{"gene":"DDR1","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2024,"finding":"DDR1 and DDR2 collagen receptors are activated in dedifferentiated mesenchymal melanoma cells and control actomyosin cytoskeleton reorganization and YAP mechanotransduction pathway in response to ECM stiffness; inhibiting both DDR receptors abrogated mechano-induced behavior and drug resistance, while forced expression in melanocytic cells induced mechanical responsiveness and a less differentiated phenotype.","method":"Pharmacological inhibition of DDR1/2, forced expression in melanocytic cells, collagen-substrate stiffness assays, YAP pathway readouts, proliferation/migration/drug-resistance phenotypic assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with defined pathway placement (YAP mechanotransduction) and multiple phenotypic readouts, single preprint lab, not peer-reviewed","pmids":["bio_10.1101_2024.08.26.609700"],"is_preprint":true},{"year":2025,"finding":"DDR1 interaction with collagen stimulates formation of membrane debris structures (collagen-tracks) left behind migrating breast cancer cells along collagen fibrils, representing a novel cell-cell communication mechanism that promotes invasion.","method":"3D matrix in vitro and in vivo deposition assays, observation of collagen-track formation with and without DDR1-ECM interaction, functional transfer assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint, single lab, mechanistic role of DDR1 described briefly without direct mutagenesis or molecular dissection","pmids":["bio_10.1101_2025.01.25.634857"],"is_preprint":true},{"year":2025,"finding":"TPKI-39 engages DDR1 (along with DDR2 and FLT1) selectively in intact cells as characterized by NanoBRET cellular target engagement assays, with DDR1 engagement not observed in cell-free biochemical assays for some type II inhibitors, indicating cellular context influences DDR1 inhibitor binding.","method":"NanoBRET cellular target engagement assay, comparison with cell-free biochemical kinase assay panel","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint, single lab, characterizes inhibitor engagement rather than DDR1 mechanism per se","pmids":["bio_10.1101_2025.10.09.681452"],"is_preprint":true}],"current_model":"DDR1 is a collagen receptor kinase that, upon engagement with ECM collagen, activates actomyosin cytoskeletal reorganization and the YAP mechanotransduction pathway in dedifferentiated cancer cells, promotes formation of invasion-associated membrane structures (collagen-tracks), and can be selectively targeted by type II kinase inhibitors in a cellular-context-dependent manner."},"narrative":{"mechanistic_narrative":"DDR1 is a collagen receptor kinase that couples engagement of ECM collagen to cytoskeletal and mechanotransduction responses in cancer cells. In dedifferentiated mesenchymal melanoma cells, DDR1 together with DDR2 is activated and drives actomyosin cytoskeleton reorganization and the YAP mechanotransduction pathway in response to ECM stiffness; dual DDR inhibition abrogates this mechano-induced behavior and associated drug resistance, while forced expression of the receptors in melanocytic cells confers mechanical responsiveness and a less differentiated phenotype [PMID:bio_10.1101_2024.08.26.609700]. DDR1 can be selectively engaged in intact cells by type II kinase inhibitors in a manner not always recapitulated in cell-free biochemical assays, indicating that cellular context shapes inhibitor binding [PMID:bio_10.1101_2025.10.09.681452]. Beyond these collagen-driven, mechanotransduction, and inhibitor-engagement findings, no further molecular dissection of DDR1 signaling has been characterized in the available corpus.","teleology":[{"year":2024,"claim":"Established that DDR1, as a collagen receptor, is an upstream driver of ECM-stiffness-dependent mechanotransduction in dedifferentiated cancer cells rather than a passive adhesion receptor.","evidence":"Pharmacological DDR1/2 inhibition, forced expression in melanocytic cells, collagen-stiffness assays with YAP and phenotypic readouts in melanoma","pmids":["bio_10.1101_2024.08.26.609700"],"confidence":"Medium","gaps":["Does not separate DDR1 from DDR2 contributions","Kinase-dependence and direct molecular link to YAP activation not dissected","Preprint, single lab, not peer-reviewed"]},{"year":2025,"claim":"Linked DDR1-collagen engagement to formation of collagen-track membrane structures, proposing a cell-cell communication route that promotes invasion.","evidence":"3D matrix deposition assays in vitro and in vivo with and without DDR1-ECM interaction, plus functional transfer assays in breast cancer","pmids":["bio_10.1101_2025.01.25.634857"],"confidence":"Low","gaps":["No direct mutagenesis or molecular dissection of DDR1's role","Single preprint, single lab","Mechanism connecting DDR1 signaling to track formation undefined"]},{"year":2025,"claim":"Showed that cellular context governs DDR1 inhibitor binding, since type II inhibitors engage DDR1 in intact cells but not always in cell-free assays.","evidence":"NanoBRET cellular target engagement assay compared against cell-free biochemical kinase panel for TPKI-39 and related inhibitors","pmids":["bio_10.1101_2025.10.09.681452"],"confidence":"Low","gaps":["Characterizes inhibitor engagement, not endogenous DDR1 mechanism","Structural basis of context-dependent binding unknown","Single preprint, single lab"]},{"year":null,"claim":"How DDR1 kinase activity mechanistically couples collagen binding to YAP activation, cytoskeletal remodeling, and collagen-track formation, and whether these roles are kinase-dependent, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct DDR1 substrate or signaling intermediate identified","DDR1-specific (vs DDR2) contributions not isolated","No structural or biochemical reconstitution of collagen-induced signaling in the corpus"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q08345","full_name":"Epithelial discoidin domain-containing receptor 1","aliases":["CD167 antigen-like family member A","Cell adhesion kinase","Discoidin receptor tyrosine kinase","HGK2","Mammary carcinoma kinase 10","MCK-10","Protein-tyrosine kinase 3A","Protein-tyrosine kinase RTK-6","TRK E","Tyrosine kinase DDR","Tyrosine-protein kinase CAK"],"length_aa":913,"mass_kda":101.1,"function":"Tyrosine kinase that functions as a cell surface receptor for fibrillar collagen and regulates cell attachment to the extracellular matrix, remodeling of the extracellular matrix, cell migration, differentiation, survival and cell proliferation. Collagen binding triggers a signaling pathway that involves SRC and leads to the activation of MAP kinases. Regulates remodeling of the extracellular matrix by up-regulation of the matrix metalloproteinases MMP2, MMP7 and MMP9, and thereby facilitates cell migration and wound healing. Required for normal blastocyst implantation during pregnancy, for normal mammary gland differentiation and normal lactation. Required for normal ear morphology and normal hearing (By similarity). Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. Also plays a role in tumor cell invasion. Phosphorylates PTPN11","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q08345/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DDR1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DDR1","total_profiled":1310},"omim":[{"mim_id":"615676","title":"TESTIS DEVELOPMENT-RELATED GENE 1, NONCODING; TDRG1","url":"https://www.omim.org/entry/615676"},{"mim_id":"603075","title":"MACULAR DEGENERATION, AGE-RELATED, 1; ARMD1","url":"https://www.omim.org/entry/603075"},{"mim_id":"600408","title":"DISCOIDIN DOMAIN RECEPTOR FAMILY, MEMBER 1; DDR1","url":"https://www.omim.org/entry/600408"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DDR1"},"hgnc":{"alias_symbol":["RTK6","CD167"],"prev_symbol":["NTRK4","PTK3A","NEP","CAK","EDDR1"]},"alphafold":{"accession":"Q08345","domains":[{"cath_id":"2.60.120.260","chopping":"27-185","consensus_level":"high","plddt":93.6113,"start":27,"end":185},{"cath_id":"2.60.120.1190","chopping":"190-367","consensus_level":"high","plddt":92.3035,"start":190,"end":367},{"cath_id":"3.30.200.20","chopping":"603-703","consensus_level":"medium","plddt":87.5257,"start":603,"end":703},{"cath_id":"1.10.510.10","chopping":"706-720_736-913","consensus_level":"medium","plddt":90.498,"start":706,"end":913}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08345","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08345-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08345-F1-predicted_aligned_error_v6.png","plddt_mean":76.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DDR1","jax_strain_url":"https://www.jax.org/strain/search?query=DDR1"},"sequence":{"accession":"Q08345","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08345.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08345/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08345"}},"corpus_meta":[{"pmid":null,"id":"bio_10.1101_2025.11.26.690649","title":"Loss of ESE3/EHF is sufficient to promote cell plasticity, transformation and androgen-independent status in the early stage of prostate carcinogenesis","date":"2025-11-30","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.26.690649","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.09.681452","title":"Cellular Context Influences Kinase Inhibitor Selectivity","date":"2025-10-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.09.681452","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.30.25337017","title":"Surface Markers on Supermeres Outperform Extracellular Vesicles in Cancer Diagnosis","date":"2025-10-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.30.25337017","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.26.609700","title":"Extracellular matrix stiffness determines the phenotypic behavior of dedifferentiated melanoma cells through a DDR1/2-dependent YAP mechanotransduction pathway","date":"2024-08-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.26.609700","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.25.634857","title":"Cancer cells transfer invasive properties through microRNAs contained in collagen-tracks","date":"2025-01-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.25.634857","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4555,"output_tokens":834,"usd":0.013088,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7308,"output_tokens":1417,"usd":0.035983,"stage2_stop_reason":"end_turn"},"total_usd":0.049071,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"DDR1 and DDR2 collagen receptors are activated in dedifferentiated mesenchymal melanoma cells and control actomyosin cytoskeleton reorganization and YAP mechanotransduction pathway in response to ECM stiffness; inhibiting both DDR receptors abrogated mechano-induced behavior and drug resistance, while forced expression in melanocytic cells induced mechanical responsiveness and a less differentiated phenotype.\",\n      \"method\": \"Pharmacological inhibition of DDR1/2, forced expression in melanocytic cells, collagen-substrate stiffness assays, YAP pathway readouts, proliferation/migration/drug-resistance phenotypic assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with defined pathway placement (YAP mechanotransduction) and multiple phenotypic readouts, single preprint lab, not peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.08.26.609700\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDR1 interaction with collagen stimulates formation of membrane debris structures (collagen-tracks) left behind migrating breast cancer cells along collagen fibrils, representing a novel cell-cell communication mechanism that promotes invasion.\",\n      \"method\": \"3D matrix in vitro and in vivo deposition assays, observation of collagen-track formation with and without DDR1-ECM interaction, functional transfer assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint, single lab, mechanistic role of DDR1 described briefly without direct mutagenesis or molecular dissection\",\n      \"pmids\": [\"bio_10.1101_2025.01.25.634857\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TPKI-39 engages DDR1 (along with DDR2 and FLT1) selectively in intact cells as characterized by NanoBRET cellular target engagement assays, with DDR1 engagement not observed in cell-free biochemical assays for some type II inhibitors, indicating cellular context influences DDR1 inhibitor binding.\",\n      \"method\": \"NanoBRET cellular target engagement assay, comparison with cell-free biochemical kinase assay panel\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint, single lab, characterizes inhibitor engagement rather than DDR1 mechanism per se\",\n      \"pmids\": [\"bio_10.1101_2025.10.09.681452\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DDR1 is a collagen receptor kinase that, upon engagement with ECM collagen, activates actomyosin cytoskeletal reorganization and the YAP mechanotransduction pathway in dedifferentiated cancer cells, promotes formation of invasion-associated membrane structures (collagen-tracks), and can be selectively targeted by type II kinase inhibitors in a cellular-context-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDR1 is a collagen receptor kinase that couples engagement of ECM collagen to cytoskeletal and mechanotransduction responses in cancer cells. In dedifferentiated mesenchymal melanoma cells, DDR1 together with DDR2 is activated and drives actomyosin cytoskeleton reorganization and the YAP mechanotransduction pathway in response to ECM stiffness; dual DDR inhibition abrogates this mechano-induced behavior and associated drug resistance, while forced expression of the receptors in melanocytic cells confers mechanical responsiveness and a less differentiated phenotype [#0]. DDR1 can be selectively engaged in intact cells by type II kinase inhibitors in a manner not always recapitulated in cell-free biochemical assays, indicating that cellular context shapes inhibitor binding [#2]. Beyond these collagen-driven, mechanotransduction, and inhibitor-engagement findings, no further molecular dissection of DDR1 signaling has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that DDR1, as a collagen receptor, is an upstream driver of ECM-stiffness-dependent mechanotransduction in dedifferentiated cancer cells rather than a passive adhesion receptor.\",\n      \"evidence\": \"Pharmacological DDR1/2 inhibition, forced expression in melanocytic cells, collagen-stiffness assays with YAP and phenotypic readouts in melanoma\",\n      \"pmids\": [\"bio_10.1101_2024.08.26.609700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not separate DDR1 from DDR2 contributions\", \"Kinase-dependence and direct molecular link to YAP activation not dissected\", \"Preprint, single lab, not peer-reviewed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked DDR1-collagen engagement to formation of collagen-track membrane structures, proposing a cell-cell communication route that promotes invasion.\",\n      \"evidence\": \"3D matrix deposition assays in vitro and in vivo with and without DDR1-ECM interaction, plus functional transfer assays in breast cancer\",\n      \"pmids\": [\"bio_10.1101_2025.01.25.634857\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mutagenesis or molecular dissection of DDR1's role\", \"Single preprint, single lab\", \"Mechanism connecting DDR1 signaling to track formation undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that cellular context governs DDR1 inhibitor binding, since type II inhibitors engage DDR1 in intact cells but not always in cell-free assays.\",\n      \"evidence\": \"NanoBRET cellular target engagement assay compared against cell-free biochemical kinase panel for TPKI-39 and related inhibitors\",\n      \"pmids\": [\"bio_10.1101_2025.10.09.681452\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Characterizes inhibitor engagement, not endogenous DDR1 mechanism\", \"Structural basis of context-dependent binding unknown\", \"Single preprint, single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DDR1 kinase activity mechanistically couples collagen binding to YAP activation, cytoskeletal remodeling, and collagen-track formation, and whether these roles are kinase-dependent, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct DDR1 substrate or signaling intermediate identified\", \"DDR1-specific (vs DDR2) contributions not isolated\", \"No structural or biochemical reconstitution of collagen-induced signaling in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie"}}