Extracellular Matrix (ECM) Project

Bottom line: the extracellular matrix is the protein and proteoglycan
network that gives tissues mechanical support, basement-membrane polarity and
adhesive signalling cues. This project actioned every row in a ten-gene human
ECM pilot spanning basement-membrane proteoglycans (AGRN, HSPG2, NID1),
interstitial matrix components (FN1, DCN, EPYC, SPARC) and the three
testicans (SPOCK1, SPOCK2, SPOCK3). As of 2026-10-16, those files contain
638 review rows: 283 ACCEPT, 187 KEEP_AS_NON_CORE, 71 REMOVE, 64 MODIFY, 16 NEW,
11 MARK_AS_OVER_ANNOTATED and 6 UNDECIDED. All ten review YAMLs are COMPLETE,
and DCN now has core_functions. The first basement-membrane ModuleReview
remains to be drafted; that follow-up is tracked in
#4070.

The largest single clean-up was FN1: its review removed 52 generic IPI
protein binding rows and modified 38 extracellular region rows to the more
specific extracellular matrix. The testican reviews kept the SPOCK paralogs
separate: SPOCK1 and SPOCK3 retain metalloendopeptidase-inhibitor activity,
whereas SPOCK2 rows were modified toward endopeptidase-regulator and
cell-motility terms because SPOCK2 counter-inhibits SPOCK1/3. EPYC gained NEW
collagen-binding, collagen-fibril-organization and matrix-constituent rows.

Overview

Extracellular-matrix proteins are large, secreted and domain-rich, and many of
their GOA rows come from high-throughput interaction or ECM-proteomics screens.
That makes them a useful test for separating true molecular roles — collagen
binding, basement-membrane scaffolding, peptidase inhibition, fibril assembly —
from generic protein binding, broad extracellular region localizations and
downstream developmental phenotypes.

The pilot deliberately mixed three slices of ECM biology:

• Basement membrane: AGRN, HSPG2, and NID1 organize perlecan/agrin,
  laminin and collagen-IV-rich sheets.
• Testicans: SPOCK1, SPOCK2 and SPOCK3 test paralog-specific review
  because SPOCK2 antagonizes the peptidase-inhibitory logic of SPOCK1 and
  SPOCK3.
• Interstitial/matricellular components: FN1, DCN, EPYC and SPARC
  cover fibronectin assembly, small leucine-rich proteoglycans and collagen
  regulation.

Review Set

2026-10-16 action snapshot

Key Findings

• FN1 drove most removals and modifications. The review removed 52 IPI
  protein binding rows and modified 38 bulk extracellular region rows to
  extracellular matrix.
• SPOCK2 needs different terms from its paralogs. SPOCK2 inhibits the
  inhibitory action of SPOCK1/3 and was not kept as a metalloendopeptidase
  inhibitor itself.
• EPYC was under-annotated. It gained NEW rows for collagen binding,
  collagen fibril organization, extracellular matrix structural constituent
  and extracellular matrix organization.
• NID1 connects the basement-membrane network. Its core functions center on
  structural matrix activity plus laminin and collagen binding.
• DCN core functions are collagen binding and TGF-beta sequestration. Its
  core_functions pair collagen binding with collagen fibril organization,
  TGF-beta binding with negative regulation of TGF-beta receptor signaling,
  and fibronectin binding. Three NEW rows add the TGF-beta binding, TGF-beta
  signalling regulation and collagen fibril organization terms that GOA lacked.

Status and Next Steps

• [x] Phase 1 row review: AGRN, HSPG2, EPYC
• [x] Phase 2 row review: SPOCK1, SPOCK2, SPOCK3
• [x] Phase 3 row review: NID1, FN1, DCN, SPARC
• [x] Validate all ten current review files
• [x] Finalize the AGRN and NID1 review statuses
• [x] Add DCN core functions
• [ ] Draft a basement-membrane ECM ModuleReview for NID1/HSPG2/AGRN plus
  laminin/collagen IV context
  (#4070)

Component Notes

SPOCK proteins (Testican family):
- Proteoglycans belonging to the SPARC/osteonectin family
- Modular structure with follistatin-like and extracellular calcium-binding domains
- Chondroitin/heparan sulfate chains
- Key finding: SPOCK2 uniquely acts as counter-inhibitor, blocking SPOCK1/3 MMP inhibition
- Roles in ECM assembly, neurogenesis, angiogenesis, and cancer

Diverse ECM proteins:
- NID1: Bridges laminin to collagen IV networks in basement membranes
- FN1: Cell adhesion, migration, wound healing
- DCN: Collagen fibrillogenesis, TGF-β regulation
- SPARC: Parent family member, Ca²⁺ binding, collagen binding, anti-adhesive