id: MODULE:ephrin_receptor_signaling title: Ephrin receptor signaling pathway module description: Membrane-tethered ephrin ligands activate Eph receptor tyrosine kinases across cell-cell contacts, producing bidirectional signals that pattern adhesion, repulsion, migration, and vascular organization. status: DRAFT evidence: - source_id: file:modules/ephrin_receptor_signaling-deep-research-falcon.md title: Ephrin receptor signaling pathway Falcon module review statement: >- Falcon/Edison module review generated 2026-06-28 is linked as supporting evidence for module boundaries, core mechanism, variation, constraints, and failure modes; open questions in that report require manual review before promotion to curated knowledge gaps. - source_id: GO:0048013 title: ephrin receptor signaling pathway statement: The module is grounded in the GO biological process term for ephrin receptor signaling pathway. - source_id: PANTHER:PTN000632671 title: PAINT node PTN000632671 for RHOA statement: Local PAINT IBD node in PTHR24072 with propagated terms C:GO:0005886, F:GO:0003924, F:GO:0005525, P:GO:0007015, P:GO:0007165; PAINT date 20260529. - source_id: PANTHER:PTN001178055 title: PAINT node PTN001178055 for RHOA statement: Local PAINT IBD node in PTHR24072 with propagated terms P:GO:0016477; PAINT date 20250903. - source_id: PANTHER:PTN001230349 title: PAINT node PTN001230349 for EPHA2 statement: Local PAINT IBD node in PTHR24416 with propagated terms C:GO:0005886, F:GO:0004714, P:GO:0007169; PAINT date 20260529. - source_id: PANTHER:PTN002784793 title: PAINT node PTN002784793 for RHOA statement: Local PAINT IBD node in PTHR24072 with propagated terms P:GO:0007266, P:GO:0043149; PAINT date 20231109. - source_id: PANTHER:PTN005273574 title: PAINT node PTN005273574 for GRB2 statement: Local PAINT IBD node in PTHR46037 with propagated terms C:GO:0005737, C:GO:0005886, C:GO:0008180, F:GO:0001784, F:GO:0005154, P:GO:0007165; PAINT date 20260530. - source_id: PANTHER:PTN008393484 title: PAINT node PTN008393484 for RHOA statement: Local PAINT IBD node in PTHR24072 with propagated terms C:GO:0005829, P:GO:0032956; PAINT date 20260529. - source_id: PANTHER:PTN000885159 title: PAINT node PTN000885159 for ephrin ligands statement: Local PAINT IBD node in PTHR11304 (Eumetazoa root) with propagated terms C:GO:0005886, F:GO:0046875, P:GO:0007411, P:GO:0048013; PAINT date 20260828. - source_id: file:interpro/panther/PTHR11304/PTHR11304-review.yaml title: PANTHER PTHR11304 (EPHRIN) family review statement: Documents family-wide coherence of PTHR11304 for GO:0048018 (receptor ligand activity) and GO:0048013 (ephrin receptor signaling pathway) across Eumetazoa root node PTN000885159, noting that PAINT currently asserts GO:0046875 (ephrin receptor binding) rather than GO:0048018. - source_id: file:genes/human/EFNB1/EFNB1-ai-review.yaml title: Human EFNB1 gene review statement: Curates human EFNB1 with GO:0048018 (receptor ligand activity) and GO:0048013 (ephrin receptor signaling pathway), replacing receptor-specific binding GO:0046875. - source_id: PMID:26790531 title: Mechanisms of ephrin-Eph signalling in development, physiology and disease. statement: Review (Kania and Klein 2016) establishing that membrane-tethered ephrin ligands engage Eph receptor tyrosine kinases to elicit short-distance bidirectional cell-cell signaling across metazoan development and homeostasis. - source_id: PMID:15928710 title: Eph receptor signalling casts a wide net on cell behaviour. statement: Review (Pasquale 2005) detailing ephrin-Eph contact signaling, receptor clustering, and downstream control of axon guidance, cell adhesion, and migration. - source_id: PMID:7973638 title: Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. statement: Demonstrates that cell-surface-bound ephrin ligands require membrane attachment or clustering to activate Eph-related receptor tyrosine kinases across cell-cell contacts. - source_id: PMID:8798744 title: Cell-cell adhesion mediated by binding of membrane-anchored ligand LERK-2 to the EPH-related receptor human embryonal kinase 2 promotes tyrosine kinase activity. statement: Shows that membrane-anchored EFNB1 (LERK-2) and EFNB2 (LERK-5) bind EphB receptors and induce juxtacrine receptor phosphorylation and cell-cell adhesion. notes: >- Curated compact signaling-pathway module generated from verified UniProt exemplar accessions and local PAINT IBD rows. PTN anchors are included only when the exemplar accession appears in an IBD seed row in interpro/panther; roles without local PAINT seeds remain grounded by verified UniProt exemplar accessions. The ephrin ligand step is grounded in PANTHER family PTHR11304 (EPHRIN) at the Eumetazoa root node PTN000885159, which propagates C:GO:0005886 (plasma membrane), P:GO:0048013 (ephrin receptor signaling pathway), P:GO:0007411 (axon guidance), and F:GO:0046875 (ephrin receptor binding). Following GO signaling-ligand conventions, the ligand step uses GO:0048018 (receptor ligand activity) rather than the receptor-specific binding term GO:0046875. PTN000885159 is kept on the ligand step even though its IBD MF is GO:0046875 rather than GO:0048018; the mismatch is documented in interpro/panther/PTHR11304/PTHR11304-review.yaml and explains why non-mammalian ephrins (such as Drosophila Ephrin and zebrafish ephrins) inherit GO:0048013 by IBA without a ligand-activity MF. (The module validator does not currently flag this term mismatch.) Boundary: the module models forward signaling only, from the ephrin ligand into the Eph-receptor-expressing cell. Ephrin reverse signaling (signaling into the ephrin-expressing cell, through ephrin-B cytoplasmic tail phosphorylation and PDZ partners, or ephrin-A co-receptors) is not modelled, although the ephrin-Eph contact is bidirectional. Falcon integration (2026-06-28): Falcon findings are linked as evidence and family-level support. Automatically extracted open-question headings were intentionally not retained as knowledge_gap entries because they were not manually curated. Machine-generated Falcon citations remain curation support and are not manually adjudicated here. module: id: ephrin_receptor_signaling label: Ephrin receptor signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: ephrin receptor signaling pathway term: id: GO:0048013 label: ephrin receptor signaling pathway description: Membrane-tethered ephrin ligands activate Eph receptor tyrosine kinases across cell-cell contacts, producing bidirectional signals that pattern adhesion, repulsion, migration, and vascular organization. context: taxa: - preferred_term: metazoa term: id: NCBITaxon:33208 label: Metazoa cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus parts: - order: 1 role: cell-cell ephrin-eph engagement node: id: ephrin_eph_cell_contact label: Ephrin-Eph cell contact module_type: REGULATORY_STEP description: Ephrin ligands engage Eph receptors at cell-cell interfaces. annotons: - id: ephrin_ligand_family label: Ephrin ligand participant: selector_type: FAMILY family: preferred_term: Ephrin ligand family (ephrin-A and ephrin-B subclasses) term: id: PANTHER:PTHR11304 label: EPHRIN representative_members: - preferred_term: EFNB2 term: id: UniProtKB:P52799 label: Ephrin-B2 (EPH-related receptor tyrosine kinase ligand 5) (LERK-5) (HTK ligand) (HTK-L) - preferred_term: EFNB1 term: id: UniProtKB:P98172 label: "Ephrin-B1 (EFL-3) (ELK ligand) (ELK-L) (EPH-related receptor tyrosine kinase ligand 2) (LERK-2) [Cleaved into: Ephrin-B1 C-terminal fragment (Ephrin-B1 CTF); Ephrin-B1 intracellular domain (Ephrin-B1 ICD)]" - preferred_term: efnb2a term: id: UniProtKB:O73874 label: Ephrin-B2a ancestral_nodes: - preferred_term: PAINT node PTN000885159 for ephrin ligands term: id: PANTHER:PTN000885159 label: PTN000885159 description: Local PAINT IBD node in PTHR11304 (Eumetazoa root) with propagated terms C:GO:0005886, F:GO:0046875, P:GO:0007411, P:GO:0048013; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000885159 in PTHR11304. evidence: - source_id: file:interpro/panther/PTHR11304/PTHR11304-review.yaml title: PANTHER PTHR11304 (EPHRIN) family review statement: Documents family-wide coherence of PTHR11304 for GO:0048018 (receptor ligand activity) and GO:0048013 (ephrin receptor signaling pathway) across Eumetazoa root node PTN000885159. role_description: Membrane-tethered ephrin ligands (GPI-anchored ephrin-A and transmembrane ephrin-B subclasses) that bind and cluster Eph receptor tyrosine kinases at sites of cell-cell contact. function: preferred_term: receptor ligand activity term: id: GO:0048018 label: receptor ligand activity processes: - preferred_term: ephrin receptor signaling pathway term: id: GO:0048013 label: ephrin receptor signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane evidence: - source_id: PMID:26790531 statement: Membrane-tethered ephrins engage Eph receptor tyrosine kinases across cell-cell contacts to elicit short-distance signaling. - source_id: PMID:7973638 statement: Cell-surface-bound ephrin ligands require membrane attachment or clustering to activate Eph-related receptor tyrosine kinases. - source_id: PANTHER:PTN000885159 statement: Local PAINT IBD node in PTHR11304 with propagated terms C:GO:0005886, F:GO:0046875, P:GO:0007411, P:GO:0048013; PAINT date 20260828. - id: epha2_epha2_receptor label: EPHA2 receptor participant: selector_type: FAMILY family: preferred_term: EPHA2 receptor family/ortholog group term: id: PANTHER:PTHR24416 label: TYROSINE-PROTEIN KINASE RECEPTOR representative_members: - preferred_term: EPHA2 term: id: UniProtKB:P29317 label: Ephrin type-A receptor 2 (EC 2.7.10.1) (Epithelial cell kinase) (Tyrosine-protein kinase receptor ECK) ancestral_nodes: - preferred_term: PAINT node PTN001230349 for EPHA2 term: id: PANTHER:PTN001230349 label: PTN001230349 description: Local PAINT IBD node in PTHR24416 with propagated terms C:GO:0005886, F:GO:0004714, P:GO:0007169; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN001230349 in PTHR24416. evidence: - source_id: file:interpro/panther/PTHR24416/PTHR24416-deep-research-falcon.md title: PTHR24416 Falcon family review statement: >- Falcon family-level GO review: ACCEPT current state (no GO terms mapped) - The absence of InterPro2GO mappings is well-justified for this highly heterogeneous family-level entry. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the epha2 receptor role in ephrin receptor signaling pathway. - id: ephb4_ephb4_receptor label: EPHB4 receptor participant: selector_type: FAMILY family: preferred_term: EPHB4 receptor family/ortholog group term: id: PANTHER:PTHR24416 label: TYROSINE-PROTEIN KINASE RECEPTOR representative_members: - preferred_term: EPHB4 term: id: UniProtKB:P54760 label: Ephrin type-B receptor 4 (EC 2.7.10.1) (Hepatoma transmembrane kinase) (Tyrosine-protein kinase TYRO11) ancestral_nodes: - preferred_term: PAINT node PTN001230349 for EPHB4 term: id: PANTHER:PTN001230349 label: PTN001230349 description: Local PAINT IBD node in PTHR24416 with propagated terms C:GO:0005886, F:GO:0004714, P:GO:0007169; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN001230349 in PTHR24416. evidence: - source_id: file:interpro/panther/PTHR24416/PTHR24416-deep-research-falcon.md title: PTHR24416 Falcon family review statement: >- Falcon family-level GO review: ACCEPT current state (no GO terms mapped) - The absence of InterPro2GO mappings is well-justified for this highly heterogeneous family-level entry. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the ephb4 receptor role in ephrin receptor signaling pathway. - order: 2 role: eph kinase activation node: id: eph_receptor_kinase_activation label: Eph receptor kinase activation module_type: REGULATORY_STEP description: Eph receptor clustering activates receptor tyrosine kinase signaling. annotons: - id: epha2_epha_receptor_kinase label: EphA receptor kinase participant: selector_type: FAMILY family: preferred_term: EphA receptor kinase family/ortholog group term: id: PANTHER:PTHR24416 label: TYROSINE-PROTEIN KINASE RECEPTOR representative_members: - preferred_term: EPHA2 term: id: UniProtKB:P29317 label: Ephrin type-A receptor 2 (EC 2.7.10.1) (Epithelial cell kinase) (Tyrosine-protein kinase receptor ECK) ancestral_nodes: - preferred_term: PAINT node PTN001230349 for EPHA2 term: id: PANTHER:PTN001230349 label: PTN001230349 description: Local PAINT IBD node in PTHR24416 with propagated terms C:GO:0005886, F:GO:0004714, P:GO:0007169; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN001230349 in PTHR24416. evidence: - source_id: file:interpro/panther/PTHR24416/PTHR24416-deep-research-falcon.md title: PTHR24416 Falcon family review statement: >- Falcon family-level GO review: ACCEPT current state (no GO terms mapped) - The absence of InterPro2GO mappings is well-justified for this highly heterogeneous family-level entry. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the epha receptor kinase role in ephrin receptor signaling pathway. - id: ephb4_ephb_receptor_kinase label: EphB receptor kinase participant: selector_type: FAMILY family: preferred_term: EphB receptor kinase family/ortholog group term: id: PANTHER:PTHR24416 label: TYROSINE-PROTEIN KINASE RECEPTOR representative_members: - preferred_term: EPHB4 term: id: UniProtKB:P54760 label: Ephrin type-B receptor 4 (EC 2.7.10.1) (Hepatoma transmembrane kinase) (Tyrosine-protein kinase TYRO11) ancestral_nodes: - preferred_term: PAINT node PTN001230349 for EPHB4 term: id: PANTHER:PTN001230349 label: PTN001230349 description: Local PAINT IBD node in PTHR24416 with propagated terms C:GO:0005886, F:GO:0004714, P:GO:0007169; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN001230349 in PTHR24416. evidence: - source_id: file:interpro/panther/PTHR24416/PTHR24416-deep-research-falcon.md title: PTHR24416 Falcon family review statement: >- Falcon family-level GO review: ACCEPT current state (no GO terms mapped) - The absence of InterPro2GO mappings is well-justified for this highly heterogeneous family-level entry. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the ephb receptor kinase role in ephrin receptor signaling pathway. - order: 3 role: adhesion and guidance output node: id: adhesion_and_guidance_output label: Adhesion and guidance output module_type: REGULATORY_STEP description: Ephrin receptor signaling controls cytoskeletal and adhesive responses. annotons: - id: rhoa_rhoa_cytoskeletal_switch label: RhoA cytoskeletal switch participant: selector_type: FAMILY family: preferred_term: RhoA cytoskeletal switch family/ortholog group term: id: PANTHER:PTHR24072 label: RHO FAMILY GTPASE representative_members: - preferred_term: RHOA term: id: UniProtKB:P61586 label: Transforming protein RhoA (EC 3.6.5.2) (Rho cDNA clone 12) (h12) ancestral_nodes: - preferred_term: PAINT node PTN000632671 for RHOA term: id: PANTHER:PTN000632671 label: PTN000632671 description: Local PAINT IBD node in PTHR24072 with propagated terms C:GO:0005886, F:GO:0003924, F:GO:0005525, P:GO:0007015, P:GO:0007165; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000632671 in PTHR24072. - preferred_term: PAINT node PTN001178055 for RHOA term: id: PANTHER:PTN001178055 label: PTN001178055 description: Local PAINT IBD node in PTHR24072 with propagated terms P:GO:0016477; PAINT date 20250903. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN001178055 in PTHR24072. - preferred_term: PAINT node PTN002784793 for RHOA term: id: PANTHER:PTN002784793 label: PTN002784793 description: Local PAINT IBD node in PTHR24072 with propagated terms P:GO:0007266, P:GO:0043149; PAINT date 20231109. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002784793 in PTHR24072. - preferred_term: PAINT node PTN008393484 for RHOA term: id: PANTHER:PTN008393484 label: PTN008393484 description: Local PAINT IBD node in PTHR24072 with propagated terms C:GO:0005829, P:GO:0032956; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008393484 in PTHR24072. evidence: - source_id: file:interpro/panther/PTHR24072/PTHR24072-deep-research-falcon.md title: PTHR24072 Falcon family review statement: >- Falcon family-level GO review: Over-annotation verdict for PTHR24072 (RHO FAMILY GTPASE): the current InterPro2GO state - no mapped GO terms - is APPROPRIATE and should be ACCEPTED as-is. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the rhoa cytoskeletal switch role in ephrin receptor signaling pathway. - id: grb2_sh2_adaptor_context label: SH2 adaptor context participant: selector_type: FAMILY family: preferred_term: SH2 adaptor context family/ortholog group term: id: PANTHER:PTHR46037 label: PROTEIN ENHANCER OF SEVENLESS 2B representative_members: - preferred_term: GRB2 term: id: UniProtKB:P62993 label: Growth factor receptor-bound protein 2 (Adapter protein GRB2) (Protein Ash) (SH2/SH3 adapter GRB2) ancestral_nodes: - preferred_term: PAINT node PTN005273574 for GRB2 term: id: PANTHER:PTN005273574 label: PTN005273574 description: Local PAINT IBD node in PTHR46037 with propagated terms C:GO:0005737, C:GO:0005886, C:GO:0008180, F:GO:0001784, F:GO:0005154, P:GO:0007165; PAINT date 20260530. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN005273574 in PTHR46037. evidence: - source_id: file:interpro/panther/PTHR46037/PTHR46037-deep-research-falcon.md title: PTHR46037 Falcon family review statement: >- Falcon family-level GO review: The current status of PTHR46037 is that no InterPro2GO terms are mapped. This is a reasonable conservative position given the family's functional heterogeneity, but it may represent an under-annotation of a well-characterized protein family. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. role_description: Curated exemplar for the sh2 adaptor context role in ephrin receptor signaling pathway. connections: - source: ephrin_eph_cell_contact target: eph_receptor_kinase_activation connection_type: CAUSES description: The initiating event promotes eph kinase activation. - source: eph_receptor_kinase_activation target: adhesion_and_guidance_output connection_type: CAUSES description: Eph receptor kinase activation leads to adhesion and guidance output.