id: MODULE:wnt_planar_cell_polarity title: Vertebrate Wnt/planar cell polarity (PCP) signalling - Wnt5a/Wnt11, ROR2/PTK7, core PCP complexes and Rho/Rac effector arms description: >- Planar cell polarity (PCP) orients cells within the plane of a tissue. It is needed for convergent extension during gastrulation, neural tube closure, orientation of inner-ear hair-cell bundles and hair follicles, and limb elongation. In vertebrates the system is set up by Wnt ligands, chiefly Wnt5a and Wnt11, which do not stabilize beta-catenin in most contexts. They act through Frizzled receptors with the ROR2 and PTK7 co-receptors and induce dose-dependent phosphorylation of the four-pass membrane protein VANGL2. The core PCP proteins form two mutually exclusive membrane complexes at opposite sides of each cell. One is Frizzled with Dishevelled, recruited through its DEP domain to the Frizzled tail. The other is VANGL with Prickle, which binds Dishevelled and antagonizes its recruitment by Frizzled. The atypical cadherin CELSR1 forms homophilic bridges between neighbouring cells and recruits both sides to the junction. Dishevelled drives two effector arms: the formin DAAM1 links it to RhoA and Rho kinase for actomyosin contractility, and Rac1 activates JNK. Together they turn polarity cues into oriented cytoskeletal behaviour and cell movement. The pathway works independently of the beta-catenin destruction complex and TCF/LEF transcription. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000200 title: wnt signaling, the planar cell polarity pathway statement: >- The module boundary follows the RGD Pathway Ontology term and its diagram. The diagram draws Wnt ligands associated with Fzd receptors, Dvls associated with Fzd receptors, Prickle1, Rac1 and Daam1, Daam1 associated with Rhoa, Prickle1 negatively affecting Dvls, Prickle1, Prickle2, Ptk7 and Scrib associated with Vangl2, Celsr1 and Scrib positively affecting Vangl2, and Rhoa and Rac1 feeding the Rho/Rac/Cdc42 (PW:0000105) and JNK MAPK (PW:0000313) subpathways. Its record text names Wnt5, Wnt7 and Wnt11 as vertebrate PCP ligands and describes the pathway as independent of beta-catenin. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000200.yaml). - source_id: GO:0060071 title: Wnt signaling pathway, planar cell polarity pathway statement: >- The GO mapping recorded for PW:0000200 (skos:closeMatch, from the RGD page and the PW definition). It is not used as a module concept because GO proposes to obsolete the Wnt/PCP signalling branch, including this term, in the PCP restructuring tracked in ai4curation/ai-gene-review#5781 (geneontology/go-ontology#32697). It is live in GO release 2026-07-26 and is kept here as the derivation record. - source_id: PMID:26566118 title: 'Wnt-Frizzled/planar cell polarity signaling: cellular orientation by facing the wind (Wnt).' statement: Review of the core Fz/Vangl PCP pathway in Drosophila and vertebrates; it describes the two mutually exclusive complexes and the dedicated PCP Wnts. supporting_text: As such, the two complexes Fz-Dsh-Dgo and Vang-Pk are resolved to mutually exclusive regions at opposite sides of each cell - source_id: PMID:26566118 title: 'Wnt-Frizzled/planar cell polarity signaling: cellular orientation by facing the wind (Wnt).' statement: The same asymmetry is seen in vertebrate PCP tissues. supporting_text: Similar observations of mutually exclusive localization of the Fz-Dsh and Vang-Pk complexes have been made in vertebrate PCP models, most notably in the mouse inner ear, skin, and limb and in the zebrafish presomitic mesoderm - source_id: PMID:28293032 title: Planar cell polarity in development and disease. statement: Review placing Wnt gradients among the global cues that orient the core PCP complexes. supporting_text: The basis of PCP establishment is the localization of mutually exclusive subsets of the core PCP proteins to opposing domains along the cell cortex, forming a pattern that propagates throughout the tissue. notes: >- Derived from RGD PW:0000200 (wnt signaling, the planar cell polarity pathway; 16 RGD-curated human genes: CELSR1, DAAM1, DVL1, DVL2, FZD3, FZD6, FZD7, FZD9, PRICKLE1, PRICKLE2, PTK7, RAC1, RHOA, SCRIB, VANGL2, WNT7B). The PCP Frizzleds (FZD3, FZD6, FZD7) enter through the referenced generic receptor step and are named in prose. Every other RGD gene except SCRIB, FZD9 and WNT7B is a part or a representative member. Added beyond RGD: WNT5A, WNT11, ROR2, VANGL1 and the ROCK and JNK kinases that complete the effector arms named by RGD's subpathway links (PW:0000105 Rho/Rac/Cdc42, PW:0000313 JNK MAPK; mentioned here only, not claimed as evidence). GO terms: the RGD-mapped GO:0060071 and its regulation terms (GO:2000095, GO:2000096) are proposed for obsoletion in GO's PCP restructuring (ai4curation/ai-gene-review#5781, upstream geneontology/go-annotation#6638 and go-ontology#32697). The module therefore uses GO:0001736 establishment of planar polarity (to be redefined, not retired) and the parent GO:0035567 non-canonical Wnt signaling pathway as concepts, and no annoton uses a term on the retirement list. The upstream-proposed core PCP module term (written there as GO:7770140) is not in GO release 2026-07-26 and is not used; once it exists it is the natural module concept. Reuse of the generic wnt_signaling module: ligand acylation and secretion and the Frizzled receptor step are included by module_ref. The receptor node carries an EXACTLY_ONE co-receptor choice whose LRP5/6 variant is canonical, so the PCP co-receptors ROR2 and PTK7 are made concrete in a separate step. Dishevelled could not be referenced: in wnt_signaling it sits on the branch-transduction node together with the canonical branch and a coarse PCP branch, so a reference would let canonical signalling satisfy this module and would nest a sketch of this module inside itself. Dishevelled is therefore restated only in its PCP-specific capacity (DEP-domain recruitment to Frizzled) with the same signalling-adaptor function. Boundary with canonical signalling: LRP5/6, Axin, APC, GSK3, beta-catenin and TCF/LEF are outside the module; DAAM1 and Rac1 act without affecting beta-catenin (PMID:11779461, PMID:12533515). PTK7 also has a reported canonical beta-catenin-binding role, which is its core function in the gene review, and here only its PCP co-receptor role is modelled. Left out: SCRIB (RGD draws a Scrib-Vangl2 association; no cached primary source was available to ground it, so it is noted rather than modelled); ANKRD6 (Diego), a Frizzled-side cytoplasmic core protein not in the RGD list; FZD9 and WNT7B (RGD-listed but with weak PCP-specific evidence); the Fat/Dachsous system, the PCP effector/CPLANE proteins (INTU, FUZ, WDPCP) and ciliary PCP outputs; Wnt/calcium signalling, which is the other non-canonical branch in wnt_signaling. Several core proteins (VANGL, PRICKLE, CELSR1) are given no molecular function, because GOA has only binding or electronic functions for the human proteins and GO has no term for a scaffold that partitions to one side of the cell. GO-CAM: no model in gocams/index.tsv is a PCP model. The seed's best GO-CAM lead (gomodel:62900b6400001749, ZDHHC7 regulating SCRIB in polarized epithelial differentiation) overlaps only through SCRIB, is about apical-basal polarity and is not linked. RHOA, RAC1 and MAPK8 appear in many human models for unrelated pathways, and none of them is linked. module: id: wnt_planar_cell_polarity label: Wnt/planar cell polarity signalling (vertebrate core PCP) module_type: SIGNALING_PATHWAY concepts: - preferred_term: establishment of planar polarity term: id: GO:0001736 label: establishment of planar polarity description: The outcome the module produces. GO plans to redefine and re-parent this term in the PCP restructuring, not to obsolete it. - preferred_term: non-canonical Wnt signaling pathway term: id: GO:0035567 label: non-canonical Wnt signaling pathway description: Parent of the RGD-mapped GO:0060071, used instead of it because GO:0060071 is proposed for obsoletion. It also states the boundary with canonical beta-catenin signalling. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane notes: Members are human gene products. Much of the mechanistic evidence comes from mouse, Xenopus and zebrafish, and from Drosophila for the core complexes; the cited evidence says which organism was studied. parts: - order: 1 role: Wnt ligand acylation and secretion in the signal-sending cell optional: true node: id: pcp_wnt_secretion label: Wnt acylation and secretion (shared with generic Wnt signalling) description: >- Included by reference to the generic Wnt signalling module. PORCN palmitoleoylation and WLS-dependent secretion are common to canonical and PCP Wnts, so they are not restated here. The part is optional because PCP can be oriented by cues other than a Wnt gradient (planar polarity in the Drosophila wing is largely Wnt-independent). module_ref: wnt_signaling#wnt_ligand_biogenesis - order: 2 role: PCP Wnt ligands node: id: pcp_ligands label: Wnt5a and Wnt11 non-canonical ligands module_type: SIGNALING_PATHWAY description: >- Wnt5a and Wnt11 are the vertebrate Wnts most clearly dedicated to PCP. In most contexts they do not stabilize beta-catenin, and graded Wnt5a orients PCP in the limb bud. variant_sets: - id: pcp_ligand_choice label: PCP Wnt ligand axis: Wnt paralog variant_kind: REALIZER selection: ONE_OR_MORE notes: Wnt5a and Wnt11 act in different tissues and may use distinct mechanisms; both bind Frizzled. RGD also lists WNT7B, which is not modelled here. variants: - id: wnt5a_ligand label: Wnt5a module_type: MOLECULAR_FUNCTION annotons: - id: wnt5a_frizzled_binding label: Wnt5a ligand participant: selector_type: GENE_PRODUCT gene_product: preferred_term: WNT5A term: id: UniProtKB:P41221 label: Protein Wnt-5a function: preferred_term: frizzled binding term: id: GO:0005109 label: frizzled binding locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Secreted PCP ligand; binds Frizzled and the ROR2 cysteine-rich domain and induces VANGL2 phosphorylation through ROR2. Frizzled binding is the function human WNT5A carries by IPI and IBA in GOA. evidence: - source_id: PMID:12839624 statement: Wnt5a binds the ROR2 cysteine-rich domain, and Wnt5a with ROR2 activates JNK and inhibits convergent extension in Xenopus. supporting_text: In vitro binding assay revealed that Wnt5a binds to the CRD of Ror2. - source_id: PMID:21316585 statement: In the mouse limb bud a Wnt5a gradient sets PCP in chondrocytes by regulating VANGL2 phosphorylation. supporting_text: In the limb bud, Wnt5a signaling gradient controls limb elongation by establishing PCP in chondrocytes along the proximal-distal axis through regulating Vangl2 phosphorylation. - id: wnt11_ligand label: Wnt11 module_type: MOLECULAR_FUNCTION annotons: - id: wnt11_frizzled_binding label: Wnt11 ligand participant: selector_type: GENE_PRODUCT gene_product: preferred_term: WNT11 term: id: UniProtKB:O96014 label: Protein Wnt-11 function: preferred_term: frizzled binding term: id: GO:0005109 label: frizzled binding locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: Secreted PCP ligand required for convergent extension (the zebrafish silberblick mutant). Human WNT11 has frizzled binding by IBA in GOA. evidence: - source_id: PMID:26566118 statement: Wnt5a and Wnt11 are the vertebrate Wnts largely dedicated to PCP. supporting_text: And then, of course, evidence from vertebrates shows that Wnt5a and Wnt11 (and possibly more Wnts) are largely dedicated to PCP - source_id: PMID:26566118 statement: Wnt11 (silberblick) and Wnt5b (pipetail) zebrafish mutants have convergent extension defects. supporting_text: The Wnt5b mutant pipetail ( ppt) and the Wnt11 mutant silberblick (slb) also exhibit a broadened and shortened A-P body axis with defective CE movement - order: 3 role: Frizzled reception (shared with generic Wnt signalling) node: id: pcp_frizzled_reception label: Frizzled receptor engagement description: >- Included by reference to the receptor step of the generic Wnt signalling module, which models Frizzled Wnt receptor activity with an EXACTLY_ONE co-receptor choice. In PCP the ROR/RYK (non-canonical) co-receptor variant is the one realized, made concrete by the next step; the LRP5/6 variant belongs to canonical signalling and is outside this module. In PCP tissues FZD3 and FZD6 (and FZD7 in Xenopus) are the Frizzleds that localize asymmetrically. The same Frizzled is the transmembrane component of the distal core complex below. module_ref: wnt_signaling#wnt_receptor_engagement evidence: - source_id: PMID:16495441 statement: Mouse FZD3 and FZD6 redundantly control neural tube closure and hair-bundle orientation, localize asymmetrically, and fail to localize correctly at the cell surface in Vangl2 mutants. supporting_text: Here, we report that Fz3 and Fz6 redundantly control neural tube closure and the planar orientation of hair bundles on a subset of auditory and vestibular sensory cells. - order: 4 role: non-canonical co-receptors node: id: pcp_coreceptors label: ROR2 and PTK7 co-receptors module_type: SIGNALING_PATHWAY description: >- ROR2 binds Wnt5a through its Frizzled-like cysteine-rich domain and forms a Wnt-induced complex with VANGL2. Wnt5a then induces dose-dependent phosphorylation of VANGL2, which links the ligand gradient to the core PCP machinery. The pseudokinase PTK7 associates with ROR2 and Wnt5a and interacts genetically with Vangl2. annotons: - id: ror2_coreceptor label: ROR2 Wnt5a receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ROR2 term: id: UniProtKB:Q01974 label: Tyrosine-protein kinase transmembrane receptor ROR2 function: preferred_term: transmembrane receptor protein tyrosine kinase activity term: id: GO:0004714 label: transmembrane receptor protein tyrosine kinase activity locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Wnt5a receptor and Frizzled co-receptor that relays Wnt dose to VANGL2 phosphorylation. The function is the reviewed core function of human ROR2; whether ROR2 kinase activity itself is needed for VANGL2 phosphorylation is not settled. evidence: - source_id: PMID:21316585 statement: VANGL2 forms a Wnt-induced receptor complex with ROR2 and is phosphorylated in proportion to Wnt dose. supporting_text: Vangl2, a core component in planar cell polarity, forms Wnt-induced receptor complex with Ror2 to sense Wnt dosages. - source_id: PMID:12839624 statement: ROR2 associates with Frizzled through its cysteine-rich domain and acts with Wnt5a in non-canonical signalling. supporting_text: Ror2 may thus act as a receptor for Wnt5a to activate non-canonical Wnt signalling. - source_id: file:genes/human/ROR2/ROR2-ai-review.yaml statement: 'Reviewed core function of human ROR2: transmembrane receptor protein tyrosine kinase activity.' - id: ptk7_coreceptor label: PTK7 pseudokinase co-receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PTK7 term: id: UniProtKB:Q13308 label: Inactive tyrosine-protein kinase 7 function: preferred_term: coreceptor activity term: id: GO:0015026 label: coreceptor activity locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Catalytically inactive receptor that forms a complex with ROR2, interacts with Wnt5a and is needed for vertebrate PCP. Coreceptor activity is a NAS row in GOA and is not a core function in the human PTK7 review, whose core function is beta-catenin binding (its canonical-pathway role); the PCP role is supported here by the cited experiments. evidence: - source_id: PMID:26499793 statement: PTK7 and ROR2 form a heterodimer and interact with Wnt5a, leading to JNK activation and cell movement. supporting_text: We demonstrate that PTK7 and ROR2 physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. - source_id: PMID:15229603 statement: Mouse Ptk7 mutation disrupts neural tube closure and hair-bundle orientation and interacts genetically with Vangl2. supporting_text: These results identify PTK7 as a novel regulator of PCP in vertebrates. - order: 5 role: asymmetric core PCP complexes node: id: pcp_core_complexes label: Core PCP asymmetric membrane complexes module_type: BIOLOGICAL_PROCESS description: >- The core PCP proteins sort into two mutually exclusive membrane complexes at opposite sides of each cell, held across cell junctions by CELSR homodimers. Frizzled with Dishevelled (with Diego/ANKRD6, not modelled) occupies one side. VANGL with Prickle occupies the other, and Prickle antagonizes Frizzled-dependent recruitment of Dishevelled, which sharpens the asymmetry. parts: - order: 1 role: intercellular bridge node: id: celsr_bridge label: CELSR1 homophilic bridge module_type: MOLECULAR_FUNCTION annotons: - id: celsr1_homophilic_adhesion label: CELSR1 (Flamingo) homophilic adhesion participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CELSR1 term: id: UniProtKB:Q9NYQ6 label: Cadherin EGF LAG seven-pass G-type receptor 1 processes: - preferred_term: homophilic cell-cell adhesion term: id: GO:0007156 label: homophilic cell-cell adhesion locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Seven-pass atypical cadherin whose intercellular homodimers recruit VANGL2 or FZD6 to the junction on each side. No molecular function is asserted; human CELSR1 has only electronic function annotations in GOA. evidence: - source_id: PMID:26566118 statement: Intercellular Celsr1 homodimers recruit Vangl2 or Fzd6 to the membrane, as Flamingo does in Drosophila. supporting_text: In addition, intercellular Celsr1 homodimers are required to recruit Vangl2 or Fzd6 to the membrane - order: 2 role: Frizzled-side (distal in the fly wing) cytoplasmic component node: id: pcp_dishevelled_side label: Dishevelled recruited to Frizzled by its DEP domain module_type: MOLECULAR_FUNCTION annotons: - id: dvl_pcp_adaptor label: Dishevelled PCP adaptor participant: selector_type: FAMILY family: preferred_term: Dishevelled (DVL1-3) description: Cytoplasmic DIX-PDZ-DEP scaffolds. Their recruitment to Frizzled through the DEP domain is what PCP needs; the DIX-domain signalosome role belongs to canonical signalling. No PANTHER family id is asserted. representative_members: - preferred_term: DVL2 (human) term: id: UniProtKB:O14641 label: Segment polarity protein dishevelled homolog DVL-2 - preferred_term: DVL1 (human) term: id: UniProtKB:O14640 label: Segment polarity protein dishevelled homolog DVL-1 function: preferred_term: signaling adaptor activity term: id: GO:0035591 label: signaling adaptor activity locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: Binds the Frizzled cytoplasmic tail through its DEP domain and couples the Frizzled side to DAAM1-RhoA and Rac1. The function is the one the generic Wnt signalling module gives Dishevelled; here it is restricted to the PCP context. evidence: - source_id: PMID:28293032 statement: Dishevelled is recruited by Frizzled through its DEP domain. supporting_text: As Fmi homodimers recruit Fz to apicolateral regions of the cell, Dsh can be recruited as well in a Fz-dependent manner through the binding of the DEP domain of Dsh to the Fz cytoplasmic tail - order: 3 role: VANGL-side (proximal in the fly wing) components node: id: pcp_vangl_side label: VANGL-Prickle complex module_type: BIOLOGICAL_PROCESS annotons: - id: vangl_pcp_core label: VANGL four-pass PCP core protein participant: selector_type: FAMILY family: preferred_term: Van Gogh-like (VANGL1, VANGL2) description: Four-pass transmembrane core PCP proteins. VANGL2 is the main PCP paralog in mouse. No PANTHER family id is asserted. representative_members: - preferred_term: VANGL2 (human) term: id: UniProtKB:Q9ULK5 label: Vang-like protein 2 - preferred_term: VANGL1 (human) term: id: UniProtKB:Q8TAA9 label: Vang-like protein 1 locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: Transmembrane anchor of the opposite complex. It recruits Prickle, is phosphorylated in a Wnt5a-ROR2-dependent way and is needed for correct Frizzled localization. No molecular function is asserted; GOA has none for human VANGL1 or VANGL2 beyond protein binding. evidence: - source_id: PMID:21316585 statement: Wnts induce dose-dependent VANGL2 phosphorylation, and VANGL2 activity depends on its phosphorylation level. supporting_text: Wnts dose-dependently induce Vangl2 phosphorylation of serine/threonine residues and Vangl2 activities depend on its levels of phosphorylation. - source_id: PMID:16495441 statement: In Vangl2 Looptail mutants, FZD3 and FZD6 fail to localize correctly. supporting_text: In the inner ear of a Vangl2 mutant (Looptail; Lp), Fz3 and Fz6 proteins accumulate to normal levels but do not localize correctly at the cell surface. - id: prickle_pcp_core label: Prickle antagonist of Dishevelled recruitment participant: selector_type: FAMILY family: preferred_term: Prickle (PRICKLE1, PRICKLE2) description: Cytoplasmic PET/LIM-domain core PCP proteins recruited by VANGL. No PANTHER family id is asserted. representative_members: - preferred_term: PRICKLE1 (human) term: id: UniProtKB:Q96MT3 label: Prickle-like protein 1 - preferred_term: PRICKLE2 (human) term: id: UniProtKB:Q7Z3G6 label: Prickle-like protein 2 locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: Recruited by VANGL; binds Dishevelled and antagonizes its Frizzled-mediated membrane recruitment, the negative feedback that keeps the two complexes apart. No molecular function is asserted; GOA has none for human PRICKLE1 or PRICKLE2 beyond binding terms. evidence: - source_id: PMID:26566118 statement: Prickle binds Dishevelled and antagonizes its Frizzled-mediated recruitment; VANGL recruits Prickle. supporting_text: Specifically, Pk can bind Dsh and antagonize its Fz-mediated membrane recruitment - source_id: PMID:26566118 statement: VANGL recruits Prickle to the membrane. supporting_text: This Pk function is supported by Vang, which recruits Pk to the membrane and binds and possibly inhibits Dsh function connections: - source: celsr_bridge target: pcp_dishevelled_side connection_type: POSITIVELY_REGULATES description: CELSR homodimers recruit Frizzled, and with it Dishevelled, to junctions. - source: celsr_bridge target: pcp_vangl_side connection_type: POSITIVELY_REGULATES description: CELSR homodimers recruit VANGL to junctions on the neighbouring cell. - source: vangl_pcp_core target: prickle_pcp_core connection_type: POSITIVELY_REGULATES description: VANGL recruits Prickle to the membrane. - source: prickle_pcp_core target: dvl_pcp_adaptor connection_type: NEGATIVELY_REGULATES description: Prickle antagonizes Frizzled-dependent membrane recruitment of Dishevelled. - order: 6 role: cytoskeletal effector arms node: id: pcp_effectors label: Dishevelled-driven Rho and Rac effector arms module_type: SIGNALING_PATHWAY description: >- Dishevelled activates RhoA and Rac1 in parallel and independently. RhoA activation through the formin DAAM1 drives Rho kinase and actomyosin contraction. Rac1 activation drives JNK. Both arms are needed for vertebrate gastrulation movements. Neither affects beta-catenin signalling. variant_sets: - id: pcp_effector_arm label: Effector arm axis: small GTPase effector branch variant_kind: ROUTE selection: ONE_OR_MORE notes: The two arms run in parallel in the same cells; which outputs matter depends on tissue. They are routes with different activities, not alternative carriers of one activity. variants: - id: daam1_rhoa_rock_arm label: DAAM1-RhoA-ROCK arm module_type: SIGNALING_PATHWAY annotons: - id: daam1_bridge label: DAAM1 Dishevelled-RhoA bridge participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DAAM1 term: id: UniProtKB:Q9Y4D1 label: Disheveled-associated activator of morphogenesis 1 function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Formin that binds both Dishevelled and RhoA and mediates Wnt-induced Dvl-Rho complex formation. Protein-macromolecule adaptor activity (the child of molecular adaptor activity for a protein bridging two proteins) is asserted from that experiment; GOA has only electronic function annotations for human DAAM1. Mouse Daam1 mutants lack PCP defects, which suggests redundancy with other formins. evidence: - source_id: PMID:11779461 statement: In human cells and Xenopus, Wnt/Fz activation of Rho needs Dvl and DAAM1, which binds both and bridges them. supporting_text: Daam1 binds to both Dvl and Rho, and mediates Wnt-induced Dvl-Rho complex formation. - source_id: PMID:26566118 statement: Mouse Daam1 mutants show no PCP defects; DAAM1 is likely redundant with other formin-homology factors. supporting_text: Similarly, mouse Daam1 mutants do not show PCP defects - id: rhoa_gtpase label: RhoA GTPase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RHOA term: id: UniProtKB:P61586 label: Transforming protein RhoA function: preferred_term: GTPase activity term: id: GO:0003924 label: GTPase activity processes: - preferred_term: Rho protein signal transduction term: id: GO:0007266 label: Rho protein signal transduction locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Activated downstream of Dishevelled and DAAM1; required for convergent extension. The function is the reviewed core function of human RHOA. evidence: - source_id: PMID:11779461 statement: Wnt/Fz signalling activates Rho through Dvl and DAAM1, and DAAM1 depletion blocks Rho activation and Xenopus gastrulation but not beta-catenin signalling. supporting_text: Inhibition or depletion of Daam1 prevents Wnt/Fz activation of Rho and of Xenopus gastrulation, but not of beta-catenin signaling. - source_id: file:genes/human/RHOA/RHOA-ai-review.yaml statement: 'Reviewed core function of human RHOA: GTPase activity.' - id: rock_kinase label: Rho kinase (ROCK) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ROCK1 term: id: UniProtKB:Q13464 label: Rho-associated protein kinase 1 function: preferred_term: protein serine/threonine kinase activity term: id: GO:0004674 label: protein serine/threonine kinase activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: RhoA effector kinase that drives actomyosin contractility. ROCK1 stands for the ROCK1/ROCK2 pair; ROCK is not in the RGD gene set and is added because the arm is incomplete without it. Kinase activity is IDA in GOA for human ROCK1. evidence: - source_id: PMID:28293032 statement: PCP-driven convergent extension needs RhoA and Rho kinase. supporting_text: Indeed, PCP-mediated convergent extension requires RhoA and Rho Kinase, as well as a host of other actin regulators such as the formin Daam1 - id: rac1_jnk_arm label: Rac1-JNK arm module_type: SIGNALING_PATHWAY annotons: - id: rac1_gtpase label: Rac1 GTPase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RAC1 term: id: UniProtKB:P63000 label: Ras-related C3 botulinum toxin substrate 1 function: preferred_term: GTPase activity term: id: GO:0003924 label: GTPase activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Forms a Wnt-induced complex with Dishevelled, separate from the Dvl-Rho complex, and activates JNK. The function is the reviewed core function of human RAC1. evidence: - source_id: PMID:12533515 statement: Wnt/Fz activation of Rac is independent of Rho and mediates JNK activation; Dvl forms a separate Wnt-induced complex with Rac. supporting_text: Wnt/Fz activation of Rac is independent of Rho and mediates Wnt/Fz activation of Jun N-terminal kinase (JNK). - source_id: file:genes/human/RAC1/RAC1-ai-review.yaml statement: 'Reviewed core function of human RAC1: GTPase activity.' - id: jnk_kinase label: JNK (MAPK8) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: MAPK8 (JNK1) term: id: UniProtKB:P45983 label: Mitogen-activated protein kinase 8 function: preferred_term: JUN kinase activity term: id: GO:0004705 label: JUN kinase activity processes: - preferred_term: JNK cascade term: id: GO:0007254 label: JNK cascade locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Terminal kinase of the Rac arm, standing for the JNK paralogs. The upstream MAP3K/MAP2K tier is the JNK MAPK module, which RGD links as PW:0000313, and is not restated here. The function is a reviewed core function of human MAPK8. evidence: - source_id: PMID:26499793 statement: Wnt5a acting through PTK7 and ROR2 leads to JNK activation. supporting_text: We demonstrate that PTK7 and ROR2 physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. - source_id: file:genes/human/MAPK8/MAPK8-ai-review.yaml statement: 'Reviewed core function of human MAPK8: JUN kinase activity.' connections: - source: pcp_wnt_secretion target: pcp_ligands connection_type: PRECEDES description: Acylated, secreted Wnt5a/Wnt11 leave the sending cell. - source: pcp_ligands target: pcp_frizzled_reception connection_type: PROVIDES_INPUT_FOR description: Wnt5a/Wnt11 bind Frizzled. - source: pcp_ligands target: pcp_coreceptors connection_type: PROVIDES_INPUT_FOR description: Wnt5a binds the ROR2 cysteine-rich domain and the PTK7-ROR2 complex. - source: pcp_coreceptors target: pcp_vangl_side connection_type: POSITIVELY_REGULATES description: The Wnt5a-ROR2 complex induces dose-dependent VANGL2 phosphorylation. - source: pcp_frizzled_reception target: pcp_dishevelled_side connection_type: PRECEDES description: Frizzled recruits Dishevelled through its DEP domain. - source: pcp_dishevelled_side target: pcp_effectors connection_type: PRECEDES description: Dishevelled activates RhoA (via DAAM1) and Rac1 in parallel.