NTN3

Summary: The POU-seeded DNA-binding-function transfer does not fit the netrin protein.

Reason: The GOA source PTN000180816 has POU-transcription-factor experimental seeds, whereas the target has the laminin/EGF/NTR architecture and netrin receptor-ligand biology. The current PTHR10574 PAINT cache contains these POU-seeded rows, so the original claim of a demonstrated wrong-family tree placement is replaced by a provenance discrepancy requiring upstream inspection. These specific Pol II sequence-recognition/TF activities are not supported by the target architecture or source-to-target functional homology; removal is not based on secreted localization alone.

Summary: Pol II transcription regulation must be evaluated independently of POU DNA-binding activity.

Reason: A receptor ligand can regulate transcription through signaling, and secretion does not exclude an additional intracellular molecular form. The POU-seeded source at PTN000180816 does not establish the relevant netrin-specific mechanism, but failure of that trace is not proof that this broader biological process is impossible. No direct target-specific participation in Pol II regulation was established in this re-review.

Summary: The POU-seeded DNA-binding-function transfer does not fit the netrin protein.

Reason: The GOA source PTN000180816 has POU-transcription-factor experimental seeds, whereas the target has the laminin/EGF/NTR architecture and netrin receptor-ligand biology. The current PTHR10574 PAINT cache contains these POU-seeded rows, so the original claim of a demonstrated wrong-family tree placement is replaced by a provenance discrepancy requiring upstream inspection. These specific Pol II sequence-recognition/TF activities are not supported by the target architecture or source-to-target functional homology; removal is not based on secreted localization alone.

Summary: A broad cytoplasmic assignment can include the intracellular secretory pathway.

Reason: Cytoplasm includes the endomembrane system, so this term is compatible with secretory trafficking; it does not require soluble mature netrin-3 in the cytosol. Primary extracellular function does not disprove an intracellular pool, although the present rule-derived assignment is not its core functional location.

Summary: This annotation is appropriate but could be more specific. NTN3 is a netrin family member that functions in axon guidance, which is a subprocess of axonogenesis. The ARBA annotation captures a relevant biological process for this protein.

Reason: Netrins are well-established axon guidance cues that regulate axonogenesis by guiding the growth and direction of axons during neural development. While GO:0007411 (axon guidance) is more specific, axonogenesis is an appropriate broader term. The annotation aligns with established netrin family function.

Summary: The DRAXIN interaction is informative evidence but generic protein binding is not a specific function.

Reason: Keep the observed interaction as context; remove the uninformative protein-binding term under project policy. DRAXIN binding should not be relabeled as binding a canonical netrin receptor.

Summary: NTN3 acts as a ligand of netrin receptors, supported by direct mouse ortholog assays.

Reason: PMID:10366627 directly tests mouse netrin-3 binding to DCC, neogenin and UNC5H1/H2/H3 and establishes orthology to human NTN2L/NTN3. Signaling receptor binding records binding only; the protein is a ligand of these receptors, so receptor ligand activity is the replacement. The receptor-specific "netrin receptor binding" term is not used because it records binding only and in GOA is carried by receptor-side proteins rather than netrins.

Proposed replacements: receptor ligand activity

Summary: This annotation is correct and represents a core localization for NTN3. The protein contains a signal peptide and is secreted to the extracellular space where it functions as an axon guidance cue.

Reason: NTN3 is a secreted protein (signal peptide residues 1-27) that localizes to the extracellular region, specifically the extracellular matrix. This is the primary functional localization for netrin family proteins where they establish chemotropic gradients for axon guidance.

Summary: This annotation is acceptable as NTN3 is a secreted protein that transits through the Golgi apparatus during biosynthesis. The annotation likely reflects Golgi localization during the secretory pathway.

Reason: As a secreted protein, NTN3 passes through the Golgi apparatus during biosynthesis and maturation. While this is not the final functional localization, it is a valid component of the secretory pathway that NTN3 uses. The annotation is not incorrect but represents transient localization rather than core function.

Summary: This is a core annotation for NTN3 supported by the primary characterization paper. PMID:9143507 describes NTN3 (then called NTN2L) as a member of the netrin family of chemotropic factors that play a central role in axon guidance. The annotation appropriately captures the primary biological function of this protein.

Reason: Axon guidance is the core biological function of netrin family proteins including NTN3. The cited paper (PMID:9143507) explicitly states that netrins play a central role in axon guidance. This is well-supported by the literature on netrin family function.

Summary: Proposed new annotation. Netrin-3 is a canonical secreted netrin ligand that binds DCC, neogenin, and UNC5-family receptors to initiate netrin signaling, but human NTN3 currently lacks a GOA annotation to GO:0038007.

Reason: In GO, receptor ligand activity (GO:0048018) is part_of signal transduction (GO:0007165), and the GO-CAM signaling receptor guideline places the ligand activity part_of the signaling pathway it initiates. Comparator check across textbook signaling pathways in projects/LIGANDS_IN_SIGNALING.md confirms that secreted protein ligands are annotated involved_in their cognate pathway terms, whereas human GOA annotates GO:0038007 only to netrin receptors and downstream effectors and omits the netrin ligands (Category A gap). PMID:10366627 demonstrates that mouse netrin-3 (the ortholog of human NTN3/NTN2L) binds DCC, neogenin, and UNC5H1/H2/H3 receptors and promotes commissural axon outgrowth.