id: MODULE:collagen_ddr_signaling title: Collagen-DDR signaling pathway module description: >- Native triple-helical collagens in the extracellular matrix bind and activate the discoidin domain receptors (DDRs), receptor tyrosine kinases on the responding cell. Collagen binding to the discoidin domain triggers slow and sustained autophosphorylation of the receptor, which then recruits intracellular signaling proteins that regulate cell adhesion, migration, proliferation, differentiation and remodelling of the surrounding matrix. status: DRAFT scope: ABSTRACT evidence: - source_id: GO:0038063 title: collagen-activated tyrosine kinase receptor signaling pathway statement: The module is grounded in the GO biological process term for signaling initiated by collagen binding to a receptor with tyrosine kinase activity. - source_id: PMID:9659899 title: The discoidin domain receptor tyrosine kinases are activated by collagen. statement: Founding paper showing that the mammalian DDR1 and DDR2 receptors bind and are activated by native triple-helical collagens. supporting_text: >- Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. Stimulation of DDR receptor tyrosine kinase activity requires the native triple-helical structure of collagen and occurs over an extended period of time. - source_id: PMID:9659900 title: An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. statement: Founding paper identifying collagens as the ligands of the previously orphan DDR receptor tyrosine kinase family. supporting_text: >- We report that the collagens serve as ligands for the previously orphan family of discoidin domain-containing receptor-like tyrosine kinases. - source_id: PMID:24725424 title: Discoidin domain receptor functions in physiological and pathological conditions. statement: Review of DDR ligand specificity, signaling and evolution, used for the module boundary and for the collagen types that act as ligands of each receptor. supporting_text: >- While fibrillar collagens are ligands for both DDRs (Shrivastava et al., 1997; Vogel et al., 1997), non-fibrillar collagens are recognised with distinct preferences. For example, DDR1, but not DDR2, binds the basement membrane collagen type IV (Shrivastava et al., 1997; Vogel et al., 1997), while DDR2 seems to preferentially bind collagen type II (Leitinger et al., 2004) and type X (Leitinger and Kwan, 2006). - source_id: PMID:21568710 title: Transmembrane collagen receptors. statement: Review placing the DDRs among several structurally unrelated classes of transmembrane collagen receptors (integrins, glycoprotein VI, LAIR-1); only the DDR branch is modelled here. supporting_text: >- A structurally diverse group of transmembrane receptors mediates the recognition of the collagen triple helix: integrins, discoidin domain receptors, glycoprotein VI, and leukocyte-associated immunoglobulin-like receptor-1. notes: >- Boundary. The module has two steps: a collagen ligand in the extracellular matrix, and a discoidin domain receptor tyrosine kinase on the responding cell. Downstream effectors (SHC1 recruitment to phosphorylated DDR1, NCK, SHP-2/PTPN11, PYK2, SRC-family kinases, ERK1/2 and the induction of matrix metalloproteinases such as MMP1 by DDR2) are not modelled as parts; none is a defining member of the pathway across species. Other collagen receptors are different pathways and are not modelled: the collagen-binding integrins (alpha1beta1, alpha2beta1, alpha10beta1, alpha11beta1), glycoprotein VI and LAIR-1 do not have tyrosine kinase activity and belong under GO:0038065 collagen-activated signaling pathway rather than its tyrosine kinase child GO:0038063. Collagen biosynthesis, secretion and fibril or network assembly are outside the module; the ligand step starts from a native, triple-helical collagen. Taxon scope. The module is scoped to Eumetazoa (NCBITaxon:6072), the taxon placement of the PAINT DDR node PTN002400507 in PTHR24416, which propagates collagen binding and protein tyrosine kinase collagen receptor activity to the DDR clade. DDR homologues are present in cnidarians, nematodes (C. elegans ddr-1 and ddr-2) and insects (Drosophila Ddr), and collagens are older still, so both required parts exist across the clade. The representative members (human DDR1, DDR2 and collagens) are examples, not a species scope. Drosophila Ddr (Q59DZ7) is not used as a representative: the Ddr gene review (genes/DROME/Ddr, Ddr-bioinformatics/RESULTS.md) finds that dipteran Ddr has lost the beta3 lysine (VAVK becomes VAVA), the catalytic-loop asparagine (HRDLATRS) and the DFG aspartate, and that the DDR2 collagen-pocket residues Trp52 and Asp69 are not conserved, so it is a predicted pseudokinase whose collagen binding is untested. Tribolium DDR and C. elegans ddr-2 keep all three catalytic residues (the honeybee predicted model keeps two, lacking the beta3 lysine, and C. elegans ddr-1 one), so the Eumetazoan scope stands, with the dipteran branch a probable loss of the kinase step. Scope criterion, shared with neurotrophin_toll_signaling: a module takes the taxon of the PAINT nodes that ground its steps; where no PAINT node grounds a step, it takes the clade in which the ligand-receptor pairing has been tested. Here the receptor node is Eumetazoan; the collagen ligand role itself is shown only in vertebrates (see the knowledge gap). Which collagens. The ligand step is a variant set by collagen class, following the receptor preferences summarised by Leitinger (PMID:24725424): fibrillar collagens I-III activate both DDR1 and DDR2; basement-membrane collagen IV activates DDR1 but not DDR2; collagen X activates DDR2 much better than DDR1 (PMID:16806867). Collagen VIII is reported to bind DDR1 (cited in PMID:24725424) and is not modelled as a separate variant. Reactome (R-HSA-2327738, R-HSA-2465890) also lists fibrillar collagen V for both receptors; the fibrillar variant's representatives are limited to the types I-III used in the founding binding studies. The ligands are in two PANTHER families (fibrillar and type IV collagens in PTHR24023 COLLAGEN ALPHA; collagen X in PTHR15427:SF48 COLLAGEN ALPHA-1(X) CHAIN), so no family id is asserted for the ligand step as a whole; each variant carries its own family. The Drosophila genome has only three collagen genes (Col4a1, viking and Multiplexin) and no fibrillar collagen. No experiment has shown that Drosophila collagen IV (Col4a1/viking) activates Ddr, so the fly type IV chains are not representatives. The only fly ligand candidate in the literature is Multiplexin (type XV/XVIII homologue, M9ND55 in PTHR24023:SF1098), from a dominant genetic interaction with Ddr in axon ensheathment (PMID:36355066). It is not modelled as a ligand variant: genetic interaction alone does not meet the evidence bar these ligand modules use (the neurotrophin_toll_signaling module leaves out Toll-2 on the same grounds), and a variant would make a satisfiability check count the fly ligand step as filled. It is recorded in the knowledge gap instead. In C. elegans the transmembrane collagen COL-99 acts genetically with ddr-1 and ddr-2 in axon guidance, also without biochemical evidence of binding; it is not modelled. Ligand function term. Each ligand annoton uses GO:0048018 receptor ligand activity, following the GO-CAM signaling receptor guideline that a ligand enables receptor ligand activity or a child. No child of receptor ligand activity fits a matrix collagen (the children are hormone, cytokine, growth factor, chemoattractant/chemorepellent, morphogen and similar activities). The main activity of these collagens is structural (GO:0005201 extracellular matrix structural constituent and related terms); that is not the role they play in this module and is not used for the ligand step. The receptor-side GO:0005518 collagen binding is a binding term carried by the receptors, not a ligand activity. Receptor family and function term. Human DDR1 (PTHR24416:SF333), DDR2 (PTHR24416:SF295) and Drosophila Ddr (PTHR24416:SF580) are in PANTHER family PTHR24416 TYROSINE-PROTEIN KINASE RECEPTOR (UniProt PANTHER cross-references), a broad receptor tyrosine kinase family; the role is restricted to the DDR subfamilies under PTN002400507. The receptor step uses GO:0038062 protein tyrosine kinase collagen receptor activity, the term asserted at PTN002400507 and carried by human DDR1 and DDR2 by IDA (PMID:9659899). Annotation state (QuickGO, queried 2026-11-06). Human: DDR1 (Q08345) and DDR2 (Q16832) enable GO:0038062 (IDA, PMID:9659899; IBA from PTN002400507) and are involved in GO:0038063 (DDR1 IDA PMID:9659899, PMID:21044884 and IMP PMID:12065315; DDR2 IDA PMID:16186108). Of the collagens, only COL4A2 (P08572, IBA from PTN000615596) and COL4A6 (Q14031, IBA from PTN000615545) are annotated to GO:0038063; COL1A1, COL1A2, COL2A1, COL3A1, COL4A1 and COL10A1 are not, and no human collagen has GO:0048018 receptor ligand activity or any descendant. Drosophila: Ddr (Q59DZ7) enables GO:0038062 and GO:0005518 (IBA from PTN002400507) and is involved in GO:0038063 (IEA, GO_REF:0000108 inferred from the MF); Multiplexin (M9ND55), Col4a1 (P08120) and viking (Q9VMV5) have no annotation to GO:0038063 and no receptor ligand activity. No human or fly protein is annotated to GO:0038065 through a collagen. Gene reviews. The human DDR1 and DDR2 reviews have GO:0038062 as their core molecular function. The Drosophila Ddr review does not (see the scope note): it MODIFIES the GO:0038062 IBA to GO:0004888 and gives Ddr's core role as wrapping-glia axon ensheathment (PMID:36355066). Reviews exist for COL1A1, COL1A2, COL2A1, COL3A1, COL4A1 and COL10A1; they keep the Reactome DDR1/DDR2 binding events as ligand context, and the COL1A1 review (updated alongside interpro/panther/PTHR24023/PTHR24023-review.yaml) carries a second core function for receptor ligand activity (GO:0048018) in collagen-activated tyrosine kinase receptor signaling pathway (GO:0038063), whereas COL1A2, COL2A1, COL3A1, COL4A1 and COL10A1 have not yet had a DDR ligand core function added (the GO:0048018 refinement proposed in the COL3A1 review is for its LAIR1 ligand role, not DDR). Receptor preference. The DDR1/DDR2 preference of each collagen class is stated in the variant labels and in this note only; the receptor step is a single annoton for both receptors with one connection, so the pairing (for example collagen IV with DDR1 but not DDR2) is not modelled in machine-readable form. module: id: collagen_ddr_signaling label: Collagen-DDR signaling pathway module_type: SIGNALING_PATHWAY description: >- A native triple-helical collagen in the extracellular matrix binds the discoidin domain of a DDR receptor tyrosine kinase on the responding cell and activates its kinase. concepts: - preferred_term: collagen-activated tyrosine kinase receptor signaling pathway term: id: GO:0038063 label: collagen-activated tyrosine kinase receptor signaling pathway context: taxa: - preferred_term: Eumetazoa term: id: NCBITaxon:6072 label: Eumetazoa parts: - order: 1 role: matrix ligand node: id: collagen_ligand label: Collagen ligand module_type: SIGNALING_PATHWAY description: A native, triple-helical collagen in the extracellular matrix that binds the discoidin domain of a DDR receptor. Different collagen classes have different receptor preferences. variant_sets: - id: collagen_ligand_class label: Collagen ligand by collagen class axis: collagen class (receptor preference) selection: ONE_OR_MORE evidence: - source_id: PMID:24725424 statement: Fibrillar collagens are ligands for both DDRs; collagen IV binds DDR1 but not DDR2; DDR2 prefers collagens II and X. supporting_text: >- DDR1, but not DDR2, binds the basement membrane collagen type IV (Shrivastava et al., 1997; Vogel et al., 1997), while DDR2 seems to preferentially bind collagen type II (Leitinger et al., 2004) and type X (Leitinger and Kwan, 2006). variants: - id: fibrillar_collagen_ligand label: Fibrillar collagen (types I-III; DDR1 and DDR2) module_type: SIGNALING_PATHWAY annotons: - id: fibrillar_collagen_ddr_ligand label: Fibrillar collagen DDR ligand participant: selector_type: FAMILY family: preferred_term: Fibrillar collagens (types I, II and III) term: id: PANTHER:PTHR24023 label: COLLAGEN ALPHA description: >- PTHR24023 contains most collagen alpha chains, including many that are not known DDR ligands. The role here is restricted to the chains of the fibrillar collagens I, II and III, which carry the GVMGFO motif bound by both DDRs. representative_members: - preferred_term: COL1A1 term: id: UniProtKB:P02452 label: Collagen alpha-1(I) chain - preferred_term: COL1A2 term: id: UniProtKB:P08123 label: Collagen alpha-2(I) chain - preferred_term: COL2A1 term: id: UniProtKB:P02458 label: Collagen alpha-1(II) chain - preferred_term: COL3A1 term: id: UniProtKB:P02461 label: Collagen alpha-1(III) chain function: preferred_term: receptor ligand activity term: id: GO:0048018 label: receptor ligand activity processes: - preferred_term: collagen-activated tyrosine kinase receptor signaling pathway term: id: GO:0038063 label: collagen-activated tyrosine kinase receptor signaling pathway locations: - preferred_term: extracellular matrix term: id: GO:0031012 label: extracellular matrix role_description: Triple-helical fibrillar collagen that binds and activates both DDR1 and DDR2. evidence: - source_id: PMID:20004161 title: Crystallographic insight into collagen recognition by discoidin domain receptor 2. statement: The major DDR2-binding site in collagens I-III is a GVMGFO motif; its structure bound to the DDR2 discoidin domain is solved. supporting_text: >- The major DDR2-binding site in collagens I-III is a GVMGFO motif (O is hydroxyproline) that also binds the matricellular protein SPARC. - source_id: Reactome:R-HSA-2327738 title: DDR1 binds collagen type I, II, III, IV, V, XI fibrils statement: Reactome records the fibrillar collagens I, II, III and V, and collagen IV, as DDR1 ligands. supporting_text: >- DDR1 binds several of the major fibrillar collagens (types I, II, III, and V) and the non-fibrillar collagen IV - source_id: Reactome:R-HSA-2465890 title: DDR2 binds collagen type I, II, III, V, X fibrils statement: Reactome records the fibrillar collagens I, II, III and V, and collagen X, as DDR2 ligands. supporting_text: >- DDR2 binds the major fibrillar collagens types I, II, III, and V) and the non-fibrillar collagen X - id: type_iv_collagen_ligand label: Basement-membrane collagen IV (DDR1) module_type: SIGNALING_PATHWAY annotons: - id: type_iv_collagen_ddr_ligand label: Collagen IV DDR1 ligand participant: selector_type: FAMILY family: preferred_term: Collagen IV alpha chains term: id: PANTHER:PTHR24023 label: COLLAGEN ALPHA description: >- Restricted to the network-forming basement-membrane collagen IV chains in PTHR24023. Collagen IV lacks the GVMGFO motif and is bound by DDR1 but not DDR2. representative_members: - preferred_term: COL4A1 term: id: UniProtKB:P02462 label: Collagen alpha-1(IV) chain - preferred_term: COL4A2 term: id: UniProtKB:P08572 label: Collagen alpha-2(IV) chain ancestral_nodes: - preferred_term: PAINT node PTN000615596 (collagen alpha-2(IV) lineage) term: id: PANTHER:PTN000615596 label: PTN000615596 description: >- Local PAINT IBD node in PTHR24023 (taxon:32524, Amniota) seeded only by mouse Col4a2 (MGI:MGI:88455), with the single propagated term P:GO:0038063 collagen-activated tyrosine kinase receptor signaling pathway; human COL4A2 inherits it as IBA. The node asserts the pathway, not the step's ligand function (GO:0048018); no PAINT node in PTHR24023 asserts a receptor ligand activity. evidence: - source_id: GO_REF:0000033 statement: IBD propagation of GO:0038063 from PAINT node PTN000615596 in PTHR24023. function: preferred_term: receptor ligand activity term: id: GO:0048018 label: receptor ligand activity processes: - preferred_term: collagen-activated tyrosine kinase receptor signaling pathway term: id: GO:0038063 label: collagen-activated tyrosine kinase receptor signaling pathway locations: - preferred_term: extracellular matrix term: id: GO:0031012 label: extracellular matrix role_description: Basement-membrane collagen IV that binds and activates DDR1. evidence: - source_id: PMID:24725424 statement: DDR1, but not DDR2, binds collagen IV. supporting_text: >- DDR1, but not DDR2, binds the basement membrane collagen type IV - id: type_x_collagen_ligand label: Collagen X (DDR2) module_type: SIGNALING_PATHWAY annotons: - id: type_x_collagen_ddr_ligand label: Collagen X DDR2 ligand participant: selector_type: FAMILY family: preferred_term: Collagen alpha-1(X) chain term: id: PANTHER:PTHR15427:SF48 label: COLLAGEN ALPHA-1(X) CHAIN description: >- Collagen X is a short-chain collagen with a C-terminal C1q-like NC1 domain, classified in PANTHER family PTHR15427 rather than PTHR24023. representative_members: - preferred_term: COL10A1 term: id: UniProtKB:Q03692 label: Collagen alpha-1(X) chain function: preferred_term: receptor ligand activity term: id: GO:0048018 label: receptor ligand activity processes: - preferred_term: collagen-activated tyrosine kinase receptor signaling pathway term: id: GO:0038063 label: collagen-activated tyrosine kinase receptor signaling pathway locations: - preferred_term: extracellular matrix term: id: GO:0031012 label: extracellular matrix role_description: Hypertrophic-cartilage collagen X that binds DDR2 and stimulates its autophosphorylation through its triple-helical region. evidence: - source_id: PMID:16806867 title: The discoidin domain receptor DDR2 is a receptor for type X collagen. statement: Collagen X binds the DDR2 extracellular domain with high affinity and stimulates DDR2 autophosphorylation; it is a much weaker DDR1 ligand. supporting_text: >- Collagen X was found to be a much better ligand for DDR2 than for DDR1. Collagen X bound to the DDR2 extracellular domain with high affinity and stimulated DDR2 autophosphorylation, the first step in transmembrane signalling. - order: 2 role: receptor node: id: ddr_receptor label: Discoidin domain receptor module_type: SIGNALING_PATHWAY description: Transmembrane discoidin domain receptor tyrosine kinase on the responding cell. The discoidin domain binds triple-helical collagen, and binding induces slow, sustained autophosphorylation of the kinase. annotons: - id: ddr_receptor_family label: DDR collagen receptor tyrosine kinase participant: selector_type: FAMILY family: preferred_term: Discoidin domain receptors (DDR1, DDR2) term: id: PANTHER:PTHR24416 label: TYROSINE-PROTEIN KINASE RECEPTOR description: >- PTHR24416 is a broad receptor tyrosine kinase family. The role is restricted to the discoidin domain receptor subfamilies PTHR24416:SF333 (EPITHELIAL DISCOIDIN DOMAIN-CONTAINING RECEPTOR 1), SF295 (DISCOIDIN DOMAIN-CONTAINING RECEPTOR 2) and SF580 (DISCOIDIN DOMAIN RECEPTOR, ISOFORM F; Drosophila Ddr) under PAINT node PTN002400507. representative_members: - preferred_term: DDR1 term: id: UniProtKB:Q08345 label: Epithelial discoidin domain-containing receptor 1 - preferred_term: DDR2 term: id: UniProtKB:Q16832 label: Discoidin domain-containing receptor 2 ancestral_nodes: - preferred_term: PAINT node PTN002400507 (DDR collagen receptors) term: id: PANTHER:PTN002400507 label: PTN002400507 description: >- Local PAINT IBD node in PTHR24416 (taxon:6072, Eumetazoa) with propagated terms F:GO:0038062 protein tyrosine kinase collagen receptor activity (seeds mouse Ddr2 MGI:MGI:1345277, human DDR1 UniProtKB:Q08345 and DDR2 UniProtKB:Q16832) and F:GO:0005518 collagen binding (the same seeds plus mouse Ddr1 MGI:MGI:99216 and RGD:619855). Drosophila Ddr inherits both terms as IBA; its gene review argues a dipteran-branch loss (predicted pseudokinase) and does not accept them. evidence: - source_id: GO_REF:0000033 statement: IBD propagation of GO:0038062 from PAINT node PTN002400507 in PTHR24416. function: preferred_term: protein tyrosine kinase collagen receptor activity term: id: GO:0038062 label: protein tyrosine kinase collagen receptor activity processes: - preferred_term: collagen-activated tyrosine kinase receptor signaling pathway term: id: GO:0038063 label: collagen-activated tyrosine kinase receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Collagen-binding transmembrane receptor tyrosine kinase that autophosphorylates on collagen binding and recruits intracellular signaling proteins. evidence: - source_id: PMID:9659899 title: The discoidin domain receptor tyrosine kinases are activated by collagen. statement: DDR1 and DDR2 bind and are activated by collagen; activated DDR1 recruits Shc and activated DDR2 up-regulates MMP-1 expression. supporting_text: >- Collagen activation of DDR1 induces phosphorylation of a docking site for the Shc phosphotyrosine binding domain, whose presence is controlled by alternative splicing. Activation of DDR2 by collagen results in the up-regulation of matrix metalloproteinase-1 expression. - source_id: PMID:24725424 title: Discoidin domain receptor functions in physiological and pathological conditions. statement: DDR homologues exist in invertebrates including worms, insects and hydra. supporting_text: >- The DDRs have a longer evolutionary history than the collagen-binding integrins: DDR homologues are found in invertebrates such as worms, insects and hydra, while collagen-binding integrins are restricted to vertebrates (Leitinger, 2011). - source_id: PMID:23147028 title: Discoidin domain receptors guide axons along longitudinal tracts in C. elegans. statement: C. elegans has two discoidin domain receptors, ddr-1 and ddr-2, that act in axon guidance. supporting_text: >- Here we characterize the role of the two discoidin domain receptors, ddr-1 and ddr-2, of the nematode C. elegans during nervous system development. connections: - source: collagen_ligand target: ddr_receptor connection_type: POSITIVELY_REGULATES description: Collagen binding to the discoidin domain activates the DDR tyrosine kinase. knowledge_gaps: - gap_statement: Which endogenous collagen activates Ddr in invertebrates is not known. In Drosophila the only evidence is a dominant genetic interaction between Ddr and Multiplexin (collagen XV/XVIII homologue); whether Multiplexin or collagen IV (Col4a1/viking) binds and activates Ddr has not been tested. Dipteran Ddr is moreover a predicted pseudokinase (lost beta3 lysine, catalytic-loop asparagine and DFG aspartate; genes/DROME/Ddr), so whether it signals as a collagen receptor at all, and how, is open. boundary: It is established that vertebrate DDR1 and DDR2 bind and are activated by native fibrillar collagens, that DDR1 binds collagen IV and DDR2 collagen X, and that Drosophila Ddr and Multiplexin interact genetically in axon ensheathment. status: OPEN gap_kind: - BIOLOGY significance: Without a biochemically defined invertebrate ligand, the ligand step of this pan-eumetazoan module is grounded only by vertebrate collagens, and the fly pathway cannot be checked for a ligand. provenance: - reference_id: PMID:36355066