CDH1 (E-cadherin) — Deep Research (manual) Manual

CDH1 (E-cadherin) — Deep Research (manual)

Provenance note. This is a manually compiled research file. The automated
deep-research providers (Perplexity, OpenAI, Falcon, etc.) were unavailable in
this environment (no API keys; prior runs reported provider timeouts), so per
the repository CLAUDE.md guidance this content is written by hand and named
-deep-research-manual.md rather than -deep-research-{provider}.md.

Every assertion is anchored to a verifiable source: either the UniProt record
(CDH1-uniprot.txt, UniProt P12830) or one of the 73 publications referenced
in CDH1-goa.tsv, all of which are cached locally in publications/. Supporting
text is quoted verbatim from the cached publication abstracts/full text.

Gene summary

CDH1 is the prototypical "classical" (type I) cadherin. UniProt summarizes its
function as: "Cadherins are calcium-dependent cell adhesion proteins. They
preferentially interact with themselves in a homophilic manner in connecting
cells... CDH1 is involved in mechanisms regulating cell-cell adhesions, mobility
and proliferation of epithelial cells... Has a potent invasive suppressor role"
[UniProt:P12830 FUNCTION, citing PubMed:11976333].

Protein architecture

Core function 1 — Calcium-dependent homophilic cell–cell adhesion

The defining molecular function. Adhesion uses two distinct interfaces:

Single-molecule work shows adhesion begins from monomers, not pre-formed cis
dimers, and that clustering is cooperative:
PMID:19114658
PMID:19114658.

Dimerization proceeds by an induced-fit, two-step mechanism: a weak Ca2+-dependent
"encounter complex" forms first, then strengthens by strand swap.
PMID:19646884
PMID:19646884.

Mechanotransduction

E-cadherin bonds are force-responsive, which lets junctions resist and tune
to mechanical load:
PMID:23112161
PMID:23112161
PMID:23112161.

Core function 2 — The cadherin–catenin complex and linkage to the actin cytoskeleton

The cytoplasmic tail nucleates the catenin complex that couples adhesion to
the cytoskeleton. UniProt: "Component of an E-cadherin/catenin adhesion complex
composed of at least E-cadherin/CDH1, beta-catenin/CTNNB1 or gamma-catenin/JUP,
and potentially alpha-catenin/CTNNA1" [UniProt:P12830 SUBUNIT, citing
PubMed:16126725, PubMed:7982500]; the juxtamembrane domain binds CTNND1
(p120-catenin) [UniProt:P12830 SUBUNIT, citing PubMed:15240885].

Core function 3 — Adherens junction assembly and desmosome nucleation

Beyond forming adherens junctions, E-cadherin seeds desmosome assembly:

Annotation note: desmosome localization (GO:0030057) for CDH1 is a genuine
but organizer/initiator role, not a structural desmosomal-cadherin role — best
treated as a real but non-core (or carefully scoped) annotation.

Trafficking, turnover and stabilization

E-cadherin surface levels are set by a balance of delivery, recycling, endocytosis
and degradation:

Regulation of adhesive activity

EMT/MET and transcriptional control of CDH1

Loss of E-cadherin is a hallmark of the epithelial–mesenchymal transition (EMT);
its re-expression drives the reverse (MET). CDH1 itself is a transcriptional
target:

Outside-in signaling

Homophilic E-cadherin engagement is not just structural — it transduces signals
that control gene expression and cell state:

Tumor suppression and disease

Pathogen receptor role (microbial infection)

E-cadherin EC1 is hijacked by pathogens:

This is appropriately a non-core function (host receptor co-opted by pathogens),
not part of CDH1's normal physiology.

Candidate core functions (for the review closeout)

Synthesis for the eventual core_functions block of CDH1-ai-review.yaml:

  1. Calcium-dependent homophilic cell–cell adhesion — trans strand-swap dimerization via EC1; the molecular activity underlying epithelial integrity (GO:0005509 calcium ion binding; GO:0098641 cadherin binding involved in cell-cell adhesion; adherens-junction adhesion BP terms).
  2. Adherens junction organization / apical junctional complex assembly — nucleating the cadherin–catenin complex and the zonula adherens, including coupling to the actin/spectrin cytoskeleton via catenins and adaptors.
  3. Invasion / tumor suppression — restraining cell motility and invasion; loss drives EMT and diffuse gastric / lobular breast cancer.

Likely non-core but genuine: desmosome assembly initiation; outside-in
transcriptional signaling; regulation of cell proliferation; pathogen-receptor
role (microbial infection — should not be a core annotation).

Caveats for annotation review

Source inventory