Death receptor apoptotic signaling pathway module

Death ligands activate death-domain receptors and FADD-containing DISC complexes, bringing initiator caspase-8 into proximity to trigger extrinsic apoptotic protease cascades, exemplified by FASLG-FAS (CD95) signaling.

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. 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. Manual APOPTOSIS audit (2026-09-30): the FAS/FADD/CASP8 seed was checked against completed death-receptor reviews and the production FASL-FAS GO-CAM; TRAIL, TNFR1, CFLAR, and CASP10 were left as explicit expansion gaps rather than merged into the FAS arm. OUT OF SCOPE - caspase-9/APAF-1 and the apoptosome (PMID:42819741): a membership handoff routed a structural study of the human caspase-9 CARD to this module. It does not belong here. This module is grounded in GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors and models the death-ligand arm only: FASLG -> FAS -> FADD -> CASP8, with TNFRSF1A as receptor context. Caspase-9 is the initiator caspase of the *intrinsic* (mitochondrial) pathway and is activated by the APAF-1/cytochrome c apoptosome, not at a DISC; neither CASP9 (UniProtKB:P55211) nor APAF1 (UniProtKB:O14727) is a participant of this module, and the paper assays neither FAS, FADD nor CASP8 (CASP8 appears in it only as a filament-forming comparator). The correct home for apoptosome-level mechanism is modules/intrinsic_apoptotic_signaling.yaml, where CASP9 and APAF1 are already annotons and where this candidate was assessed and recorded as not modelled. Note that CASP8 and CASP9 share the PANTHER family this module selects on (PTHR10454 CASPASE), so a family-level selector could in principle sweep caspase-9 literature in here, and the shared PAINT node PTN000047947 does not separate them either - it is cited for CASP8 in this module and for CASP9 in the intrinsic module, carrying the same generic C:GO:0005737 / F:GO:0004197 / P:GO:0006915 propagation. What keeps the initiator-caspase role extrinsic is only the representative member, UniProtKB:Q14790 (CASP8); treat the family term as context, not as the role's identity. Route apoptosome, CYCS, APAF1 and CASP9 findings to the intrinsic module, and effector CASP3/6/7 findings to modules/apoptotic_execution_phase.yaml. Ligands in Signaling Pathways upgrade (2026-10-25, Tranche 4A): replaced GENE_PRODUCT selectors on FASLG, FAS, and FADD with PANTHER subfamily selectors (PTHR11471:SF33, PTHR46874:SF1, PTHR15077:SF10) anchored to local PAINT IBD nodes, added GO:0036337 (Fas signaling pathway) alongside GO:0008625, and populated function, processes, locations, and evidence on all annotons.