Netrin signaling pathway module

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.

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.