling reaches SNAI1/AKT not mechanistically traced
    • Generalizability beyond ovarian CAFs untested
  15. 2022 Medium

    Identifying β-catenin, STAT3, SRF and Hippo-effector linkages extended the DDR2 transcriptional network into EMT, immunosuppression, survival, and cell-cycle control.

    Evidence Co-IP (DDR2-β-catenin), fractionation, luciferase reporters (PD-L1/CCL20, SRF targets), and YAP1/WWTR1 nuclear translocation studies across HCC, cardiac fibroblast, and lens epithelial models

    PMID:32412792 PMID:36471363 PMID:38969205 PMID:39900894

    Open questions at the time
    • Whether these interactions are direct or signaling-dependent partly unresolved
    • Ferroptosis link rests on low-confidence single-lab data

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DDR2 mechanically couples collagen binding to slow, sustained autophosphorylation and selects between its many divergent downstream programs (Runx2 vs SNAIL1 vs anti-osteoclast complex vs kinase-independent outputs) in a context-specific manner remains unresolved.
  • No full-length structural model of activated receptor
  • Determinants of cell-type-specific effector selection unknown
  • Integration of kinase-dependent and kinase-independent functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1474244 Extracellular matrix organization 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
CBL-BCTNNB1DDR1HSP47NRP1PLXNA1SHP-2SRC
Complex memberships
DDR1-DDR2 heteromeric receptorDDR2-Nrp1-PlexinA1 complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 The discoidin domain of DDR2 is sufficient for collagen I binding with high affinity and for transmembrane receptor signaling. Three spatially adjacent surface loops within the DDR2 discoidin domain constitute the collagen recognition site; mutation of these loops abolishes both collagen binding and collagen-dependent receptor activation. Recombinant extracellular domain production, solid-phase binding assays, loop-exchange mutagenesis, receptor signaling assays The Journal of biological chemistry High 12611880
2008 The minimal collagen sequence required for DDR2 binding and activation is the triple-helical motif GVMGFO (O = hydroxyproline). Single triple-helical peptides comprising this motif are sufficient to activate DDR2 transmembrane signaling, indicating that fibrillar collagen is not required. Collagen II Toolkit peptide screen, truncation and alanine-substitution peptides, DDR2 binding and phosphorylation assays The Journal of biological chemistry High 18201965
2004 The D2 period of collagen II contains a specific DDR2 binding site; deletion of D2 abolishes DDR2 binding and receptor autophosphorylation, whereas D3 and D4 periods are dispensable. Recombinant collagen II variants with specific D-period deletions, DDR2 binding assays, autophosphorylation assays Journal of molecular biology High 15544808
2006 Collagen X is a ligand for DDR2 that binds the DDR2 extracellular domain with high affinity and stimulates DDR2 autophosphorylation. Unlike fibrillar collagens, collagen X binding requires regions beyond the discoidin domain; the triple-helical region of collagen X activates DDR2 whereas the NC1 domain binds but does not activate. Solid-phase binding assays with recombinant DDR2 extracellular domain, autophosphorylation assays, RT-PCR and immunohistochemistry for spatial expression Matrix biology High 16806867
2001 DDR2 overexpression in hepatic stellate cells enhances proliferation and Matrigel invasion via increased expression of active MMP-2; kinase-dead DDR2 does not produce these effects, establishing that DDR2 kinase activity is required. Stable overexpression of wild-type, constitutively active chimeric, truncated, and kinase-dead DDR2; proliferation assays; Matrigel invasion; MMP-2 activity assays The Journal of clinical investigation High 11696582
2001 DDR2 kinase activity is required for normal cell proliferation in vivo; DDR2-deficient mice exhibit dwarfism and reduced chondrocyte proliferation, and introduction of wild-type but not kinase-dead DDR2 rescues the proliferation defect of DDR2-/- fibroblasts in vitro. DDR2 knockout mouse generation, bone phenotype analysis, skin wound healing model, fibroblast rescue with wild-type vs. kinase-dead DDR2 EMBO reports High 11375938
2010 DDR2 regulates osteoblast differentiation by activating ERK, which in turn phosphorylates and activates the transcription factor Runx2. A gain-of-function Runx2 mutant with ERK-independent phosphorylation rescues osteogenic phenotypes in DDR2-silenced cells, placing DDR2 upstream of ERK-Runx2 in osteoblastogenesis. shRNA knockdown, constitutively active DDR2 overexpression, ERK inhibitors, Runx2 phosphorylation assays, epistasis with Runx2 mutants Journal of bone and mineral research High 20734453
2010 ATF4 transcriptionally upregulates DDR2 expression by binding a C/EBP site at -1150 bp in the DDR2 promoter via cooperation with C/EBPβ; DDR2 in turn activates Runx2 through p38 MAPK to promote osteoblast differentiation. ATF4 knockdown/overexpression, promoter reporter assays, ATF4 mutants deficient in C/EBPβ binding, p38 MAPK inhibition Journal of bone and mineral research High 20564243
2013 SHP-2 tyrosine phosphorylation is dependent on DDR2 kinase activity downstream of collagen stimulation. Multiple DDR2 lung cancer mutants (L63V, G505S) phosphorylate SHP-2, whereas the kinase-impaired I638F mutant shows diminished DDR2 and SHP-2 phosphorylation. Quantitative phosphoproteomics (7-time-point temporal analysis), biochemical validation of SHP-2 phosphorylation, targeted proteomic profiling of DDR2 mutant panel The Biochemical journal High 23822953
2014 The cytoplasmic juxtamembrane 2 (JM2) region of DDR2 is required for receptor dimerization and efficient collagen binding, both of which are critical for receptor activation. Overexpression of the JM2-containing domain suppresses collagen-induced colony formation, proliferation, and invasion via inhibition of MMP-2 and MMP-9. Deletion constructs, collagen-binding assays, receptor dimerization analysis, dominant-negative overexpression, proliferation and invasion assays International journal of cancer Medium 24740739
2013 Acquired resistance to dasatinib in DDR2-dependent lung cancer cells occurs via two distinct mechanisms: (1) a T654I gatekeeper mutation in DDR2, and (2) loss of NF1 that activates a RAS-ERK bypass pathway. Targeted exome sequencing of resistant cell lines, functional validation of resistance mechanisms Molecular cancer therapeutics Medium 24296828
2011 Mutations in the DDR2 kinase domain (e.g., L63V, G505S) confer gain-of-function oncogenic activity; expression of mutant DDR2 leads to cellular transformation blocked by dasatinib. Squamous lung cancer cell lines with DDR2 mutations are selectively killed by DDR2 RNAi or dasatinib. Sanger sequencing of tyrosine kinome, RNAi knockdown, transformation assays, xenograft models, dasatinib treatment Cancer discovery High 22328973
2008 Loss-of-function DDR2 missense mutations cause SMED-SL through mutations in the tyrosine kinase domain (T713I, I726R, R752C). These mutations map to the conserved kinase domain of DDR2. Homozygosity mapping, Sanger sequencing of DDR2 gene in affected families American journal of human genetics Medium 19110212
2010 SMED-SL DDR2 missense mutants (T713I, I726R, R752C) are retained in the endoplasmic reticulum and fail to reach the plasma membrane, abolishing collagen-induced receptor activation. A fourth mutant (E113K) traffics normally but fails to bind collagen, identifying two distinct loss-of-function mechanisms. Expression of point mutants in human cell lines, subcellular localization studies, collagen activation assays, Western blot Human molecular genetics High 20223752
2018 Recurrent activating DDR2 variants (L610P, Y740C) causing Warburg-Cinotti syndrome increase DDR2 phosphorylation in patient fibroblasts in a ligand-independent manner, suggesting reduced receptor autoinhibition. Dasatinib prevents DDR2 autophosphorylation in these fibroblasts. Sequencing of affected families, phosphorylation analysis in patient-derived fibroblasts, dasatinib treatment American journal of human genetics Medium 30449416
2015 DDR2 and SRC are binding partners; SRC activity is tied to DDR2 activation, and dual inhibition of DDR2 and SRC leads to enhanced suppression of DDR2-mutant lung cancer cell lines compared to DDR2 inhibition alone. Co-immunoprecipitation (DDR2-SRC interaction), selective DDR2 inhibitors, dual DDR2/SRC inhibition, antiproliferative assays ACS chemical biology Medium 26390252
2015 DDR2 suppresses osteoclastogenesis by forming a DDR2-Nrp1-PlexinA1 complex that blocks PlexinA1-mediated stimulation of osteoclast differentiation. DDR2 prevents PlexinA1 from interacting with TREM2 and DAP12. Neuropilin-1 (Nrp1) was identified as a DDR2-interacting protein. Co-immunoprecipitation, DDR2 overexpression/knockdown, osteoclastogenesis assays, bone resorption assays, adenovirus delivery in ovariectomized mouse model Science signaling High 25805889
2015 Nrp1 co-localizes with DDR2 at the cell membrane, physically interacts with DDR2, and prolongs DDR2 protein half-life without altering DDR2 mRNA, thereby enhancing DDR2 phosphorylation and ERK1/2-Runx2 signaling during osteoblast differentiation. Co-immunoprecipitation, immunofluorescence co-localization, half-life determination assay, overexpression/silencing of Nrp1 Cellular physiology and biochemistry Medium 25924845
2011 Collagen I induces DDR1 expression in primary human lung fibroblasts via sequential activation of DDR2, JAK2, and ERK1/2 MAPK, culminating in recruitment of transcription factor PEA3 to the DDR1 promoter. Inhibition of any step in this pathway abrogates DDR1 induction. DDR2 inhibition/knockdown, JAK2 and ERK1/2 inhibitors, promoter reporter assays, ChIP for PEA3 recruitment The Journal of biological chemistry Medium 21335558
2016 Collagen II-activated DDR2 induces CYR61 expression through activation of transcription factor AP-1; CYR61 in turn activates MMP1 via ETS1, forming a Collagen II-DDR2-AP-1-CYR61-ETS1-MMP1 signaling loop in rheumatoid arthritis fibroblast-like synoviocytes. Collagen stimulation, phospho-DDR2 detection, CYR61 and MMP1 expression, AP-1 and ETS1 transcription factor analysis, shRNA in vitro and in vivo (CIA rat model) Journal of bone and mineral research Medium 27653023
2015 DDR2 promotes HCC invasion and migration by activating ERK2, which stabilizes SNAIL1 protein (demonstrated by cycloheximide chase experiments showing increased SNAIL1 half-life). This signaling axis upregulates MT1-MMP and MMP2 expression and is activated by type I collagen. DDR2 overexpression/knockdown, cycloheximide chase, ERK2 activation assays, invasion/migration assays, collagen I stimulation Journal of experimental & clinical cancer research Medium 26362312
2008 The extracellular domain of DDR2, expressed as a membrane-anchored kinase-dead protein on the cell surface, inhibits collagen fibrillogenesis by reducing the rate and quantity of collagen deposition and altering fiber morphology, independent of DDR2 kinase activity. Stable expression of kinase-dead DDR2 in mouse osteoblasts, transmission electron microscopy, fluorescence microscopy, hydroxyproline assays Journal of molecular biology Medium 18996394
2009 Soluble extracellular domains of DDR1 and DDR2 secreted by cells inhibit collagen fibrillogenesis, reducing collagen deposition rate, quantity, and altering fiber morphology, identifying a kinase-independent function for secreted DDR ECDs in ECM remodeling. Stable secretion of DDR1/DDR2 ECDs from osteoblasts, transmission electron microscopy, fluorescence microscopy, hydroxyproline assays Journal of molecular biology Medium 19900459
2009 DDR2 is involved in regulation of focal adhesion kinase (FAK) levels in vascular smooth muscle cells: FAK is downregulated on fibrillar collagen matrices, this is correlated with DDR2 tyrosine phosphorylation, and siRNA depletion of DDR2 blocks FAK downregulation. Collagen fibril matrices of varying stiffness, siRNA depletion of DDR2, FAK and DDR2 phosphorylation measurement by Western blot Biomaterials Medium 19762078
2013 Collagen-DDR2 signaling mediates upregulation of lysyl oxidase in osteoblasts; DDR2 shRNA knockdown blocks collagen-induced lysyl oxidase increases. Advanced glycation of collagen (CML-collagen) disrupts DDR2 binding and activation, explaining reduced lysyl oxidase in diabetic bone. DDR2 shRNA knockdown, primary osteoblast cultures, collagen vs. CML-collagen comparison, lysyl oxidase protein measurements Bone Medium 24120383
2019 DDR2 in cancer-associated fibroblasts (CAFs) controls tumor stiffness by reorganizing collagen fibers at the tumor-stromal boundary through mechanotransduction: DDR2 controls full collagen-binding integrin activation via Rap1-mediated Talin1 and Kindlin2 recruitment, promoting lung metastasis. DDR2 depletion in mouse/human CAFs, collagen fiber imaging, integrin activation assays, Rap1/Talin1/Kindlin2 co-localization and functional studies, in vivo breast tumor models eLife High 31144616
2019 HSP47 binds to the DDR2 ectodomain (demonstrated by Co-IP) and is required for DDR2 protein stability and cell-surface membrane localization. HSP47 silencing reduces DDR2 protein stability and membrane dynamics, suppressing cancer cell migration and invasion. Co-immunoprecipitation, HSP47 silencing, photoconvertible protein technique, total internal reflection fluorescence (TIRF) microscopy, migration/invasion assays The Journal of biological chemistry High 31570520
2018 A small molecule allosteric inhibitor (WRG-28) of the DDR2 extracellular domain inhibits receptor-ligand interactions via allosteric modulation, blocking tumor invasion, migration, and tumor-stromal interactions. Small molecule screening, DDR2 extracellular domain binding assays, tumor invasion and migration assays, in vivo lung colonization model PNAS Medium 30061414
2021 DDR2 tyrosine kinase activity is not strictly required for tumor invasion and in vivo metastasis; kinase-independent DDR2 actions in tumor cells support Matrigel invasion and lung metastasis. Paracrine DDR2 signaling between tumor cells and CAFs also supports invasion independent of kinase activity. Kinase-dead DDR2 mutant expression, Matrigel invasion assays, in vivo metastasis models, paracrine co-culture experiments Journal of cell science Medium 34477203
2012 DDR2 plays a role in fibroblast migration that is independent of both the adhesion ligand (fibronectin or collagen) and collagen-induced DDR2 tyrosine kinase activation. DDR2 silencing inhibits spreading and migration on fibronectin even without detectable DDR2 tyrosine kinase activation. siRNA silencing of DDR2, 2D migration on fibronectin and collagen surfaces, 3D collagen matrix migration, tyrosine phosphorylation assays Biochemical and biophysical research communications Medium 23131558
2021 DDR2 depletion in melanoma cells increases sensitivity to BRAF/MEK inhibition through a collagen-rich matrix. Drug-induced ECM resistance (MMDR) is mediated by drug-induced linear clustering of phosphorylated DDR1 and DDR2. DDR-dependent MMDR fosters a pro-survival NIK/IKKα/NF-κB2 pathway. DDR1/DDR2 depletion, pharmacological targeting, phospho-DDR imaging, NF-κB2 pathway analysis, xenograft models EMBO molecular medicine Medium 34957688
2018 DDR1 and DDR2 physically interact with each other (demonstrated by Co-IP), and high co-expression of both receptors leads to inhibition of cell proliferation. ERK activation is higher in cells co-expressing DDR1 and DDR2. DDR1 but not DDR2 is implicated in cell adhesion to collagen I. Co-immunoprecipitation, HEK293T overexpression, dominant-negative truncation mutants, ERK/JAK2 activation assays, proliferation and adhesion assays Cell adhesion & migration Medium 29616590
2020 DDR2 acts via ERK1/2 MAPK-activated SRF transcription factor to enhance expression of antiapoptotic cIAP2 in cardiac fibroblasts (resistance to oxidative injury), and to upregulate Skp2-mediated post-translational degradation of p27 to promote G1-S cell cycle transition. Gene knockdown and overexpression, promoter binding assays, ERK1/2 and SRF inhibition, flow cytometry, WRG-28 collagen-DDR2 blocking American journal of physiology. Heart and circulatory physiology Medium 32412792
2016 C. elegans DDR-2 (ortholog of DDR2) functions upstream of the Met-like RTK SVH-2 and SHC-1 scaffold in axon regeneration following injury. DDR-2 is activated by EMB-9 collagen type IV; overexpression of svh-2 and shc-1 suppresses the axon regeneration delay in ddr-2 mutants, placing DDR-2 upstream in a DDR-2→SHC-1→SVH-2→JNK pathway. C. elegans genetic epistasis, axon regeneration assays post-injury, overexpression suppression analysis, SHC-1 interaction with DDR-2 and SVH-2 PLoS genetics Medium 27984580
2023 DDR2 in ovarian cancer-associated fibroblasts promotes collagen production through arginase activity; DDR2-depleted CAFs have decreased ornithine and polyamine levels and reduced collagen production. DDR2 regulates arginase-1 transcription via SNAI1, which binds the arginase-1 promoter in a DDR2-dependent manner. DDR2 depletion in CAFs, arginase activity assays, metabolomics (ornithine/polyamine measurement), ChIP for SNAI1 at arginase-1 promoter, rescue experiments with arginase-1 overexpression and exogenous polyamines Oncogene Medium 37996700
2023 Stromal DDR2 in fibroblasts regulates glycolysis through an AKT/SNAI1 axis suppressing fructose-1,6-bisphosphatase and increasing hexokinase activity. DDR2 inhibition decreases LOXL2 secretion; adding back LOXL2 to DDR2-deficient fibroblasts rescues tumor cell invasion. DDR2 depletion in fibroblasts, glycolytic enzyme activity assays, protein secretion analysis, LOXL2 rescue experiments, in vivo peritoneal metastasis model Molecular cancer research Medium 37527178
2024 DDR2 forms a complex with Src kinase in lens epithelial cells, leading to nuclear translocation of YAP1 and WWTR1 (Hippo pathway effectors), which alters expression of ferroptosis-related genes and enhances ferroptosis sensitivity. RNA sequencing, DDR2-Src interaction studies, nuclear fractionation of YAP1/WWTR1, DDR2 inhibitor treatment, in vitro and in vivo ferroptosis assays Cell death & disease Low 39900894
2021 DDR2 induces STAT3 phosphorylation and nuclear translocation; activated STAT3 in turn enhances DDR2 expression, forming a positive feedback loop. This DDR2/STAT3 loop upregulates PD-L1 and CCL20 transcription (confirmed by dual luciferase reporter assay), promoting immunosuppressive tumor microenvironment in oxaliplatin-resistant HCC. DDR2/STAT3 knockdown, phosphorylation assays, immunofluorescence, dual luciferase reporter assay for PD-L1 and CCL20 promoters, MDSC migration assays Cellular and molecular gastroenterology and hepatology Medium 38969205
2014 A novel DDR2 frameshift mutation (c.2468_2469delCT, p.S823Cfs*2) causes SMED-SL by retaining the mutant protein in the endoplasmic reticulum, as demonstrated by confocal microscopy and deglycosylation assays, resulting in deficient collagen-induced receptor activation. Sanger sequencing, confocal microscopy for subcellular localization, deglycosylation assay, Western blotting, collagen activation assay BMC medical genetics Medium 24725993
2016 DDR2 E655K mutation reduces protein expression due to enhanced binding to ubiquitin ligase Cbl-b and proteasomal degradation; treatment with a proteasome inhibitor restores DDR2 E655K protein levels. Collagen stimulation normally decreases cellular proliferation via p38 activation in DDR2 wild-type cells, but this growth-suppressive effect is weakened in DDR2 E655K cells. Overexpression of DDR2 mutants, collagen stimulation, p38 activation assays, Co-IP with Cbl-b, proteasome inhibitor treatment, proliferation assays Clinical cancer research Medium 26826182
2022 DDR2 interacts with β-catenin (demonstrated by Co-IP); CEBPA-DT lncRNA promotes DDR2 expression via hnRNPC, and DDR2 facilitates nuclear translocation of β-catenin to activate Snail1 transcription, promoting EMT and HCC metastasis. Co-immunoprecipitation (DDR2-β-catenin interaction), subcellular protein fractionation, DDR2 inhibitor experiments, in vivo metastasis models Journal of experimental & clinical cancer research Medium 36471363

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer discovery 379 22328973
2001 DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. The Journal of clinical investigation 213 11696582
2001 The collagen receptor DDR2 regulates proliferation and its elimination leads to dwarfism. EMBO reports 212 11375938
2003 Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2. Identification of collagen binding sites in DDR2. The Journal of biological chemistry 166 12611880
2008 Characterization of high affinity binding motifs for the discoidin domain receptor DDR2 in collagen. The Journal of biological chemistry 156 18201965
2019 Targeting DDR2 enhances tumor response to anti-PD-1 immunotherapy. Science advances 110 30801016
2006 The discoidin domain receptor DDR2 is a receptor for type X collagen. Matrix biology : journal of the International Society for Matrix Biology 105 16806867
2017 Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth. Cell reports 96 28147276
2019 DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs. eLife 95 31144616
2011 An essential role of discoidin domain receptor 2 (DDR2) in osteoblast differentiation and chondrocyte maturation via modulation of Runx2 activation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 94 20734453
2021 DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway. Oncogene 89 33603168
2018 Inhibition of tumor-microenvironment interaction and tumor invasion by small-molecule allosteric inhibitor of DDR2 extracellular domain. Proceedings of the National Academy of Sciences of the United States of America 88 30061414
2008 Mutations in DDR2 gene cause SMED with short limbs and abnormal calcifications. American journal of human genetics 87 19110212
2004 The D2 period of collagen II contains a specific binding site for the human discoidin domain receptor, DDR2. Journal of molecular biology 72 15544808
2021 The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer. International journal of molecular sciences 71 34207360
2015 DDR2 facilitates hepatocellular carcinoma invasion and metastasis via activating ERK signaling and stabilizing SNAIL1. Journal of experimental & clinical cancer research : CR 69 26362312
2010 Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 69 20564243
2008 A novel dwarfism with gonadal dysfunction due to loss-of-function allele of the collagen receptor gene, Ddr2, in the mouse. Molecular endocrinology (Baltimore, Md.) 68 18483174
2010 Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients. Human molecular genetics 66 20223752
2014 Discoidin domain receptor 2 (DDR2) promotes breast cancer cell metastasis and the mechanism implicates epithelial-mesenchymal transition programme under hypoxia. The Journal of pathology 64 25130389
2013 Phosphoproteomics of collagen receptor networks reveals SHP-2 phosphorylation downstream of wild-type DDR2 and its lung cancer mutants. The Biochemical journal 64 23822953
2016 Targeting of Discoidin Domain Receptor 2 (DDR2) Prevents Myofibroblast Activation and Neovessel Formation During Pulmonary Fibrosis. Molecular therapy : the journal of the American Society of Gene Therapy 62 27350126
2015 Tyrosine kinase discoidin domain receptors DDR1 and DDR2 are coordinately deregulated in triple-negative breast cancer. Breast cancer research and treatment 62 25667101
2011 Collagen I induces discoidin domain receptor (DDR) 1 expression through DDR2 and a JAK2-ERK1/2-mediated mechanism in primary human lung fibroblasts. The Journal of biological chemistry 58 21335558
2016 Integrated Molecular Profiling of Human Gastric Cancer Identifies DDR2 as a Potential Regulator of Peritoneal Dissemination. Scientific reports 57 26934957
2015 DDR2 inhibition reduces migration and invasion of murine metastatic melanoma cells by suppressing MMP2/9 expression through ERK/NF-κB pathway. Acta biochimica et biophysica Sinica 55 25733533
2009 Inhibition of collagen fibrillogenesis by cells expressing soluble extracellular domains of DDR1 and DDR2. Journal of molecular biology 52 19900459
2021 Targeting Discoidin Domain Receptors DDR1 and DDR2 overcomes matrix-mediated tumor cell adaptation and tolerance to BRAF-targeted therapy in melanoma. EMBO molecular medicine 50 34957688
2015 Characterization of DDR2 Inhibitors for the Treatment of DDR2 Mutated Nonsmall Cell Lung Cancer. ACS chemical biology 49 26390252
2022 LncRNA CEBPA-DT promotes liver cancer metastasis through DDR2/β-catenin activation via interacting with hnRNPC. Journal of experimental & clinical cancer research : CR 45 36471363
2013 Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 loss. Molecular cancer therapeutics 45 24296828
2011 Osteoarthritis-like changes in the heterozygous sedc mouse associated with the HtrA1-Ddr2-Mmp-13 degradative pathway: a new model of osteoarthritis. Osteoarthritis and cartilage 44 22155431
2023 DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression. Oncogene 43 37996700
2013 Collagen advanced glycation inhibits its Discoidin Domain Receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts. Bone 43 24120383
2005 Expression of Discoidin Domain Receptor 2 (DDR2) in the developing heart. Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada 43 16060979
2019 Circ-LAMP1 promotes T-cell lymphoblastic lymphoma progression via acting as a ceRNA for miR-615-5p to regulate DDR2 expression. Gene 42 30922709
2014 A host deficiency of discoidin domain receptor 2 (DDR2) inhibits both tumour angiogenesis and metastasis. The Journal of pathology 41 24293323
2018 Distribution of KRAS, DDR2, and TP53 gene mutations in lung cancer: An analysis of Iranian patients. PloS one 36 30048458
2014 Adaptive responses to dasatinib-treated lung squamous cell cancer cells harboring DDR2 mutations. Cancer research 36 25348954
2009 The relative roles of collagen adhesive receptor DDR2 activation and matrix stiffness on the downregulation of focal adhesion kinase in vascular smooth muscle cells. Biomaterials 34 19762078
2014 Overexpression of DDR2 contributes to cell invasion and migration in head and neck squamous cell carcinoma. Cancer biology & therapy 33 24556606
2014 Identification of type II and III DDR2 inhibitors. Journal of medicinal chemistry 32 24754677
2014 Identification of novel driver mutations of the discoidin domain receptor 2 (DDR2) gene in squamous cell lung cancer of Chinese patients. BMC cancer 32 24885564
2008 Regulation of collagen fibrillogenesis by cell-surface expression of kinase dead DDR2. Journal of molecular biology 32 18996394
2016 DDR2 Induces Gastric Cancer Cell Activities via Activating mTORC2 Signaling and Is Associated with Clinicopathological Characteristics of Gastric Cancer. Digestive diseases and sciences 31 27010547
2015 DDR2 (discoidin domain receptor 2) suppresses osteoclastogenesis and is a potential therapeutic target in osteoporosis. Science signaling 31 25805889
2015 Molecular genetic studies on EGFR, KRAS, BRAF, ALK, PIK3CA, PDGFRA, and DDR2 in primary pulmonary adenoid cystic carcinoma. Diagnostic pathology 31 26373952
2022 DDR2 Expression in Cancer-Associated Fibroblasts Promotes Ovarian Cancer Tumor Invasion and Metastasis through Periostin-ITGB1. Cancers 27 35884543
2014 A novel mutation in DDR2 causing spondylo-meta-epiphyseal dysplasia with short limbs and abnormal calcifications (SMED-SL) results in defective intra-cellular trafficking. BMC medical genetics 27 24725993
2016 Targeting DDR2 in head and neck squamous cell carcinoma with dasatinib. International journal of cancer 26 27434411
2018 DDR1 and DDR2 physical interaction leads to signaling interconnection but with possible distinct functions. Cell adhesion & migration 25 29616590
2016 DDR2-CYR61-MMP1 Signaling Pathway Promotes Bone Erosion in Rheumatoid Arthritis Through Regulating Migration and Invasion of Fibroblast-Like Synoviocytes. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 25 27653023
2015 NSCLC Driven by DDR2 Mutation Is Sensitive to Dasatinib and JQ1 Combination Therapy. Molecular cancer therapeutics 25 26206333
2014 The intracellular juxtamembrane domain of discoidin domain receptor 2 (DDR2) is essential for receptor activation and DDR2-mediated cancer progression. International journal of cancer 24 24740739
2010 The collagen receptor DDR2 is expressed during early cardiac development. Anatomical record (Hoboken, N.J. : 2007) 24 19479965
1996 Structure and functional analysis of the multistress response gene DDR2 from Saccharomyces cerevisiae. Biochemical and biophysical research communications 23 8954934
2019 Parity predisposes breasts to the oncogenic action of PAPP-A and activation of the collagen receptor DDR2. Breast cancer research : BCR 22 31046834
2016 Synthesis and biological evaluation of novel dasatinib analogues as potent DDR1 and DDR2 kinase inhibitors. Chemical biology & drug design 22 27589335
2010 Expression of discoidin domain receptors (DDR2) in alcoholic liver fibrosis in rats. Archives of medical research 22 21199726
2023 Exploring the Cellular and Molecular Mechanism of Discoidin Domain Receptors (DDR1 and DDR2) in Bone Formation, Regeneration, and Its Associated Disease Conditions. International journal of molecular sciences 21 37834343
2016 The C. elegans Discoidin Domain Receptor DDR-2 Modulates the Met-like RTK-JNK Signaling Pathway in Axon Regeneration. PLoS genetics 21 27984580
2018 Recurrent, Activating Variants in the Receptor Tyrosine Kinase DDR2 Cause Warburg-Cinotti Syndrome. American journal of human genetics 20 30449416
2023 Stromal DDR2 Promotes Ovarian Cancer Metastasis through Regulation of Metabolism and Secretion of Extracellular Matrix Proteins. Molecular cancer research : MCR 19 37527178
2020 Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts. Scientific reports 19 32047176
2012 Discoidin domain receptor 2 (DDR2) regulates proliferation of endochondral cells in mice. Biochemical and biophysical research communications 19 23022180
2024 DDR2/STAT3 Positive Feedback Loop Mediates the Immunosuppressive Microenvironment by Upregulating PD-L1 and Recruiting MDSCs in Oxaliplatin-Resistant HCC. Cellular and molecular gastroenterology and hepatology 18 38969205
2018 DDR1 and DDR2 in skin. Cell adhesion & migration 18 29952722
2017 DDR2 facilitates papillary thyroid carcinoma epithelial mesenchymal transition by activating ERK2/Snail1 pathway. Oncology letters 18 29250189
2021 Tyrosine kinase-independent actions of DDR2 in tumor cells and cancer-associated fibroblasts influence tumor invasion, migration and metastasis. Journal of cell science 17 34477203
2020 Coordinated regulation of cell survival and cell cycle pathways by DDR2-dependent SRF transcription factor in cardiac fibroblasts. American journal of physiology. Heart and circulatory physiology 17 32412792
2012 DDR2 plays a role in fibroblast migration independent of adhesion ligand and collagen activated DDR2 tyrosine kinase. Biochemical and biophysical research communications 17 23131558
2022 COL10A1-DDR2 axis promotes the progression of pancreatic cancer by regulating MEK/ERK signal transduction. Frontiers in oncology 16 36530986
2016 Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non-Small Cell Lung Cancer: Double-Edged Sword of DDR2. Clinical cancer research : an official journal of the American Association for Cancer Research 16 26826182
2015 Nrp1, a Neuronal Regulator, Enhances DDR2-ERK-Runx2 Cascade in Osteoblast Differentiation via Suppression of DDR2 Degradation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 16 25924845
2014 Whole genome analyses of a well-differentiated liposarcoma reveals novel SYT1 and DDR2 rearrangements. PloS one 16 24505276
2013 Discoidin domain receptor 2 (DDR2) regulates body size and fat metabolism in mice. Transgenic research 15 24036888
2010 Discoidin domain receptor 2 (DDR2) is required for maintenance of spermatogenesis in male mice. Molecular reproduction and development 15 19681157
2023 miR-199a-3p promotes gastric cancer progression by promoting its stemness potential via DDR2 mediation. Cellular signalling 14 36813149
2021 Amplification of DDR2 mediates sorafenib resistance through NF-κB/c-Rel signaling in hepatocellular carcinoma. Cell biology international 14 33969575
2018 Coupling of a specific photoreactive triple-helical peptide to crosslinked collagen films restores binding and activation of DDR2 and VWF. Biomaterials 14 30099278
2023 Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy. Nature communications 13 37919278
2023 Novel insights into the role of Discoidin domain receptor 2 (DDR2) in cancer progression: a new avenue of therapeutic intervention. Matrix biology : journal of the International Society for Matrix Biology 13 38081526
2022 Co-expression of DDR2 and IFITM1 promotes breast cancer cell proliferation, migration and invasion and inhibits apoptosis. Journal of cancer research and clinical oncology 13 35761108
2012 DDR2 polymorphisms and mRNA expression in lung cancers of Japanese patients. Oncology letters 13 22807955
2010 The role of collagen receptors Endo180 and DDR-2 in the foreign body reaction against non-crosslinked collagen and gelatin. Biomaterials 13 21071084
2022 The tyrosine kinase inhibitor nilotinib targets the discoidin domain receptor DDR2 in calcific aortic valve stenosis. British journal of pharmacology 12 35751904
2019 Role of discoidin domain receptor 2 (DDR2) and microRNA-182 in survival of women with high-grade serous ovarian cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 30810094
2019 Heat shock protein 47 (HSP47) binds to discoidin domain-containing receptor 2 (DDR2) and regulates its protein stability. The Journal of biological chemistry 12 31570520
2018 DDR2 overexpression in oral squamous cell carcinoma is associated to lymph node metastasis. Cancer biomarkers : section A of Disease markers 12 29945346
2017 Prevalence of Mutations in Discoidin Domain-Containing Receptor Tyrosine Kinase 2 (DDR2) in Squamous Cell Lung Cancers in Korean Patients. Cancer research and treatment 12 28161936
2016 Modular Total Syntheses of the Alkaloids Discoipyrroles A and B, Potent Inhibitors of the DDR2 Signaling Pathway. Organic letters 12 26829876
2009 Transcriptome analysis reveals an unexpected role of a collagen tyrosine kinase receptor gene, Ddr2, as a regulator of ovarian function. Physiological genomics 12 19671659
2002 Elevated expression of tyrosine kinase DDR2 in primary biliary cirrhosis. Autoimmunity 12 12765478
2022 DDR2 coordinates EMT and metabolic reprogramming as a shared effector of FOXQ1 and SNAI1. Cancer research communications 11 36713812
2020 Knockdown of Long Non-Coding RNA (lncRNA) Colon Cancer-Associated Transcript-1 (CCAT1) Suppresses Oral Squamous Cell Carcinoma Proliferation, Invasion, and Migration by Inhibiting the Discoidin Domain Receptor 2 (DDR2)/ERK/AKT Axis. Medical science monitor : international medical journal of experimental and clinical research 11 32009633
2020 DDR2, a discoidin domain receptor, is a marker of periosteal osteoblast and osteoblast progenitors. Journal of bone and mineral metabolism 11 32415375
2017 Role of a novel immune modulating DDR2-expressing population in silica-induced pulmonary fibrosis. PloS one 11 28700752
2017 Mutational Landscape of DDR2 Gene in Lung Squamous Cell Carcinoma Using Next-generation Sequencing. Clinical lung cancer 11 29129434
2015 Novel DDR2 mutation identified by whole exome sequencing in a Moroccan patient with spondylo-meta-epiphyseal dysplasia, short limb-abnormal calcification type. American journal of medical genetics. Part A 11 26463668
2025 Enhanced ferroptosis sensitivity promotes the formation of highly myopic cataract via the DDR2-Hippo pathway. Cell death & disease 10 39900894

Missed literature

Know a paper Affinage missed for DDR2? Flag it for the maintainers and the community.

No submissions yet.