CD2AP curation notes

2026-06-19

• Deep-research attempt with just deep-research-falcon human CD2AP --fallback perplexity-lite timed out after 180 seconds with no generated research artifact, so this manual review uses cached UniProt, GOA, PANTHER family, and publication evidence.
• CD2AP is best treated as an SH3-domain scaffolding/adaptor protein that links membrane and junctional proteins to actin-rich cortical structures. The original CMS/CD2AP paper reports that the protein is cytoplasmic, colocalizes with F-actin and p130(Cas) in membrane ruffles and leading edges, and that ectopic expression changes actin cytoskeleton organization PMID:10339567.
• Core localization annotations are cytoplasm, actin cytoskeleton/filamentous actin, ruffle, leading edge, plasma membrane/cell periphery, vesicle/endosomal compartments, and junctional structures. UniProt summarizes CD2AP as acting between membrane proteins and actin cytoskeleton, anchoring the podocyte slit diaphragm to actin, and participating in epithelial junction formation.
• Homodimerization and multimeric SH3-mediated complexes are supported. The structural paper states that CD2AP/CMS family endocytic adaptors engage multiple effectors and can couple cargo trafficking to the cytoskeleton PMID:17020880, and reports that CD2 and Cbl-b peptides mediate multimerization of CMS SH3 domains PMID:17020880.
• The broad protein binding annotations should not be accepted as core terms. Several are real interaction observations, but CD2AP's informative molecular role is adaptor/scaffold activity, SH3/proline-rich partner recognition, actin association, or specific complex context rather than generic protein binding.
• Epithelial junction evidence is strong. A full-text JCB paper reports that SH3BP1 formed a complex with JACOP/paracingulin and CD2AP, and that both scaffold proteins were required for normal Cdc42 signaling and junction formation PMID:22891260. This supports anchoring junction, actin filament organization, and negative regulation of small GTPase signaling annotations.
• CD2AP is also part of the submembrane actin/junction module through CapZ. The same paper states that CD2AP is part of the submembrane actin cytoskeleton and binds/regulates CapZ PMID:22891260.
• Podocyte slit diaphragm localization is biologically central for CD2AP in vivo, even though several slit-diaphragm details in the current GOA set are electronically transferred. I accepted slit diaphragm/anchoring junction context because it is consistent with UniProt and the established renal disease association.
• Neuronal axon/dendrite and synapse annotations are plausible Alzheimer/endosomal context but are not the primary evolved function of CD2AP. The RIN3 Alzheimer paper shows that RIN3 recruited BIN1 and CD2AP to early endosomes and that RIN3/CD2AP expression affected APP cleavage/trafficking in neuronal models PMID:32552912. I kept axon/dendrite/synapse context non-core rather than making it the defining function.
• The tau secretion annotation from PMID:27044754 is experimental but the cached record is abstract-only and the abstract names FRMD4A rather than CD2AP. Following the project rule not to overrule curators from incomplete evidence, I marked this annotation UNDECIDED rather than removing it PMID:27044754.
• High-throughput cadhesome, exosome, AD network, and interactome annotations are useful context but not core molecular function evidence. Cadherin binding from E-cadherin proximity proteomics is over-specific for CD2AP because the paper describes a large cadhesome proximity/interactome resource rather than direct CD2AP cadherin binding PMID:25468996.

2026-06-20 Second-Pass Review Notes

Second-pass audit confirmed the existing action calls and reference-review
coverage. No YAML changes were needed in this pass.

The single UNDECIDED annotation remains GO:0050714 positive regulation of
protein secretion from PMID:27044754. The cached record is abstract-only and
foregrounds FRMD4A rather than exposing the CD2AP-specific experimental result.
Because the annotation is experimental, it should remain UNDECIDED rather than
be removed without full-text or supplementary-data review.

The core function remains SH3-domain scaffold/adaptor activity linking membrane,
endocytic, junctional, and slit-diaphragm partner complexes to actin-rich
cortical structures. Alzheimer relevance should be represented through
endosomal trafficking modules involving RIN3/BIN1/CD2AP and APP/tau-related
cellular phenotypes, not as generic protein-binding function.

Falcon deep research integration (2026-06-21)

A freshly-grounded Falcon/Edison deep-research report (CD2AP-deep-research-falcon.md, ~22 cited
sources) is now available; it corroborates the existing review's core picture well — CD2AP as a
multi-SH3 scaffold/adaptor linking nephrin/podocin slit-diaphragm and junctional complexes to actin,
plus endocytic/vesicle trafficking and Alzheimer relevance — and adds no contradictions, only
context. The following Falcon-sourced citations are NOT yet independently verified against full text.

Genuinely new or refined findings beyond the current notes/review:

• Explicit nephrin–podocin–CD2AP–actin axis: CD2AP scaffolds the slit-diaphragm receptor nephrin and
  binds the podocin C-terminus, coupling slit-diaphragm signaling to F-actin via cortactin and
  synaptopodin [Blaine & Dylewski, Cells 2020, doi:10.3390/cells9071700; Ha, World J Nephrol 2013,
  doi:10.5527/wjn.v2.i1.1]. This refines the existing review, which treats slit diaphragm largely as
  electronically-transferred localization rather than a named nephrin/podocin partner module.
• Insulin-responsive Glut4 trafficking: CD2AP forms a complex with the clathrin adaptor GGA2 and
  co-fractionates with Glut4/IRAP/sortilin; loss of CD2AP disrupts GSV/clathrin recycling and
  attenuates insulin-stimulated glucose uptake in podocytes [Tolvanen et al., J Cell Sci 2015,
  doi:10.1242/jcs.175075]. This is a NEW functional module not represented in the existing review.
• Neuronal NGF/TrkA trophic-signaling scaffold: CD2AP is enriched in TrkA+ basal-forebrain
  cholinergic neurons, co-localizes with Rab5 endosomes, and couples TrkA to PI3K-p85/Akt to support
  NGF-dependent axon growth and retrograde signaling [Fitzsimons et al., bioRxiv 2024,
  doi:10.1101/2024.07.24.604961 — preprint, treat cautiously]. Refines the currently generic
  neuron-projection/synapse non-core annotations toward a specific NGF/Rab5 retrograde-trafficking role.
• MYO1F/CASS podosome and phagocytic-cup module: proximity-labeling (BioID) in myeloid cells places
  CD2AP with ASAP1, SH3BP2 and SH3KBP1/CIN85 in an SH3-dependent "CASS" adaptor group recruited to
  podosomes and phagocytic cups in macrophages/microglia [Arden et al., J Cell Sci 2024,
  doi:10.1242/jcs.264357]. This adds molecular partners and a phagocytosis context to the existing
  KEEP_AS_NON_CORE podosome annotation (GO:0002102).
• Dose-sensitive synaptic role: heterozygous Cd2ap mice show altered dendritic branching/spine
  density, impaired ubiquitin-proteasome activity, increased paired-pulse facilitation, and mild
  learning deficits, supporting a haploinsufficient presynaptic requirement [SH3-superfamily/synaptic
  work cited as Mehrabipour et al., Cells 2023, doi:10.3390/cells12162054 — NOTE: this token is cited
  by Falcon for synaptic-plasticity claims that read like a separate mouse study, so the citation
  mapping should be checked against full text before reuse].
• Glioblastoma CD2AP–TRIM5–NF-κB axis: CD2AP stabilizes TRIM5 and promotes NF-κB activity and GBM
  progression [Zhang et al., Cell Death Dis 2024, doi:10.1038/s41419-024-07094-7]. New disease context
  (oncogenic), absent from the existing review; would be non-core if curated.
• OCRL/IPIP27A link: CD2AP associates with the inositol-5-phosphatase OCRL via IPIP27A in podocytes,
  tying it to endosomal trafficking and actin polymerization [Preston et al., Pediatr Nephrol 2020,
  doi:10.1007/s00467-019-04317-4]. Corroborates the endocytic-adaptor theme.

Discrepancies / annotations to revisit:
- No direct contradictions with the existing review or its action calls.
- The Glut4/GGA2/insulin-trafficking and NGF/TrkA/Rab5 modules suggest the existing endocytic-adaptor
core could be strengthened with a clathrin/endocytic-vesicle process term (e.g. consider whether
GO:0072583 clathrin-dependent endocytosis or GO:0006897 endocytosis better captures the
Tolvanen/Arden evidence than relying on GO:0030276 clathrin binding alone). Defer pending full-text
verification.
- The MYO1F/CASS data (Arden 2024) provide a concrete molecular basis for the GO:0002102 podosome
KEEP_AS_NON_CORE call and could be cited there if verified.
- Per project guidelines, do not promote any of these to "protein binding"; route new partner
evidence through specific adaptor/SH3/actin or process terms instead.