id: MODULE:netrin_signaling title: Netrin signaling pathway module description: >- Netrins are secreted laminin-related guidance cues. A netrin binds receptors of the DCC family (vertebrate DCC, Drosophila Frazzled) on a responding cell to mediate attraction, and receptors of the UNC5 family to mediate repulsion, steering migrating cells and axons toward or away from the netrin source. status: DRAFT scope: ABSTRACT evidence: - source_id: GO:0038007 title: netrin-activated signaling pathway statement: The module is grounded in the GO biological process term for netrin-activated signaling. - source_id: PMID:21558366 title: 'Netrins: versatile extracellular cues with diverse functions.' statement: Review of netrin signalling mechanisms in vertebrate and invertebrate systems, used for the module boundary. supporting_text: >- Netrins are secreted proteins that were first identified as guidance cues, directing cell and axon migration during neural development. - source_id: PMID:11719202 title: Short- and long-range repulsion by the Drosophila Unc5 netrin receptor. statement: Netrins act through two receptor families, DCC (attraction and repulsion) and UNC5 (repulsion only). supporting_text: >- They act through receptors of the DCC and UNC5 families. DCC receptors have been implicated in both attraction and repulsion by Netrins. UNC5 receptors are required only for repulsion. notes: >- Boundary. The module has two steps: a secreted netrin ligand, and a netrin receptor on the responding cell, with attractive (DCC family) and repulsive (UNC5 family) receptor variants. Intracellular transducers (FAK/PTK2, SRC-family kinases, TRIM9, Rho-family GTPase regulators), the co-receptor candidates DSCAM and neogenin, and laminins in the same PANTHER family are not modelled as parts. The module is species-neutral; the representative members (human NTN1, NTN3, DCC and UNC5A-D; Drosophila NetA, NetB, fra and unc-5) are examples, not a species scope. Human NTN4, NTN5 and the GPI-anchored netrin-Gs (NTNG1, NTNG2) are omitted because they diverge from the canonical secreted DCC/UNC5 ligand role: NTN4 is a laminin-gamma-like basement-membrane protein that binds laminin gamma-1 rather than acting as a canonical DCC ligand, and NTNG1/NTNG2 signal through netrin-G ligands NGL-1/NGL-2 (LRRC4C/LRRC4) rather than DCC or UNC5. The taxon scope Eumetazoa (NCBITaxon:6072) tracks the taxon placement of the PAINT netrin clade node PTN008501429 (whereas the Slit-Robo module uses Bilateria, NCBITaxon:33213, matching its PAINT node PTN002911633). Ligand function term. The ligand step uses GO:0048018 receptor ligand activity, following the GO-CAM signaling receptor guideline ("a ligand 'enables' receptor ligand activity (GO:0048018) or a child"). Neither chemoattractant nor chemorepellent activity fits on its own because netrins do both. The receptor-specific GO:1990890 netrin receptor binding is not used: it records binding only, is not under receptor ligand activity, and in GOA is carried by receptor-side proteins (DSCAM, tubulins) rather than by netrins. The NTN1 and NTN3 gene reviews use receptor ligand activity as their core function and propose NEW annotations to GO:0038007. Annotation state (GOA GAFs dated 2026-05-21). Human: UNC5A-D are annotated to GO:0038007, but DCC, NTN1 and NTN3 are not, and no netrin has a receptor ligand activity MF. Drosophila: fra and unc-5 are annotated to GO:0038007 (IEA), but NetA and NetB are annotated only to axon guidance terms and have no MF annotation. module: id: netrin_signaling label: Netrin signaling pathway module_type: SIGNALING_PATHWAY description: >- A secreted netrin binds a DCC-family receptor to attract, or an UNC5-family receptor to repel, a migrating cell or growth cone. concepts: - preferred_term: netrin-activated signaling pathway term: id: GO:0038007 label: netrin-activated signaling pathway context: taxa: - preferred_term: Eumetazoa term: id: NCBITaxon:6072 label: Eumetazoa parts: - order: 1 role: secreted ligand node: id: netrin_ligand label: Netrin ligand module_type: SIGNALING_PATHWAY description: A secreted netrin (UNC-6/netrin-1 class) presented by the signal-sending tissue, such as the CNS midline. annotons: - id: netrin_ligand_family label: Netrin ligand participant: selector_type: FAMILY family: preferred_term: Netrin ligands (netrin subset of the netrin/laminin family) term: id: PANTHER:PTHR10574 label: NETRIN/LAMININ-RELATED description: >- PTHR10574 also contains laminin chains and non-canonical netrin-named subfamilies that do not act as secreted DCC/UNC5 ligands. The role here is restricted to the canonical secreted netrin subfamilies PTHR10574:SF378, SF431 and SF437 (NETRIN-1), SF292 (NETRIN-3), and SF365 (NETRIN-A-RELATED, including Drosophila NetA/NetB and C. elegans UNC-6) under PAINT node PTN008501429, excluding the GPI-anchored synaptic adhesion subfamilies SF28 (NETRIN-G1) and SF27 (NETRIN-G2), the laminin-gamma-like basement-membrane subfamily SF282 (NETRIN-4), and SF262/SF383/SF443 (NETRIN-5). representative_members: - preferred_term: NTN1 term: id: UniProtKB:O95631 label: Netrin-1 - preferred_term: NTN3 term: id: UniProtKB:O00634 label: Netrin-3 - preferred_term: NetA term: id: UniProtKB:Q24567 label: Netrin-A - preferred_term: NetB term: id: UniProtKB:Q24568 label: Netrin-B ancestral_nodes: - preferred_term: PAINT node PTN008501429 (netrins) term: id: PANTHER:PTN008501429 label: PTN008501429 description: >- Local PAINT IBD node in PTHR10574 (taxon:6072) with propagated terms C:GO:0005604, P:GO:0008045 and P:GO:0016358. Its IBD seeds include Drosophila NetA (FB:FBgn0015773) and NetB (FB:FBgn0015774), mouse Ntn1 (MGI:105088), C. elegans WBGene00006746 and two zebrafish genes (ZFIN:ZDB-GENE-990415-168, ZFIN:ZDB-GENE-990415-169). evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008501429 in PTHR10574. function: preferred_term: receptor ligand activity term: id: GO:0048018 label: receptor ligand activity processes: - preferred_term: netrin-activated signaling pathway term: id: GO:0038007 label: netrin-activated signaling pathway locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Secreted netrin that binds DCC-family and UNC5-family receptors. evidence: - source_id: PMID:8780646 title: 'Guidance cues at the Drosophila CNS midline: identification and characterization of two Drosophila Netrin/UNC-6 homologs.' statement: Drosophila has two netrins, NetA and NetB. supporting_text: >- We have identified two Drosophila homologs of this protein family (Netrin-A and Netrin-B). - source_id: PMID:8780645 title: 'Genetic analysis of Netrin genes in Drosophila: Netrins guide CNS commissural axons and peripheral motor axons.' statement: Drosophila netrins are required for commissural and motor axon guidance. supporting_text: >- Thus, Drosophila Netrins are required for the guidance of commissural axons at the midline, and of motor axons to their target muscles. - order: 2 role: receptor node: id: netrin_receptor label: Netrin receptor module_type: SIGNALING_PATHWAY description: Transmembrane netrin receptor on the responding cell or growth cone. The receptor family present determines whether the response is attraction or repulsion. variant_sets: - id: netrin_receptor_response label: Netrin receptor by response axis: attraction versus repulsion selection: ONE_OR_MORE evidence: - source_id: PMID:11719202 statement: DCC receptors mediate attraction and some repulsion; UNC5 receptors mediate repulsion only. supporting_text: >- DCC receptors have been implicated in both attraction and repulsion by Netrins. UNC5 receptors are required only for repulsion. variants: - id: dcc_family_receptor label: DCC-family receptor (attraction) module_type: SIGNALING_PATHWAY annotons: - id: dcc_family_netrin_receptor label: DCC-family netrin receptor participant: selector_type: FAMILY family: preferred_term: DCC family netrin receptors (DCC, Frazzled, UNC-40) description: >- No PANTHER id is asserted. DCC is in PTHR44170:SF8 (NETRIN RECEPTOR DCC) and Frazzled in PTHR44170:SF54, and the parent family PTHR44170 is a broad immunoglobulin-superfamily grouping named PROTEIN SIDEKICK. representative_members: - preferred_term: DCC term: id: UniProtKB:P43146 label: Netrin receptor DCC - preferred_term: fra term: id: UniProtKB:A1Z920 label: Frazzled, isoform A function: preferred_term: netrin receptor activity term: id: GO:0005042 label: netrin receptor activity processes: - preferred_term: netrin-activated signaling pathway term: id: GO:0038007 label: netrin-activated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Netrin-binding transmembrane receptor that mediates attraction toward the netrin source. evidence: - source_id: PMID:8861902 title: Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. statement: DCC binds netrin-1 and is required for netrin-1-dependent commissural axon outgrowth. supporting_text: >- These results indicate that DCC is a receptor or a component of a receptor that mediates the effects of netrin-1 on commissural axons - source_id: PMID:8861904 title: frazzled encodes a Drosophila member of the DCC immunoglobulin subfamily and is required for CNS and motor axon guidance. statement: Frazzled is the Drosophila DCC-family receptor for Netrin-dependent axon guidance. supporting_text: >- suggest that Frazzled may function in vivo as a receptor or component of a receptor mediating Netrin-dependent axon guidance - id: unc5_family_receptor label: UNC5-family receptor (repulsion) module_type: SIGNALING_PATHWAY annotons: - id: unc5_family_netrin_receptor label: UNC5-family netrin receptor participant: selector_type: FAMILY family: preferred_term: UNC5 family netrin receptors term: id: PANTHER:PTHR12582 label: NETRIN RECEPTOR UNC5 representative_members: - preferred_term: UNC5A term: id: UniProtKB:Q6ZN44 label: Netrin receptor UNC5A - preferred_term: UNC5B term: id: UniProtKB:Q8IZJ1 label: Netrin receptor UNC5B - preferred_term: UNC5C term: id: UniProtKB:O95185 label: Netrin receptor UNC5C - preferred_term: UNC5D term: id: UniProtKB:Q6UXZ4 label: Netrin receptor UNC5D - preferred_term: unc-5 term: id: UniProtKB:Q95TU8 label: Netrin receptor unc-5 function: preferred_term: netrin receptor activity term: id: GO:0005042 label: netrin receptor activity processes: - preferred_term: netrin-activated signaling pathway term: id: GO:0038007 label: netrin-activated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Netrin-binding transmembrane receptor that mediates repulsion away from the netrin source, alone or together with a DCC-family receptor. evidence: - source_id: PMID:9126742 title: Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors. statement: Vertebrate UNC5 homologues bind netrin. supporting_text: >- We provide evidence that these two UNC-5 homologues, as well as the rcm gene product, are netrin-binding proteins, supporting the hypothesis that UNC-5 and its relatives are netrin receptors. - source_id: PMID:11719202 title: Short- and long-range repulsion by the Drosophila Unc5 netrin receptor. statement: Drosophila Unc5 is a repulsive netrin receptor; long-range repulsion also requires Frazzled. supporting_text: >- Both short- and long-range repulsion require Netrin function, but only long-range repulsion requires Frazzled. connections: - source: netrin_ligand target: netrin_receptor connection_type: POSITIVELY_REGULATES description: Netrin binding activates the DCC-family or UNC5-family receptor.