DDR1 (discoidin domain receptor 1) is a single-pass type I receptor tyrosine kinase that is activated by native triple-helical collagen. Its N-terminal discoidin domain binds the GVMGFO motif of fibrillar collagens I-III and, unlike its paralog DDR2, also recognises basement-membrane collagen IV. DDR1 exists as ligand-independent dimers at the plasma membrane; collagen binding induces slow, sustained autophosphorylation of cytoplasmic tyrosines that recruit SH2- and PTB-domain signalling proteins such as ShcA (in the DDR1b splice form), Nck2 and SHP-2. DDR1 is expressed mainly in epithelial cells and regulates cell adhesion to collagen, migration, matrix-metalloproteinase expression and survival. Mouse knockouts show defects in mammary gland morphogenesis and lactation, blastocyst implantation and body size, and DDR1 is overexpressed in several carcinomas.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: Kinase-domain InterPro mapping; refine to the collagen receptor kinase activity. Reason: DDR1 is an active receptor tyrosine kinase, but the informative activity is collagen-triggered receptor kinase activity. Human DDR1 binds and is activated by native triple-helical collagens (PMID:9659899, PMID:21044884), so this broad kinase term is refined to GO:0038062, which the gene already carries (IBA, IDA). This matches the DDR2 review and modules/collagen_ddr_signaling.yaml. Proposed replacements: protein tyrosine kinase collagen receptor activity Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:21044884 Triple-helical peptides containing the GVMGFO motif induced DDR1 transmembrane signalling |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000120 | MODIFY | Summary: Tyrosine kinase class from automated mapping; refine to collagen receptor kinase activity. Reason: DDR1 is an active receptor tyrosine kinase, but the informative activity is collagen-triggered receptor kinase activity. Human DDR1 binds and is activated by native triple-helical collagens (PMID:9659899, PMID:21044884), so this broad kinase term is refined to GO:0038062, which the gene already carries (IBA, IDA). This matches the DDR2 review and modules/collagen_ddr_signaling.yaml. Proposed replacements: protein tyrosine kinase collagen receptor activity Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:9659899 Stimulation of DDR receptor tyrosine kinase activity requires the native triple-helical structure of collagen |
| GO:0004714 transmembrane receptor protein tyrosine kinase activity | IEA GO_REF:0000120 | MODIFY | Summary: Generic receptor tyrosine kinase activity; refine to the collagen-specific receptor activity. Reason: DDR1 is an active receptor tyrosine kinase, but the informative activity is collagen-triggered receptor kinase activity. Human DDR1 binds and is activated by native triple-helical collagens (PMID:9659899, PMID:21044884), so this broad kinase term is refined to GO:0038062, which the gene already carries (IBA, IDA). This matches the DDR2 review and modules/collagen_ddr_signaling.yaml. Proposed replacements: protein tyrosine kinase collagen receptor activity Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. |
| GO:0004714 transmembrane receptor protein tyrosine kinase activity | TAS PMID:9659899 The discoidin domain receptor tyrosine kinases are activated... | MODIFY | Summary: The cited founding paper shows DDR1 is a collagen-activated receptor tyrosine kinase; the collagen-specific term is supported. Reason: PMID:9659899 shows that DDR1 binds native triple-helical collagen and that collagen stimulates its tyrosine kinase activity and phosphorylation of a Shc docking site. GO:0038062 (a child of transmembrane receptor protein tyrosine kinase activity) captures exactly this and is already asserted from the same paper by IDA. Proposed replacements: protein tyrosine kinase collagen receptor activity Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:9659899 Stimulation of DDR receptor tyrosine kinase activity requires the native triple-helical structure of collagen PMID:9659899 Collagen activation of DDR1 induces phosphorylation of a docking site for the Shc phosphotyrosine binding domain |
| GO:0005515 protein binding | IPI PMID:16337946 Pinpointing phosphotyrosine-dependent interactions downstrea... | MODIFY | Summary: Collagen-dependent recruitment of the SH2 adaptor NCK2 to phosphorylated DDR1. Reason: Koo et al. show that the SH2 domain-containing adaptor Nck2 binds DDR1 in a collagen-dependent, phosphotyrosine-dependent manner. DDR1 supplies the phosphotyrosine docking site and the partner binds through its SH2 domain, so the informative MF for DDR1 is SH2 domain binding. Bare protein binding is uninformative per project policy. Proposed replacements: SH2 domain binding Supporting Evidence: PMID:16337946 Nck2 and Shp-2, two SH2 domain-containing proteins, bind to DDR1 in a collagen-dependent manner |
| GO:0005515 protein binding | IPI PMID:16337946 Pinpointing phosphotyrosine-dependent interactions downstrea... | MODIFY | Summary: Collagen-dependent recruitment of SHP-2 (PTPN11) SH2 domains to DDR1 pTyr740. Reason: SHP-2 binds DDR1 phospho-Tyr740 within an ITIM consensus in a collagen-dependent manner via its SH2 domains (PMID:16337946). Refine generic protein binding to SH2 domain binding, describing DDR1 as the docking-site provider. Proposed replacements: SH2 domain binding Supporting Evidence: PMID:16337946 Nck2 and Shp-2, two SH2 domain-containing proteins, bind to DDR1 in a collagen-dependent manner PMID:16337946 The binding site of Shp-2 was mapped to tyrosine-740 of DDR1 within an ITIM-consensus sequence |
| GO:0005515 protein binding | IPI PMID:18190796 KIBRA interacts with discoidin domain receptor 1 to modulate... | MODIFY | Summary: DDR1 PPxY motif binds the WW domains of KIBRA (WWC1). Reason: Hilton et al. show that KIBRA binds a PPxY WW-domain binding motif in DDR1 and dissociates on collagen I or IV treatment. The DDR1-side function is WW domain binding (GO:0050699), more informative than protein binding. Proposed replacements: WW domain binding Supporting Evidence: PMID:18190796 KIBRA binds to a WW domain binding motif, PPxY, in the tyrosine kinase receptor DDR1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: BioPlex affinity-capture association between DDR1 and DDR2. Reason: High-throughput BioPlex affinity-capture MS in HEK293T and HCT116 cells reports DDR1 with DDR2 (the cached text does not discuss the pair individually). DDR2 is a receptor tyrosine kinase, so the partner-class term receptor tyrosine kinase binding is informative; this mirrors the DDR2 review of the reciprocal row. Tagged co-complex capture does not establish a direct interface or functional heterodimer. Proposed replacements: receptor tyrosine kinase binding Supporting Evidence: PMID:33961781 Here we present BioPlex 3.0, the most complete model of the human interactome to date, accompanied by a second interaction network acquired in HCT116 cells. |
| GO:0005515 protein binding | IPI PMID:35384245 Physical and functional interactome atlas of human receptor ... | MODIFY | Summary: RTK interactome reports DDR1-DDR2 association. Reason: The RTK interactome atlas (AP-MS/BioID with tagged receptors in HEK293 cells) records a DDR1-DDR2 association; DDR1 itself appears in the study as a collagen receptor bait. Refine to receptor tyrosine kinase binding, consistent with the DDR2 review of the same pair, without inferring cross-activation. Proposed replacements: receptor tyrosine kinase binding Supporting Evidence: PMID:35384245 In this study, we performed systematic AP‐MS and BioID analyses of ~ 90% of human RTKs in their activated state. |
| GO:0005518 collagen binding | IBA GO_REF:0000033 | ACCEPT | Summary: Collagen binding is conserved across the DDR clade (PTN002400507). Reason: Collagen recognition by the discoidin domain is the ligand-binding half of the DDR1 receptor activity. DDR1 binds native triple-helical fibrillar collagens I-III (GVMGFO motif) and, unlike DDR2, basement-membrane collagen IV. The PAINT node PTN002400507 covers DDR1, DDR2 and orthologs; DDR1 in its own WITH/FROM reflects its experimental grounding. Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:21044884 the basement membrane collagen IV being exclusively recognised by DDR1 |
| GO:0005518 collagen binding | IDA PMID:9659899 The discoidin domain receptor tyrosine kinases are activated... | ACCEPT | Summary: Founding demonstration that DDR1 binds collagen. Reason: Collagen recognition by the discoidin domain is the ligand-binding half of the DDR1 receptor activity. DDR1 binds native triple-helical fibrillar collagens I-III (GVMGFO motif) and, unlike DDR2, basement-membrane collagen IV. Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:9659899 Stimulation of DDR receptor tyrosine kinase activity requires the native triple-helical structure of collagen |
| GO:0005518 collagen binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer from mouse Ddr1; consistent with direct human evidence. Reason: Collagen recognition by the discoidin domain is the ligand-binding half of the DDR1 receptor activity. DDR1 binds native triple-helical fibrillar collagens I-III (GVMGFO motif) and, unlike DDR2, basement-membrane collagen IV. Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:21044884 the basement membrane collagen IV being exclusively recognised by DDR1 |
| GO:0005518 collagen binding | IMP PMID:12065315 Tyrosine kinase activity of discoidin domain receptor 1 is n... | ACCEPT | Summary: Ddr1-null SMCs fail to attach to collagen I; rescued by DDR1b and by kinase-dead DDR1. Reason: Collagen recognition by the discoidin domain is the ligand-binding half of the DDR1 receptor activity. DDR1 binds native triple-helical fibrillar collagens I-III (GVMGFO motif) and, unlike DDR2, basement-membrane collagen IV. In PMID:12065315 kinase-dead DDR1 restored attachment to collagen, consistent with collagen binding by the receptor ectodomain independent of kinase activity. Supporting Evidence: PMID:12065315 DDR1(-/-) SMCs exhibited impaired attachment to and migration toward a type I collagen substrate PMID:12065315 kinase-dead mutants of DDR1 restored attachment but not migration and MMP production |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding by the kinase domain. Reason: DDR1 has a catalytically active tyrosine kinase domain with conserved ATP-binding residues (UniProt FT BINDING 616..624, 655) and collagen-induced autophosphorylation. ATP binding is a necessary component of the kinase activity; accepted as in the DDR2 review. Supporting Evidence: file:human/DDR1/DDR1-uniprot.txt Autophosphorylated in response to fibrillar collagen binding. |
| GO:0005576 extracellular region | HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu... | KEEP AS NON CORE | Summary: Detected in human colostrum aqueous phase by proteomics. Reason: A soluble DDR1 ectodomain is released by constitutive and collagen-induced shedding, and a kinase-less isoform (DDR1d) is annotated secreted, which plausibly explains detection in colostrum. Extracellular release is not where DDR1 performs its receptor function. Supporting Evidence: PMID:24725424 Constitutive DDR1 shedding was first noticed by Alves et al. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular-location mapping from isoform 3 (Secreted). Reason: This row maps from the UniProt "Secreted" location of isoform 3 (DDR1d), which lacks the kinase domain and is likely an NMD target; shed ectodomain also exists. Peripheral to the receptor function. Supporting Evidence: file:human/DDR1/DDR1-uniprot.txt [Isoform 3]: Secreted PMID:24725424 Constitutive DDR1 shedding was first noticed by Alves et al. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane location inherited across RTKs. Reason: DDR1 is a single-pass type I membrane receptor whose discoidin domain senses extracellular collagen and whose kinase domain signals intracellularly; the plasma membrane is where the core activity happens. Supporting Evidence: file:human/DDR1/DDR1-uniprot.txt [Isoform 1]: Cell membrane; Single-pass type I membrane protein. PMID:8390675 interrupted by a predicted transmembrane sequence |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence shows plasma membrane. Reason: DDR1 is a single-pass type I membrane receptor whose discoidin domain senses extracellular collagen and whose kinase domain signals intracellularly; the plasma membrane is where the core activity happens. Supporting Evidence: file:human/DDR1/DDR1-uniprot.txt [Isoform 1]: Cell membrane; Single-pass type I membrane protein. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Automated plasma membrane assignment. Reason: DDR1 is a single-pass type I membrane receptor whose discoidin domain senses extracellular collagen and whose kinase domain signals intracellularly; the plasma membrane is where the core activity happens. Supporting Evidence: file:human/DDR1/DDR1-uniprot.txt [Isoform 1]: Cell membrane; Single-pass type I membrane protein. |
| GO:0005886 plasma membrane | TAS PMID:8390675 A receptor tyrosine kinase found in breast carcinoma cells h... | ACCEPT | Summary: Original cloning paper predicts a transmembrane receptor. Reason: DDR1 is a single-pass type I membrane receptor whose discoidin domain senses extracellular collagen and whose kinase domain signals intracellularly; the plasma membrane is where the core activity happens. Supporting Evidence: PMID:8390675 interrupted by a predicted transmembrane sequence |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2327738 | ACCEPT | Summary: Reactome places DDR1 collagen binding at the plasma membrane. Reason: DDR1 is a single-pass type I membrane receptor whose discoidin domain senses extracellular collagen and whose kinase domain signals intracellularly; the plasma membrane is where the core activity happens. Supporting Evidence: Reactome:R-HSA-2327738 DDR1 binds several of the major fibrillar collagens (types I, II, III, and V) and the non-fibrillar collagen IV |
| GO:0007155 cell adhesion | TAS PMID:8302582 Identification and chromosomal mapping of a receptor tyrosin... | MODIFY | Summary: Speculative cell-adhesion role from the cloning paper; DDR1 does mediate attachment to collagen matrix. Reason: The 1994 cloning paper inferred an adhesion role from domain architecture only (cell-cell interactions). Later experiments show DDR1 mediates cell attachment to collagen substrates, kinase-independently (PMID:12065315), which is cell-matrix adhesion; the gene already carries the descendant smooth muscle cell-matrix adhesion. Refine the general term to GO:0007160 cell-matrix adhesion. Proposed replacements: cell-matrix adhesion Supporting Evidence: PMID:8302582 The structure of this receptor kinase suggests that it belongs to a new family of receptors involved in cell-cell interactions PMID:12065315 DDR1(-/-) SMCs exhibited impaired attachment to and migration toward a type I collagen substrate PMID:12065315 kinase-dead mutants of DDR1 restored attachment but not migration and MMP production |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: Generic RTK signaling; refine to the collagen-activated pathway. Reason: DDR1 is a receptor tyrosine kinase; the specific pathway it initiates is the collagen-activated tyrosine kinase receptor signaling pathway (GO:0038063), a descendant already asserted by IDA/IMP. Consistent with the DDR2 review. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001230349 SUPPORTS TRANSFER Deep RTK node correctly asserts generic RTK signalling for all descendants; DDR1 is within the clade. The claim is true but the collagen-specific descendant GO:0038063 is supported for DDR1 by direct evidence, so the row is refined rather than challenged. Proposed replacements: collagen-activated tyrosine kinase receptor signaling pathway Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:21044884 Triple-helical peptides containing the GVMGFO motif induced DDR1 transmembrane signalling |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: Generic RTK signaling from InterPro; refine to the collagen-activated pathway. Reason: Refine to GO:0038063 as for the IBA row; direct human evidence shows collagen triggers DDR1 signalling. Proposed replacements: collagen-activated tyrosine kinase receptor signaling pathway Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:21044884 Triple-helical peptides containing the GVMGFO motif induced DDR1 transmembrane signalling |
| GO:0010715 regulation of extracellular matrix disassembly | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer of DDR1 regulation of matrix disassembly. Reason: Ddr1-null aortic SMCs have reduced MMP-2 and MMP-9 activity, rescued by DDR1b but not kinase-dead DDR1. MMP induction is a downstream output of collagen-DDR1 signalling, not a core receptor activity. Supporting Evidence: PMID:12065315 Matrix metalloproteinase-2 (MMP-2) and MMP-9 activities were concomitantly reduced in these cells PMID:12065315 kinase-dead mutants of DDR1 restored attachment but not migration and MMP production |
| GO:0010715 regulation of extracellular matrix disassembly | IMP PMID:12065315 Tyrosine kinase activity of discoidin domain receptor 1 is n... | KEEP AS NON CORE | Summary: DDR1 kinase is required for MMP-2/9 activity in SMCs. Reason: Ddr1-null aortic SMCs have reduced MMP-2 and MMP-9 activity, rescued by DDR1b but not kinase-dead DDR1. MMP induction is a downstream output of collagen-DDR1 signalling, not a core receptor activity. Supporting Evidence: PMID:12065315 Matrix metalloproteinase-2 (MMP-2) and MMP-9 activities were concomitantly reduced in these cells PMID:12065315 kinase-dead mutants of DDR1 restored attachment but not migration and MMP production |
| GO:0014909 smooth muscle cell migration | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer; SMC migration. Reason: DDR1 kinase activity is needed for SMC migration toward collagen I (PMID:12065315), a cell-type-specific outcome of collagen receptor signalling. Supporting Evidence: PMID:12065315 DDR1(-/-) SMCs exhibited impaired attachment to and migration toward a type I collagen substrate PMID:12065315 kinase-dead mutants of DDR1 restored attachment but not migration and MMP production |
| GO:0014909 smooth muscle cell migration | IMP PMID:12065315 Tyrosine kinase activity of discoidin domain receptor 1 is n... | KEEP AS NON CORE | Summary: Ddr1-null SMCs migrate poorly toward collagen I. Reason: DDR1 kinase activity is needed for SMC migration toward collagen I (PMID:12065315), a cell-type-specific outcome of collagen receptor signalling. Supporting Evidence: PMID:12065315 DDR1(-/-) SMCs exhibited impaired attachment to and migration toward a type I collagen substrate PMID:12065315 kinase-dead mutants of DDR1 restored attachment but not migration and MMP production |
| GO:0016020 membrane | IEA GO_REF:0000002 | TOO GENERAL | Summary: Membrane; entailed by the accepted plasma membrane term. Reason: True but uninformative: the more specific plasma membrane term is accepted elsewhere in this review. Supporting Evidence: file:human/DDR1/DDR1-uniprot.txt [Isoform 1]: Cell membrane; Single-pass type I membrane protein. |
| GO:0038062 protein tyrosine kinase collagen receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved collagen receptor kinase activity of the DDR clade. Reason: DDR1 binds native triple-helical collagen through its discoidin domain and this stimulates its tyrosine kinase activity (PMID:9659899). GVMGFO-containing triple-helical peptides from fibrillar collagens induce DDR1 signalling, and DDR1 uniquely recognises collagen IV (PMID:21044884). This is the core molecular function. PTN002400507 places this at the DDR subfamily node. Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. |
| GO:0038062 protein tyrosine kinase collagen receptor activity | IDA PMID:21044884 Collagen binding specificity of the discoidin domain recepto... | ACCEPT | Summary: Collagen-motif peptides activate DDR1; collagen IV recognised by DDR1. Reason: DDR1 binds native triple-helical collagen through its discoidin domain and this stimulates its tyrosine kinase activity (PMID:9659899). GVMGFO-containing triple-helical peptides from fibrillar collagens induce DDR1 signalling, and DDR1 uniquely recognises collagen IV (PMID:21044884). This is the core molecular function. Supporting Evidence: PMID:21044884 Triple-helical peptides containing the GVMGFO motif induced DDR1 transmembrane signalling PMID:21044884 the basement membrane collagen IV being exclusively recognised by DDR1 |
| GO:0038062 protein tyrosine kinase collagen receptor activity | IDA PMID:9659899 The discoidin domain receptor tyrosine kinases are activated... | ACCEPT | Summary: Collagen activates DDR1 kinase. Reason: DDR1 binds native triple-helical collagen through its discoidin domain and this stimulates its tyrosine kinase activity (PMID:9659899). GVMGFO-containing triple-helical peptides from fibrillar collagens induce DDR1 signalling, and DDR1 uniquely recognises collagen IV (PMID:21044884). This is the core molecular function. Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:9659899 Stimulation of DDR receptor tyrosine kinase activity requires the native triple-helical structure of collagen |
| GO:0038062 protein tyrosine kinase collagen receptor activity | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction; correct and supported by direct evidence. Reason: DDR1 binds native triple-helical collagen through its discoidin domain and this stimulates its tyrosine kinase activity (PMID:9659899). GVMGFO-containing triple-helical peptides from fibrillar collagens induce DDR1 signalling, and DDR1 uniquely recognises collagen IV (PMID:21044884). This is the core molecular function. Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:21044884 Triple-helical peptides containing the GVMGFO motif induced DDR1 transmembrane signalling |
| GO:0038063 collagen-activated tyrosine kinase receptor signaling pathway | IDA PMID:21044884 Collagen binding specificity of the discoidin domain recepto... | ACCEPT | Summary: GVMGFO peptides induce DDR1 transmembrane signalling. Reason: Collagen binding triggers DDR1 autophosphorylation and phosphotyrosine docking-site formation (Shc, Nck2, SHP-2) that initiates downstream signalling; DDR1 is the receptor that executes the first steps of this pathway. Supporting Evidence: PMID:21044884 Triple-helical peptides containing the GVMGFO motif induced DDR1 transmembrane signalling |
| GO:0038063 collagen-activated tyrosine kinase receptor signaling pathway | IDA PMID:9659899 The discoidin domain receptor tyrosine kinases are activated... | ACCEPT | Summary: Collagen-induced DDR1 phosphorylation of a Shc docking site. Reason: Collagen binding triggers DDR1 autophosphorylation and phosphotyrosine docking-site formation (Shc, Nck2, SHP-2) that initiates downstream signalling; DDR1 is the receptor that executes the first steps of this pathway. Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:9659899 Collagen activation of DDR1 induces phosphorylation of a docking site for the Shc phosphotyrosine binding domain |
| GO:0038063 collagen-activated tyrosine kinase receptor signaling pathway | IMP PMID:12065315 Tyrosine kinase activity of discoidin domain receptor 1 is n... | ACCEPT | Summary: DDR1 kinase required for collagen-induced SMC migration and MMP production. Reason: Collagen binding triggers DDR1 autophosphorylation and phosphotyrosine docking-site formation (Shc, Nck2, SHP-2) that initiates downstream signalling; DDR1 is the receptor that executes the first steps of this pathway. Supporting Evidence: PMID:12065315 kinase-dead mutants of DDR1 restored attachment but not migration and MMP production |
| GO:0038083 peptidyl-tyrosine autophosphorylation | IDA PMID:21044884 Collagen binding specificity of the discoidin domain recepto... | ACCEPT | Summary: Collagen-peptide-induced DDR1 tyrosine autophosphorylation. Reason: DDR1 activation is read out as autophosphorylation of cytoplasmic tyrosines; this is an intrinsic step of the receptor mechanism. Supporting Evidence: PMID:21044884 which results in slow and sustained autophosphorylation of cytoplasmic tyrosine residues PMID:21044884 Triple-helical peptides containing the GVMGFO motif induced DDR1 transmembrane signalling |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | ACCEPT | Summary: RTKs form signaling receptor complexes; DDRs are pre-formed dimers. Reason: DDRs form ligand-independent stable non-covalent dimers that bind collagen as dimers; DDR1 is therefore part of a homodimeric signalling receptor complex. Consistent with the DDR2 review. Supporting Evidence: PMID:24725424 The DDRs are unusual RTKs in that they form ligand-independent stable dimers that are non-covalently linked |
| GO:0043235 signaling receptor complex | IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | ACCEPT | Summary: MGI IDA from a PX-FERM (SNX17/SNX27/SNX31) cargo study; receptor-complex membership is consistent with DDR1 being a pre-formed dimer. Reason: The cached full text of PMID:23382219 does not name DDR1 (the receptor tyrosine kinase cargo panel is presumably in figures or supplementary data), so the exact data the curator used could not be checked. The claim itself is sound: DDRs form ligand-independent stable dimers and bind collagen as dimers, i.e. DDR1 is part of a signalling receptor complex. Deferring to the curator per project policy, and consistent with the accepted IBA row. Supporting Evidence: PMID:24725424 The DDRs are unusual RTKs in that they form ligand-independent stable dimers that are non-covalently linked |
| GO:0044319 wound healing, spreading of cells | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer; wound healing cell spreading. Reason: UniProt summarises that DDR1 promotes SMC migration and thereby contributes to arterial wound healing. The underlying evidence (PMID:12065315) is SMC migration toward collagen in vitro; wound healing is a tissue-level outcome of that signalling. Supporting Evidence: file:human/DDR1/DDR1-uniprot.txt Promotes smooth muscle cell migration, and thereby contributes to arterial wound healing. |
| GO:0044319 wound healing, spreading of cells | IMP PMID:12065315 Tyrosine kinase activity of discoidin domain receptor 1 is n... | KEEP AS NON CORE | Summary: SMC migration defect in Ddr1-null cells. Reason: UniProt summarises that DDR1 promotes SMC migration and thereby contributes to arterial wound healing. The underlying evidence (PMID:12065315) is SMC migration toward collagen in vitro; wound healing is a tissue-level outcome of that signalling. Supporting Evidence: PMID:12065315 DDR1(-/-) SMCs exhibited impaired attachment to and migration toward a type I collagen substrate PMID:12065315 kinase-dead mutants of DDR1 restored attachment but not migration and MMP production |
| GO:0046777 protein autophosphorylation | IDA PMID:9659899 The discoidin domain receptor tyrosine kinases are activated... | ACCEPT | Summary: Collagen-induced DDR1 autophosphorylation. Reason: Collagen stimulates DDR1 tyrosine kinase activity and phosphorylation of its own Shc docking site; autophosphorylation is the receptor activation mechanism. Supporting Evidence: PMID:9659899 Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. PMID:9659899 Collagen activation of DDR1 induces phosphorylation of a docking site for the Shc phosphotyrosine binding domain file:human/DDR1/DDR1-uniprot.txt Autophosphorylated in response to fibrillar collagen binding. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Context-dependent PI3K/Akt activation downstream of DDR1. Reason: DDR1 activation is linked to PI3K/Akt signalling in several cell types; this is a downstream, context-dependent output, kept as non-core as in the DDR2 review. Supporting Evidence: PMID:24725424 DDR1 activation is further linked to the PI-3 kinase/Akt signalling pathway in a variety of human normal and cancer cell lines |
| GO:0061302 smooth muscle cell-matrix adhesion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog transfer; SMC-matrix adhesion. Reason: Ddr1-null SMCs show impaired attachment to collagen I, restored by DDR1b and by kinase-dead DDR1, so DDR1 participates in SMC-collagen adhesion as an adhesion receptor. Cell-type-specific; not the core signalling function. Supporting Evidence: PMID:12065315 DDR1(-/-) SMCs exhibited impaired attachment to and migration toward a type I collagen substrate PMID:12065315 kinase-dead mutants of DDR1 restored attachment but not migration and MMP production |
| GO:0061302 smooth muscle cell-matrix adhesion | IMP PMID:12065315 Tyrosine kinase activity of discoidin domain receptor 1 is n... | KEEP AS NON CORE | Summary: Ddr1-null SMCs attach poorly to collagen I. Reason: Ddr1-null SMCs show impaired attachment to collagen I, restored by DDR1b and by kinase-dead DDR1, so DDR1 participates in SMC-collagen adhesion as an adhesion receptor. Cell-type-specific; not the core signalling function. Supporting Evidence: PMID:12065315 DDR1(-/-) SMCs exhibited impaired attachment to and migration toward a type I collagen substrate PMID:12065315 kinase-dead mutants of DDR1 restored attachment but not migration and MMP production |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: Detected in parotid saliva exosome proteome. Reason: High-throughput exosome proteomics; a plasma-membrane receptor can be carried on exosomes. No functional significance shown. Supporting Evidence: PMID:19199708 we catalogued 491 proteins in the exosome fraction of human parotid saliva |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine-learning grouping term for developmental processes. Reason: This high-level grouping class comes from an ARBA rule, not gene-specific evidence. Ddr1-null mice do show mammary gland, implantation and growth defects (PMID:11283268), but these are indirect tissue consequences of collagen receptor signalling, and the term conveys little beyond that. Supporting Evidence: PMID:11283268 the alveolar epithelium failed to secrete milk proteins into the lumen of the mammary gland PMID:24725424 The most pronounced defect are mammary gland branching abnormalities, with the epithelium failing to secrete milk. |
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Download this section (compressed HTML)Q: What DDR1 data in PMID:23382219 underlie the MGI IDA for signaling receptor complex, given that the study addresses PX-FERM binding to NPxY sorting motifs rather than receptor complex membership?
Q: Do DDR1a and DDR1b differ in which collagen-induced outputs they drive, given that only DDR1b carries the ShcA docking site?
Experiment: Compare collagen I- versus collagen IV-induced DDR1 phosphorylation sites and adaptor recruitment in epithelial cells expressing DDR1a or DDR1b only, by quantitative phosphoproteomics.
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