Generic Wnt signaling pathway module

A generic, taxon-neutral decomposition of Wnt signaling as a module. Wnt signaling is an ancient metazoan cell-cell communication system in which secreted, lipid-modified Wnt glycoproteins act on neighboring cells to control proliferation, cell-fate specification, polarity, and stem-cell maintenance. The module is phrased as a set of conserved functions and pathway segments rather than a fixed gene list, so it can represent invertebrate and vertebrate implementations and the multiple paralogous family members at each step. It captures the shared upstream events (Wnt acylation, secretion, and receptor engagement) and then branches into the canonical beta-catenin-dependent pathway and the beta-catenin-independent (planar-cell-polarity and calcium) pathways. The canonical branch is modeled with both its ligand-off state (the beta-catenin destruction complex driving beta-catenin turnover) and its ligand-on state (signalosome assembly, destruction-complex inhibition, beta-catenin stabilization, nuclear entry, and TCF/LEF-dependent transcription).

MODULE:generic_wnt_signalingDRAFTSignaling Pathwaymodules/wnt_signaling.yaml
Wnt signaling pathwayGO:0016055
GO:0016055
Wnt signaling pathway
The module is grounded in the GO biological-process term for the Wnt signaling pathway.
GO:0060070
canonical Wnt signaling pathway
The canonical branch is grounded in the GO term for the canonical (beta-catenin-dependent) Wnt signaling pathway.
GO:0035567
non-canonical Wnt signaling pathway
The beta-catenin-independent branches are grounded in the GO term for non-canonical Wnt signaling.
Reactome:R-HSA-195721
Signaling by WNT
Reactome represents Wnt signaling as a set of conserved subpathways spanning ligand biogenesis, receptor activation, and downstream transcriptional and non-canonical responses.
Reactome:R-HSA-201681
TCF dependent signaling in response to WNT
Reactome models the canonical output as TCF/LEF-dependent transcription driven by stabilized beta-catenin.
PANTHER:PTN000139394
PAINT Frizzled receptor ancestral node
Local PAINT IBD seed rows place the curated FZD1 exemplar in PTHR11309 node PTN000139394 with Wnt receptor activity and canonical Wnt signaling terms, anchoring the receptor tier where the cache supports it.
PANTHER:PTN000093831
PAINT Wnt ligand frizzled-binding node
Local PAINT IBD seed rows for a curated Wnt-family exemplar support frizzled binding in PTHR10878 node PTN000093831; this is used as a family-level ligand-role ancestry anchor, not as a WNT3A-specific claim.

This is intentionally a generic family-level sketch. Each step is realized in concrete organisms by specific paralogs (e.g. ~19 WNT ligands, ~10 Frizzled receptors, three Dishevelled and three Axin/two GSK3 paralogs in mammals); the abstract FAMILY and ANY_WITH_FUNCTION selectors below carry a few representative UniProt members only to orient the family, not to limit it. Extracellular tuning of the pathway (R-spondin/LGR potentiation, RNF43/ZNRF3 receptor turnover, and the secreted antagonists DKK, SFRP, and WIF) is represented as a regulatory interface rather than as core transduction steps. A species-specific module can specialize each abstract participant with concrete genes, tissues, compartments, and the relevant paralog complement.

14Nodes
8Parts
2Variant Sets
5Variants
18Annotons
9Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:generic_wnt_signaling deep-research report alongside the module YAML.

Leaf nodes lacking representative members

5 leaf node(s) with no concrete protein grounding:

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (2/13 grounded genes reviewed)

2 complete review(s) · 1 with deep research · 11 missing review · 1 reviewed but lacking deep research

Gene Review Complete Deep research
AXIN1 O15169 ✓ ✓ ✓
GSK3B P49841 ✓ ✓ ✗
DVL1 (human) O14640 ✗ — —
LRP6 (human) O75581 ✗ — —
APC (human) P25054 ✗ — —
CTNNB1 (human) P35222 ✗ — —
CSNK1A1 (human) P48729 ✗ — —
WNT3A (human) P56704 ✗ — —
WLS (human) Q5T9L3 ✗ — —
PORCN (human) Q9H237 ✗ — —
TCF7L2 (human) Q9NQB0 ✗ — —
FZD1 (human) Q9UP38 ✗ — —
BTRC (human) Q9Y297 ✗ — —

Details

Context
metazoaNCBITaxon:33208
plasma membraneGO:0005886 cytosolGO:0005829 nucleusGO:0005634
Generic Wnt signaling pathwaySignaling Pathwaywnt_signaling
Wnt signaling pathwayGO:0016055
Context
metazoaNCBITaxon:33208
plasma membraneGO:0005886 cytosolGO:0005829 nucleusGO:0005634

Connections

Secreted, acylated Wnt from the sending cell engages receptors on the receiving cell.
Receptor/co-receptor engagement selects and initiates the downstream branch.
R-spondin/LGR blocks RNF43/ZNRF3-mediated Frizzled turnover, raising surface receptor and sensitizing cells to Wnt.
RNF43/ZNRF3 ubiquitinate Frizzled to lower surface receptor abundance.
Secreted DKK (on LRP5/6) and SFRP/WIF (sequestering Wnt) reduce productive receptor engagement.
Part 1: Wnt ligand biogenesis and secretion (signal-sending cell)
Wnt ligand acylation and secretionBiological Processwnt_ligand_biogenesis

In the signal-sending cell, nascent Wnt is lipid-modified in the ER by the membrane-bound O-acyltransferase Porcupine, which attaches palmitoleate to a conserved serine. This acylation is required both for Wnt secretion and for receptor binding. The acylated Wnt is then bound by the dedicated cargo receptor Wntless/WLS and trafficked to the cell surface for release.

Wnt protein secretionGO:0061355

Annotons

Porcupine-mediated Wnt palmitoleoylation
porcn_wnt_acylation
Participant: Family: Porcupine O-acyltransferase family (MBOAT)
Family:
Porcupine O-acyltransferase family (MBOAT) ER membrane-bound O-acyltransferase that acylates Wnt ligands.
Representative Members: PORCN (human)UniProtKB:Q9H237

Function

protein-serine O-palmitoleoyltransferase activity (Wnt acylation)GO:0008374
Substrates: nascent Wnt protein palmitoleoyl-CoA
Products: palmitoleoylated Wnt protein

Locations

endoplasmic reticulum membraneGO:0005789

Committed, rate-limiting modification that licenses Wnt for secretion and high-affinity receptor binding; the principal target of porcupine-inhibitor Wnt-pathway drugs.

Wntless/WLS-mediated Wnt secretion
wls_wnt_secretion
Participant: Family: Wntless/WLS cargo-receptor family
Family:
Wntless/WLS cargo-receptor family Multipass membrane protein that escorts acylated Wnt from the Golgi to the cell surface.
Representative Members: WLS (human)UniProtKB:Q5T9L3

Function

Wnt cargo receptor / secretion transporterGO:0038024
Cargo: palmitoleoylated Wnt protein

Processes

Wnt protein secretionGO:0061355

Binds lipidated Wnt and traffics it through the secretory pathway; recycled via retromer back to the Golgi.

Secreted Wnt ligand
wnt_ligand
Participant: Family: Wnt ligand family
Family:
Wnt ligand family Secreted, palmitoleoylated, cysteine-rich glycoprotein morphogens (e.g. ~19 WNT paralogs in mammals).
Representative Members: WNT3A (human)UniProtKB:P56704

Function

Wnt receptor ligand / frizzled bindingGO:0005109
Targets: Frizzled receptor Wnt co-receptor (LRP5/6 or ROR/RYK)

The diffusible signal; different Wnt paralogs preferentially engage canonical or non-canonical branches depending on receptor context.

Part 2: Wnt reception at the target-cell surface
Wnt-Frizzled-co-receptor engagementBiological Processwnt_receptor_engagement

On the signal-receiving cell, Wnt binds the cysteine-rich domain of a Frizzled seven-transmembrane receptor. A co-receptor determines branch identity: the single-pass LRP5/6 co-receptor commits to the canonical branch, whereas ROR1/2 and RYK route to non-canonical branches.

Wnt receptor activityGO:0042813

Annotons

Frizzled receptor
fzd_receptor
Participant: Family: Frizzled receptor family
Family:
Frizzled receptor family Seven-transmembrane Wnt receptors with an extracellular cysteine-rich domain (CRD).
Representative Members: FZD1 (human)UniProtKB:Q9UP38

Function

Wnt-activated receptor activityGO:0042813
Targets: Dishevelled

Locations

plasma membraneGO:0005886

Primary Wnt-binding receptor; CRD engages the palmitoleoyl group and core of Wnt.

Variant set: Wnt co-receptor variants by co-receptor / branch identity (Exactly One)
LRP5/6 co-receptor (canonical)Regulatory Steplrp_coreceptor_variant

Annotons

LRP5/6 single-pass co-receptor
lrp_coreceptor
Participant: Family: LRP5/LRP6 Wnt co-receptor family
Family:
LRP5/LRP6 Wnt co-receptor family Single-pass LDL-receptor-related co-receptors required for canonical signaling.
Representative Members: LRP6 (human)UniProtKB:O75581

Function

Wnt co-receptor activityGO:0017147

Forms the ternary Wnt-Frizzled-LRP6 complex; its phosphorylated cytoplasmic tail recruits Axin, committing to the canonical branch.

ROR/RYK co-receptor (non-canonical)Regulatory Stepror_ryk_coreceptor_variant

Annotons

ROR1/2 or RYK co-receptor
ror_ryk_coreceptor
Participant: Any With Function: Wnt co-receptor activity (non-canonical)
Required Function:
Wnt co-receptor activity (non-canonical)GO:0017147
Receptor tyrosine kinase / pseudokinase co-receptors routing to PCP or Ca2+ branches.

Function

non-canonical Wnt co-receptor activityGO:0017147

Directs Wnt input toward beta-catenin-independent outputs.

Part 3: branch-specific signal transduction
Branch-specific Wnt transductionSignaling Pathwaywnt_branch_transduction

Downstream of receptor engagement, Dishevelled is recruited to Frizzled and the pathway diverges. The branch realized depends on ligand, receptor, and cellular context; more than one branch may be active in a tissue.

Annotons

Dishevelled recruitment to Frizzled
dvl_recruitment
Participant: Family: Dishevelled (DVL) scaffold family
Family:
Dishevelled (DVL) scaffold family Cytoplasmic scaffold (DIX, PDZ, DEP domains) recruited to activated Frizzled; shared hub for all branches.
Representative Members: DVL1 (human)UniProtKB:O14640

Function

signaling adaptor activity (Frizzled-recruited scaffold)GO:0035591

Locations

plasma membraneGO:0005886

Common transducer: nucleates Wnt signalosome assembly in the canonical branch and organizes Rho/Rac and Ca2+ effectors in the non-canonical branches.

Variant set: Wnt signaling branch variants by signaling branch (One Or More)
Canonical (beta-catenin-dependent) branchSignaling Pathwaycanonical_branch

The beta-catenin-dependent branch. In the absence of Wnt, a cytoplasmic destruction complex keeps beta-catenin low; Wnt engagement inactivates this complex, allowing beta-catenin to accumulate, enter the nucleus, and convert TCF/LEF factors into transcriptional activators.

canonical Wnt signaling pathwayGO:0060070

Connections

In the Wnt-off state the destruction complex keeps beta-catenin low.
Wnt-on signalosome inhibits the destruction complex.
Relief of degradation allows beta-catenin to accumulate.
Nuclear beta-catenin partners with TCF/LEF to activate transcription.
Part 1: ligand-off state - beta-catenin destruction
Beta-catenin destruction complex (Wnt-off)Regulatory Stepdestruction_complex_off_state

Without Wnt, the Axin-scaffolded destruction complex (Axin, APC, CK1, GSK3) sequentially phosphorylates beta-catenin, marking it for SCF(beta-TrCP)-mediated ubiquitination and proteasomal degradation, so cytoplasmic beta-catenin stays low and TCF/LEF targets are repressed.

beta-catenin destruction complexGO:0030877

Annotons

Axin/APC/CK1/GSK3 destruction complex
destruction_complex
Participant: Protein Complex: beta-catenin destruction complex
Protein Complex:
beta-catenin destruction complexGO:0030877
Active units:
Axin scaffold
Participant: Family: Axin scaffold family
Family:
Axin scaffold family Concentration-limiting scaffold that assembles the destruction complex.
Representative Members: AXIN1 (human)UniProtKB:O15169
Role: rate-limiting scaffold of the destruction complex
APC
Participant: Family: APC tumor-suppressor family
Family:
APC tumor-suppressor family Large scaffold that binds beta-catenin and Axin; mutated in most colorectal cancers.
Representative Members: APC (human)UniProtKB:P25054
Role: co-scaffold; promotes beta-catenin capture and turnover
Casein kinase 1 (priming kinase)
Participant: Family: Casein kinase 1 family
Family:
Casein kinase 1 family Priming Ser/Thr kinase that phosphorylates beta-catenin at Ser45.
Representative Members: CSNK1A1 (human)UniProtKB:P48729
Role: priming kinase
Function:
protein serine/threonine kinase activityGO:0004674
GSK3 (processive kinase)
Participant: Family: GSK3 family
Family:
GSK3 family Ser/Thr kinase that phosphorylates the beta-catenin degron after CK1 priming.
Representative Members: GSK3B (human)UniProtKB:P49841
Role: processive kinase generating the phosphodegron
Function:
protein serine/threonine kinase activityGO:0004674

Function

beta-catenin phosphorylation for destructionGO:0004674
Targets: beta-catenin

CK1 priming (Ser45) followed by GSK3 phosphorylation (Thr41/Ser37/Ser33) creates the beta-TrCP degron.

SCF(beta-TrCP) ubiquitination of beta-catenin
btrc_ubiquitination
Participant: Family: beta-TrCP F-box family (SCF E3 ligase substrate receptor)
Family:
beta-TrCP F-box family (SCF E3 ligase substrate receptor) F-box protein recognizing the doubly-phosphorylated beta-catenin degron.
Representative Members: BTRC (human)UniProtKB:Q9Y297

Function

ubiquitin-protein transferase activity (phosphodegron-dependent)GO:0004842
Targets: phosphorylated beta-catenin

Processes

protein ubiquitinationGO:0016567

Polyubiquitinates phospho-beta-catenin, targeting it to the 26S proteasome.

Part 2: ligand-on state - signalosome and destruction-complex inhibition
Wnt signalosome and destruction-complex inhibition (Wnt-on)Regulatory Stepsignalosome_on_state

Wnt engagement clusters Frizzled-LRP6 with Dishevelled into a Wnt signalosome. CK1/GSK3 phosphorylate the LRP6 cytoplasmic PPPSP motifs, which recruit Axin to the membrane and inhibit the destruction complex, so beta-catenin is no longer phosphorylated and degraded.

Wnt signalosomeGO:1990909

Annotons

Wnt signalosome assembly and LRP6 phosphorylation
signalosome_assembly
Participant: Protein Complex: Wnt signalosome (Frizzled-LRP6-Dishevelled-Axin)
Protein Complex:
Wnt signalosome (Frizzled-LRP6-Dishevelled-Axin)GO:1990909

Function

signaling adaptor activity (recruits Axin to phospho-LRP6, sequestering the destruction complex)GO:0035591
Targets: beta-catenin destruction complexGO:0030877

Processes

Wnt signalosome assemblyGO:1904887 positive regulation of canonical Wnt signaling pathwayGO:0090263

Membrane recruitment of Axin to phospho-LRP6 disables beta-catenin phosphorylation, the switch that turns the canonical pathway on.

Part 3: beta-catenin stabilization and nuclear entry
Beta-catenin stabilization and nuclear translocationRegulatory Stepbeta_catenin_stabilization

Newly synthesized beta-catenin, no longer degraded, accumulates in the cytoplasm and translocates to the nucleus.

Annotons

Beta-catenin (stabilized effector)
beta_catenin
Participant: Family: beta-catenin / Armadillo family
Family:
beta-catenin / Armadillo family Armadillo-repeat effector and transcriptional co-activator of the canonical branch (moonlights at adherens junctions).
Representative Members: CTNNB1 (human)UniProtKB:P35222

Function

transcription factor binding (binds TCF/LEF to recruit co-activators)GO:0008134
Targets: TCF/LEF transcription factor

Locations

cytosolGO:0005829 nucleusGO:0005634

Accumulation and nuclear import of beta-catenin is the quantitative readout of canonical pathway activation.

Part 4: nuclear transcriptional output
TCF/LEF-dependent transcriptional activationRegulatory Steptcf_lef_transactivation

In the nucleus, beta-catenin binds TCF/LEF DNA-binding factors, displacing Groucho/TLE co-repressors and recruiting co-activators to switch Wnt target genes from repressed to active.

beta-catenin-TCF complexGO:1990907

Annotons

TCF/LEF DNA-binding factor
tcf_lef_factor
Participant: Family: TCF/LEF HMG-box transcription factor family
Family:
TCF/LEF HMG-box transcription factor family Sequence-specific DNA-binding factors that switch between repression (with TLE) and activation (with beta-catenin).
Representative Members: TCF7L2 (human)UniProtKB:Q9NQB0

Function

DNA-binding transcription factor activity (beta-catenin-dependent switch)GO:0003700

Locations

nucleusGO:0005634

Provides DNA-binding specificity; beta-catenin supplies the transactivation function.

Beta-catenin transcriptional co-activator role
beta_catenin_coactivator
Participant: Any With Function: transcription coactivator activity
Required Function:
transcription coactivator activityGO:0003713 Stabilized beta-catenin acting in the nucleus.

Function

transcription coactivator activityGO:0003713
Targets: TCF/LEF-bound Wnt target promoters

Converts TCF/LEF from repressor to activator at Wnt target genes.

Non-canonical planar cell polarity (PCP) branchSignaling Pathwaypcp_branch

Beta-catenin-independent branch in which Wnt-Frizzled-Dishevelled signaling, via ROR/RYK and the core PCP proteins, activates small GTPases (RhoA, Rac1) and downstream kinases (ROCK, JNK) to control cytoskeletal organization, oriented cell behavior, and convergent extension.

Wnt signaling pathway, planar cell polarity pathwayGO:0060071

Annotons

Rho/Rac GTPase and JNK effector arm
pcp_rho_rac_effectors
Participant: Any With Function: Rho/Rac-dependent cytoskeletal effector signaling
Required Function:
Rho/Rac-dependent cytoskeletal effector signaling
Dishevelled-organized small-GTPase and kinase effectors controlling polarity.

Processes

Rho protein signal transductionGO:0007266 establishment of planar polarityGO:0001736 JNK cascadeGO:0007254

Couples Wnt input to actin/microtubule polarity rather than transcription.

Non-canonical Wnt/calcium branchSignaling Pathwaycalcium_branch

Beta-catenin-independent branch in which Wnt-Frizzled signaling acts through heterotrimeric G proteins and phospholipase C to raise intracellular calcium, activating CaMKII, calcineurin/NFAT, and PKC.

Wnt signaling pathway, calcium modulating pathwayGO:0007223

Annotons

PLC / Ca2+ / CaMKII-PKC effector arm
calcium_effectors
Participant: Any With Function: calcium-mobilizing Wnt effector signaling
Required Function:
calcium-mobilizing Wnt effector signaling
G-protein/PLC-driven calcium release and calcium-dependent kinases/phosphatases.

Processes

phospholipase C-activating G protein-coupled receptor signaling pathwayGO:0007200 release of sequestered calcium ion into cytosolGO:0051209

Calcium-dependent output; can antagonize the canonical branch in some contexts.

Part 4: extracellular and receptor-level regulatory interface (optional)
Wnt regulatory interfaceRegulatory Stepwnt_regulatory_interface

Conserved modulators that set pathway sensitivity. Secreted antagonists (DKK acting on LRP5/6; SFRP and WIF sequestering Wnt) dampen signaling, while the R-spondin/LGR4-6 system blocks RNF43/ZNRF3-mediated ubiquitination and turnover of Frizzled, thereby potentiating signaling.

Annotons

RNF43/ZNRF3 Frizzled turnover (negative)
rnf43_znrf3_receptor_turnover
Participant: Any With Function: ubiquitin-protein transferase activity (Frizzled receptor)
Required Function:
ubiquitin-protein transferase activity (Frizzled receptor)GO:0004842
Transmembrane E3 ligases that ubiquitinate Frizzled to reduce surface receptor.

Function

ubiquitin-protein transferase activityGO:0004842
Targets: Frizzled receptor

Processes

negative regulation of canonical Wnt signaling pathwayGO:0090090

Lowers Frizzled abundance; antagonized by R-spondin/LGR.

R-spondin/LGR potentiation (positive)
rspo_lgr_potentiation
Participant: Any With Function: R-spondin receptor / Wnt-potentiating activity
Required Function:
R-spondin receptor / Wnt-potentiating activity
R-spondin ligands with LGR4-6 receptors that neutralize RNF43/ZNRF3.

Processes

positive regulation of canonical Wnt signaling pathwayGO:0090263

Stabilizes surface Frizzled, sensitizing cells (notably stem cells) to Wnt.

Secreted Wnt antagonists (DKK/SFRP/WIF)
secreted_antagonists
Participant: Any With Function: Wnt-protein binding / co-receptor antagonist
Required Function:
Wnt-protein binding / co-receptor antagonistGO:0017147
Secreted factors that sequester Wnt or block LRP5/6.

Processes

negative regulation of Wnt signaling pathwayGO:0030178

Extracellular dampening of pathway input.