{"gene":"ROR2","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2003,"finding":"Wnt5a binds directly to the extracellular cysteine-rich domain (CRD) of Ror2, and Ror2 associates via its CRD with Frizzled2 (rFz2). Wnt5a and Ror2 together activate the non-canonical JNK pathway and inhibit convergent extension movements in Xenopus, placing Ror2 as a receptor/co-receptor for Wnt5a in non-canonical Wnt signaling.","method":"In vitro binding assay (CRD-Wnt5a), co-immunoprecipitation (Ror2-rFz2), JNK activation assay in cultured cells, Xenopus convergent extension assay, Ror2-/- and Wnt5a-/- mouse phenotypic comparison","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, functional JNK activation, in vivo Xenopus rescue, replicated across mouse and frog models in single study with multiple orthogonal methods","pmids":["12839624"],"is_preprint":false},{"year":2004,"finding":"Ror2 associates with casein kinase Iε (CKIε) primarily via its cytoplasmic C-terminal proline-rich domain (PRD). CKIε phosphorylates Ror2 on serine/threonine residues in its ST2 domain, which in turn induces Ror2 autophosphorylation on tyrosine residues within the PRD (not the kinase domain). This CKIε-mediated activation of Ror2 then leads to tyrosine phosphorylation of GRK2 downstream.","method":"Co-immunoprecipitation, site-directed mutagenesis of tyrosine residues, in-cell phosphorylation assays, deletion mapping of Ror2 domains","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — co-IP, mutagenesis of autophosphorylation sites, domain deletion mapping, single lab but multiple orthogonal methods","pmids":["15375164"],"is_preprint":false},{"year":2004,"finding":"Ror2 physically interacts with BRI-b (BMPR1B) in a ligand-independent heteromeric complex requiring Ror2's CRD domain, and Ror2 is transphosphorylated by BRI-b within this complex. Ror2 modulates GDF5 signaling by inhibiting Smad1/5 and activating a Smad-independent pathway, both required for chondrogenic differentiation.","method":"Co-immunoprecipitation, transphosphorylation assay, Smad1/5 reporter assay, ATDC5 chondrogenic differentiation, genetic epistasis in Ror2/BRI-b/Gdf5 compound mutant mice","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical co-IP, in vitro transphosphorylation, functional reporter assays, confirmed by in vivo genetic epistasis in triple mutant mice","pmids":["15569154"],"is_preprint":false},{"year":2006,"finding":"Ror2 mediates Wnt5a-induced cell migration via its extracellular CRD (required for Wnt5a binding) and its cytoplasmic PRD. Ror2 drives filopodia formation through actin reorganization by associating with filamin A via the PRD. Disruption of filopodia by knockdown of either Ror2 or filamin A inhibits Wnt5a-induced migration.","method":"Co-immunoprecipitation (Ror2-filamin A), domain deletion/mutation, siRNA knockdown of Ror2 and filamin A, cell migration assays, filopodia quantification by fluorescence imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, domain mapping, multiple cell lines with siRNA and rescue, single lab with multiple orthogonal methods","pmids":["17101698"],"is_preprint":false},{"year":2007,"finding":"XWnt-5A/Xror2 signals through PI3-kinase and Cdc42 to activate the JNK cascade (via ATF2 and c-Jun) to transcriptionally upregulate XPAPC, independent of the canonical β-catenin pathway. This represents an alternative non-canonical Wnt branch controlling convergent extension in Xenopus gastrulation.","method":"Xenopus loss-of-function (morpholino), epistasis analysis (PI3K inhibitors, dominant-negative Cdc42), reporter assays for ATF2/c-Jun, XPAPC expression rescue","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in Xenopus, pharmacological pathway dissection, functional rescue experiments, multiple orthogonal methods in one study","pmids":["17488628"],"is_preprint":false},{"year":2007,"finding":"Wnt5a induces serine/threonine phosphorylation of Ror2 in a GSK-3α-dependent manner. GSK-3 inhibitors (LiCl, SB216763) or GSK-3α siRNA block Wnt5a-induced Ror2 phosphorylation and cell migration. Purified GSK-3α/β can directly phosphorylate immunoprecipitated Ror2 in vitro.","method":"In vitro kinase assay (purified GSK-3 on immunoprecipitated Ror2), GSK-3 inhibitors, siRNA knockdown of GSK-3α/β, western blot for phospho-Ror2","journal":"Genes to cells","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase reconstitution plus cellular pharmacological and siRNA validation, single lab but multiple methods","pmids":["17986005"],"is_preprint":false},{"year":2008,"finding":"Wnt5a induces Ror2 homodimerization and tyrosine autophosphorylation in osteoblastic cells, and increases phosphorylation of the Ror2 substrate 14-3-3β, demonstrating classical RTK signaling activation. Wnt3a binds Ror2 but does not induce homodimerization or tyrosine phosphorylation.","method":"Co-immunoprecipitation for homodimerization, phosphotyrosine western blot, substrate phosphorylation assay (14-3-3β), Ror2 siRNA knockdown in osteoblast differentiation assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for dimerization, phosphorylation assays, functional osteoblast readout; single lab with multiple methods","pmids":["18615587"],"is_preprint":false},{"year":2008,"finding":"TAK1 (MAP3K) interacts with the intracellular domain of Ror2 and phosphorylates its C-terminal STP domain. This TAK1-dependent serine/threonine phosphorylation induces subsequent tyrosine phosphorylation of Ror2 (including a MAPK-like TGY motif) independent of Ror2's own kinase domain. A second cytosolic factor, PRTB, also interacts with Ror2 and TAK1 to enhance this phosphorylation. Wnt1 binding displaces TAK1 from Ror2, while Wnt3a and Wnt5a do not, providing ligand-dependent regulation.","method":"Co-immunoprecipitation, phosphorylation assays, domain deletion analysis, Wnt ligand displacement assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and phosphorylation experiments with domain mapping, single lab, multiple orthogonal methods","pmids":["18762249"],"is_preprint":false},{"year":2009,"finding":"Ror2 tyrosine kinase activity is required for transduction of Wnt5a non-canonical signaling. Mutation/deletion analysis showed kinase-dead Ror2 cannot mediate Wnt5a inhibition of β-catenin signaling. Loss of Ror2 in vivo (Ror2 null mice) results in increased Axin2-LacZ canonical Wnt reporter activity, confirming that Ror2 inhibits Wnt/β-catenin signaling in intact tissue.","method":"Kinase-dead and deletion mutants, Wnt reporter assays (β-catenin-TCF), in vivo Axin2-LacZ reporter in Ror2 null mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis of kinase domain plus in vivo reporter validation in knockout mice, multiple orthogonal approaches","pmids":["19720827"],"is_preprint":false},{"year":2009,"finding":"ROR2 mediates Wnt5A-dependent melanoma metastasis. Wnt5A increases ROR2 expression and induces PKC-dependent, clathrin-mediated internalization of ROR2. ROR2 knockdown decreases Wnt5A downstream signaling and inhibits Wnt5A-mediated metastasis in vitro and in vivo.","method":"siRNA knockdown of ROR2, in vitro and in vivo metastasis assays, pharmacological inhibition of PKC and clathrin, western blot for downstream signaling","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with in vivo xenograft validation, pharmacological dissection of internalization, single lab","pmids":["19802008"],"is_preprint":false},{"year":2010,"finding":"Ror2 associates with Frizzled7 (Fz7) via its extracellular CRD to form a receptor complex required for Wnt5a-induced Dishevelled (Dvl) polymerization and AP-1 activation. The cytoplasmic region of Ror2 is not required for Dvl regulation. Polymerized Dvl co-localizes with Rac1, and suppression of Rac1 inhibits Wnt5a-induced AP-1 activation. Both DIX and DEP domains of Dvl are indispensable for polymerization and AP-1 activation.","method":"Co-immunoprecipitation (Ror2-Fz7), Dvl polymerization assay, AP-1 reporter assay, siRNA knockdown, domain deletions, Rac1 co-localization imaging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with domain mapping, functional AP-1 reporter, Dvl polymerization assay, Rac1 localization, multiple orthogonal methods in one study","pmids":["20457807"],"is_preprint":false},{"year":2010,"finding":"ShcA is an intracellular binding partner of Ror2, interacting via its SH2 domain with a conserved phospho-tyrosine binding motif in Ror2. Wnt5a induces clustering of Ror2 at the cell membrane and recruitment of ShcA to the Ror2 receptor complex. ShcA is required for Wnt5a/Ror2-mediated upregulation of xPAPC in Xenopus.","method":"Co-immunoprecipitation (Ror2-ShcA), live imaging of Ror2 clustering, morpholino knockdown in Xenopus, PAPC expression assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP with domain mapping, functional in vivo Xenopus assay, single lab","pmids":["20732301"],"is_preprint":false},{"year":2012,"finding":"Wnt5a-Ror2 signaling in osteoclast precursors enhances osteoclastogenesis by activating JNK, which recruits c-Jun to the RANK promoter to increase RANK expression, thereby enhancing RANKL-induced osteoclastogenesis. Osteoclast precursor-specific Ror2 deficiency impairs osteoclastogenesis. A soluble form of Ror2 acts as a Wnt5a decoy receptor and abrogates bone destruction in arthritis.","method":"Conditional knockout mice (osteoclast-specific Ror2 KO), c-Jun ChIP on RANK promoter, JNK inhibitor, soluble Ror2 decoy in mouse arthritis model","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout, ChIP assay, in vivo arthritis model with decoy receptor, multiple orthogonal approaches, high-impact journal","pmids":["22344299"],"is_preprint":false},{"year":2014,"finding":"ROR2 kinase domains of human ROR1 and ROR2 are catalytically deficient (pseudokinases), in contrast to the active C. elegans ortholog CAM-1. Non-consensus residues in ROR1/2 reduce kinase activity, and restoring consensus residues does not restore robust kinase function. The membrane-bound extracellular domain alone of ROR1 or ROR2 is sufficient to suppress canonical Wnt3a signaling and enhance Wnt5a suppression of Wnt3a.","method":"In vitro kinase activity assays of purified kinase domains, site-directed mutagenesis of non-consensus residues, domain deletion constructs, Wnt reporter assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution with mutagenesis, functional Wnt reporter assays, comparative evolutionary analysis across orthologs","pmids":["25029443"],"is_preprint":false},{"year":2014,"finding":"Ror2 physically interacts with Wnt11 and mediates Wnt11 signaling in zebrafish. Intracellular Tyr-647 and Ser-863 of Ror2 are essential for Wnt11 signal transduction. Dishevelled and RhoA act downstream of Wnt11-Ror2 to regulate convergence and extension movements.","method":"Co-immunoprecipitation (Ror2-Wnt11), site-directed mutagenesis of Ror2 (Y647, S863), dominant-negative Ror2, zebrafish morpholino and convergence/extension assays, epistasis with RhoA and Dvl","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — co-IP, mutagenesis of key residues, in vivo zebrafish epistasis, multiple orthogonal methods","pmids":["24928507"],"is_preprint":false},{"year":2015,"finding":"PTK7 associates with ROR2 to form a heterodimeric complex in mammalian cells. PTK7 and ROR2 physically and functionally interact with WNT5A leading to JNK activation and cell movements. In Xenopus, Ror2 can rescue PTK7 loss-of-function migration defects, but a kinase-dead Ror2 mutant cannot, indicating Ror2 kinase activity is required for this rescue.","method":"Co-immunoprecipitation (PTK7-ROR2), JNK activation assay, Xenopus PTK7 morpholino rescue with Ror2, kinase-dead Ror2 mutant rescue experiment, live cell imaging","journal":"The Journal of biological chemistry / PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, functional rescue experiments with kinase-dead mutant, in vivo Xenopus validation, independently reported by two groups (PMID 26499793 and 26680417)","pmids":["26499793","26680417"],"is_preprint":false},{"year":2015,"finding":"ROR2 functions as a Wnt receptor required to maintain basal NMDAR-mediated synaptic transmission. ROR2 activation by non-canonical Wnt ligand activates PKC and JNK and acutely enhances NMDAR synaptic responses in hippocampal neurons.","method":"Electrophysiology (NMDAR-mediated synaptic currents), ROR2 knockdown, PKC and JNK inhibitors, Wnt ligand application to neurons","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with pharmacological pathway dissection, single lab, functional KD phenotype","pmids":["25825749"],"is_preprint":false},{"year":2016,"finding":"Wnt5a induces ROR1/ROR2 heterooligomerization, which recruits guanine exchange factors (GEFs) to activate Rac1 and RhoA, promoting CLL cell proliferation and migration. The extracellular Kringle domain of ROR1 is required for ROR1/ROR2 heterooligomerization; the CRD or intracellular PRD of ROR1 is required for GEF recruitment. siRNA silencing of either ROR1 or ROR2 blocks these effects.","method":"Co-immunoprecipitation, siRNA silencing of ROR1 and ROR2, domain deletion mutants (Kringle, CRD, PRD), Rac1/RhoA GTPase activation assays, in vivo xenograft in immune-deficient mice","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with domain mapping, GTPase activation assays, siRNA validation, in vivo xenograft, multiple orthogonal methods","pmids":["26690702"],"is_preprint":false},{"year":2017,"finding":"Ror2 signaling promotes tumor invasiveness by upregulating IFT20, which regulates Golgi ribbon formation by affecting the GM130-AKAP450 complex (promoting Golgi-derived microtubule nucleation) and enhances transport efficiency through the Golgi complex, enabling polarized secretion for cell migration and invasion.","method":"siRNA knockdown of IFT20 and Ror2, GM130-AKAP450 complex analysis, Golgi morphology imaging, microtubule nucleation assay, invasion assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with mechanistic follow-up on Golgi complex, single lab, multiple functional assays","pmids":["28127051"],"is_preprint":false},{"year":2017,"finding":"Wnt5a-Ror2 signaling in osteoclasts promotes bone resorption via Rho activation followed by Pkn3 binding to and enhancement of c-Src kinase activity, which is critical for actin ring formation. Osteoclast-specific Ror2 KO mice show increased bone mass, impaired bone resorption, and reduced c-Src/Pkn3 interaction. This phenotype is rescued by constitutively active RhoA.","method":"Osteoclast-specific Ror2 conditional KO mice, Pkn3-/- mice, co-immunoprecipitation (Pkn3-c-Src), c-Src kinase assay, actin ring formation assay, bone morphometry, constitutively active RhoA rescue","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mice, global KO mice, co-IP, kinase assay, in vivo rescue with constitutively active RhoA, multiple orthogonal methods","pmids":["28851822"],"is_preprint":false},{"year":2017,"finding":"Ror2 depletion in mammary epithelium increases branching and alters differentiation; loss of Ror2 causes marked changes in actin cytoskeleton-related genes and RhoA pathway alterations in in vitro branching morphogenesis models. Ror2 also antagonizes canonical Wnt/β-catenin signaling in vivo in mammary tissue.","method":"Lentiviral shRNA knockdown of Ror2 in vivo (mammary gland), microarray gene expression analysis, in vitro branching morphogenesis assay with cytoskeletal imaging, RhoA pathway analysis","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo lentiviral KD with microarray, functional branching morphogenesis assay, pathway analysis, single lab","pmids":["25624393"],"is_preprint":false},{"year":2018,"finding":"CK1ε associates with Ror2 (independent of p120-catenin, unlike its association with canonical Wnt receptors), stabilizes Ror2 protein, and is activated by Wnt5a via Fz-associated PP2A within the Ror2-Fz complex. p120-catenin maintains Ror2 at the plasma membrane; depletion of p120-catenin causes rapid clathrin-dependent internalization of Ror2. Both CK1ε and p120-catenin regulate downstream Wnt5a responses (SIAH2 transcription, cell invasion, actin polarization).","method":"Co-immunoprecipitation (CK1ε-Ror2, p120-Ror2), PP2A activity assay, clathrin inhibitor, siRNA knockdown, cell fractionation, SIAH2 reporter, invasion assay, actin imaging","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple co-IPs, mechanistic pathway dissection, functional assays, single lab","pmids":["29465811"],"is_preprint":false},{"year":2019,"finding":"Lrp4 interacts with and activates Ror2 in hippocampal neural stem/progenitor cells; Ror2 mutation impairs NSPC proliferation downstream of Agrin-Lrp4 signaling.","method":"Co-immunoprecipitation (Lrp4-Ror2), Ror2 conditional knockout in NSPCs, BrdU/EdU proliferation assays, genetic epistasis (Lrp4 mutation blocks Ror2 activity)","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus conditional KO, functional NSPC proliferation readout, single lab","pmids":["31268420"],"is_preprint":false},{"year":2020,"finding":"ROR2 signaling induces G-protein and Rho-dependent nuclear accumulation of YAP (mechanotransducer), and YAP inhibition is required but not sufficient for ROR2 blockade-induced chondrogenesis in OA. ROR2 blockade suppresses ADAMTS-4 and ADAMTS-5 expression and promotes chondrogenic differentiation, independent of Wnt signaling.","method":"ROR2 siRNA/overexpression, YAP nuclear translocation imaging, Rho and G-protein inhibitors, ADAMTS enzyme expression assay, mouse instability OA model with ROR2 siRNA, human chondrocyte organoids","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell models, in vivo mouse OA model, human organoid model, pharmacological pathway dissection, multiple orthogonal methods","pmids":["32938794"],"is_preprint":false},{"year":2020,"finding":"ROR2 in the Wnt5a/Ror2 axis promotes Wnt5a-induced NF-κB nuclear translocation and inflammatory cytokine (IL-6, IL-8, IL-1β) secretion in bronchial epithelial cells; ROR2 siRNA blocks NF-κB activity and cytokine release.","method":"siRNA knockdown of Ror2 and Wnt5a, NF-κB nuclear translocation assay, ELISA for cytokines, PM2.5 stimulation model","journal":"International journal of chronic obstructive pulmonary disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA experiment, single lab, limited mechanistic depth","pmids":["33122903"],"is_preprint":false},{"year":2020,"finding":"A mammalian Wnt5a-Ror2-Vangl2 cascade controls the cytoskeleton in alveolar epithelial cells and myofibroblasts to regulate PDGF secretion, type I cell shape changes, and myofibroblast migration for alveologenesis.","method":"Conditional knockout mice (cell-type specific), cytoskeletal imaging, PDGF secretion assay, cell migration assay, genetic epistasis (Wnt5a-Ror2-Vangl2)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO models, functional cellular assays, genetic epistasis establishing pathway order, single lab with multiple orthogonal methods","pmids":["32394892"],"is_preprint":false},{"year":2021,"finding":"Ror2-mediated non-canonical Wnt signaling in dental mesenchyme regulates cell proliferation during tooth root development via Cdc42 as a downstream mediator; activation of Cdc42 rescues cell proliferation and root development size defects in Ror2 mutant mice.","method":"Dental mesenchyme-specific Ror2 conditional KO mice, Cdc42 activity assays, cell proliferation (BrdU), constitutively active Cdc42 rescue experiment","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with functional readout and genetic rescue via activated Cdc42, in vivo model","pmids":["33323370"],"is_preprint":false},{"year":2022,"finding":"ROR2 in hair follicle stem cells (HFSCs) is required for Wnt-activated signaling needed for HFSC activation and self-renewal, and also maintains ATM/ATR-dependent DNA damage response for long-term HFSC maintenance. In β-catenin-null HFSCs, ROR2-PKC signaling acts as a compensatory pathway to protect the stem cell pool.","method":"Ror2-depleted HFSC analysis (conditional KO), β-catenin KO HFSCs, ATM/ATR DNA damage assays, PKC inhibitor experiments, hair cycle analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, multiple functional readouts, PKC pathway dissection, genetic interaction with β-catenin KO, single lab with multiple orthogonal methods","pmids":["35915068"],"is_preprint":false},{"year":2023,"finding":"WNT5a signaling through ROR2 activates the Hippo pathway (increasing phosphorylation of MST1/2, LATS1, MOB1, YAP1) to suppress YAP1 activity and tumor growth. Deletion of MST1/2 abrogates the WNT5a response. In ROR2-negative cells, WNT5a suppresses Hippo (via NF2/Merlin phosphorylation), revealing that ROR2 expression status determines whether WNT5a activates or suppresses Hippo. YAP1 activity also feeds back to stimulate ROR2 and WNT5a expression.","method":"ROR2 knockout/knockdown, MST1/2 deletion, phosphorylation assays (MST1/2, LATS1, MOB1, YAP1), prostate cancer organoid and xenograft models, NF2/Merlin phosphorylation assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO of pathway components, phosphoprotein assays, in vivo organoid and xenograft models, multiple orthogonal methods establishing pathway order","pmids":["36622276"],"is_preprint":false},{"year":2023,"finding":"Active Wnt5b-Ror2 complexes form in producing cells and are loaded onto cytonemes (long signaling filopodia) for transfer to receiving cells in zebrafish. The transferred Ror2 complexes can activate Wnt-PCP signaling in receiving cells independently of the receiving cell's own Ror2 receptor status. Cytoneme-mediated Wnt5b-Ror2 complex spreading affects convergence and extension in zebrafish gastrula.","method":"Live fluorescence imaging of Wnt5b-Ror2 fluorescent fusions on cytonemes, cell transplantation experiments, convergence/extension assays in zebrafish, Ror2 loss-of-function receiving cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging of tagged complexes, transplantation/mosaic experiments in zebrafish, loss-of-function validation, multiple orthogonal approaches in high-impact journal","pmids":["38123680"],"is_preprint":false},{"year":2023,"finding":"Cancer-associated fibroblasts (CAFs) transfer ROR2 to gastric cancer cells via cytonemes (signaling filopodia), and the transferred ROR2 activates Wnt/JNK signaling in receiving cells, promoting their polarization and migration. Blockage of ROR2 function in CAFs reduces paracrine Wnt/JNK signaling and migration of gastric cancer cells.","method":"High-resolution live imaging of fluorescent ROR2 transfer, JNK signaling reporter in receiving cells, ROR2 blockade in CAFs, zebrafish in vivo migration assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct imaging of receptor transfer, functional signaling readout in receiving cells, in vivo zebrafish validation, multiple orthogonal methods","pmids":["37722040"],"is_preprint":false},{"year":2009,"finding":"Differential protein stability and membrane localization of ROR2 mutants underlies the distinct phenotypes of BDB1 vs. Robinow syndrome: BDB1 mutant proteins are stable and reach the cell membrane, while RRS mutant proteins are less abundant and retained intracellularly. A gradient of membrane-associated ROR2 correlates with clinical phenotype severity, confirmed in compound heterozygous mice.","method":"Stably transfected cell lines expressing BDB1 and RRS mutants, cell fractionation, western blot for protein stability, membrane protein fraction quantification, compound heterozygous mouse crosses","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative membrane fractionation across multiple mutants, in vivo genetic confirmation in compound mouse models, mechanistic model validated by multiple approaches","pmids":["19640924"],"is_preprint":false},{"year":2023,"finding":"ROR2 activates the ERK/CREB signaling pathway to upregulate the transcription factor ASCL1, which drives lineage plasticity (stem-cell-like and neuronal programs) in prostate cancer following AR pathway inhibition.","method":"ROR2 overexpression/knockdown in PCa cells, ERK/CREB phosphorylation assays, ASCL1 expression assay, chromatin assays, functional lineage marker analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation assays, transcription factor expression analysis with genetic manipulation, single lab, functional lineage readout","pmids":["37552603"],"is_preprint":false},{"year":2020,"finding":"ROR2 suppresses prostate cancer metastasis via upregulation of PIAS3 (through suppression of miR-199a-5p), which decreases AKT2 phosphorylation, inhibiting EMT and migration/invasion in vitro and in orthotopic xenograft models.","method":"ROR2 overexpression in PCa cell lines, miRNA array and western blot, PIAS3 and AKT2 expression analysis, orthotopic xenograft model, tissue microarray IHC","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional validation with molecular mechanism (miR-199a-5p-PIAS3-AKT2), single lab with multiple orthogonal approaches","pmids":["32415173"],"is_preprint":false},{"year":2021,"finding":"ROR2 promotes sphingomyelin biosynthesis by inhibiting STK4 phosphorylation, which promotes FOXO1 nuclear translocation where it represses SMS1 transcription; loss of ROR2 in DPSCs reduces sphingomyelin levels and promotes cellular senescence.","method":"ROR2 knockdown/overexpression, STK4 phosphorylation assay, FOXO1 nuclear localization imaging, ChIP for FOXO1 on SMS1 promoter, sphingomyelin measurement, senescence assays","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, phosphorylation assays, functional lipid biochemistry, single lab with multiple methods","pmids":["34278704"],"is_preprint":false},{"year":2018,"finding":"ROR2 in spinal neurons modulates neuropathic pain by phosphorylating GluN2B (NMDAR subunit) at Ser1303 and Tyr1472 via PKC and Src family kinase pathways. Intrathecal Wnt5a injection induces pain behaviors that are blocked by GluN2B, PKC, or Src inhibitors. CCI-induced spinal ROR2 upregulation involves CpG demethylation of the ROR2 promoter.","method":"Immunoprecipitation for GluN2B phosphorylation, siRNA knockdown of ROR2, intrathecal Wnt5a injection, pharmacological inhibitors (PKC, Src, GluN2B), CCI mouse model, bisulfite sequencing of ROR2 promoter","journal":"British journal of anaesthesia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for substrate phosphorylation, pharmacological pathway dissection, functional pain behavior readout, single lab","pmids":["30916039"],"is_preprint":false}],"current_model":"ROR2 is a transmembrane receptor tyrosine kinase (with largely pseudokinase activity in humans) that acts as a receptor and co-receptor for non-canonical Wnt ligands (principally Wnt5a, and also Wnt5b, Wnt11): Wnt5a binding to the extracellular CRD induces Ror2 homodimerization/heterodimerization (with Frizzled, PTK7, or ROR1), recruits intracellular effectors including CKIε, GSK-3α, TAK1, and filamin A via its cytoplasmic proline-rich domain, and activates downstream cascades including JNK/AP-1, Rac1, RhoA-Pkn3-cSrc, PI3K/AKT, Hippo/YAP, and PKC, while simultaneously inhibiting canonical β-catenin/TCF signaling; Ror2-Wnt5a complexes can also be transferred intercellularly via cytonemes to activate signaling in recipient cells regardless of their own ROR2 status."},"narrative":{"mechanistic_narrative":"ROR2 is a single-pass transmembrane receptor for non-canonical Wnt ligands that governs cell polarity, migration, and tissue morphogenesis while antagonizing canonical Wnt/β-catenin signaling [PMID:12839624, PMID:19720827]. Wnt5a binds directly to the extracellular cysteine-rich domain (CRD), which also mediates assembly of ROR2 into receptor complexes with Frizzled, PTK7, and ROR1, and into ligand-independent complexes with BMPR1B [PMID:12839624, PMID:15569154, PMID:26499793, PMID:26680417, PMID:26690702]. Although the human ROR2 kinase domain is catalytically deficient (a pseudokinase), ligand engagement still drives ROR2 phosphorylation: serine/threonine priming by CKIε, GSK-3α, and TAK1 within its ST/STP/STP motifs precedes tyrosine autophosphorylation in the cytoplasmic proline-rich domain (PRD) rather than the kinase domain, and the membrane-bound extracellular domain alone suffices to suppress canonical Wnt3a signaling [PMID:15375164, PMID:17986005, PMID:18762249, PMID:25029443]. Through its PRD, ROR2 recruits intracellular effectors—including filamin A, ShcA, and CKIε—to reorganize the actin cytoskeleton and form filopodia for Wnt5a-induced migration [PMID:15375164, PMID:17101698, PMID:20732301]. Downstream, ROR2 activates a branching set of cascades: PI3K/Cdc42 and Dishevelled-Rac1 feeding JNK/AP-1 transcription, RhoA-Pkn3-cSrc actin-ring assembly, and Hippo-dependent control of YAP [PMID:17488628, PMID:20457807, PMID:28851822, PMID:36622276]. These activities place ROR2 at the center of skeletal and connective-tissue development—chondrogenesis, osteoclastogenesis, tooth root, alveolar, and mammary morphogenesis—and of disease processes in cancer invasion and metastasis [PMID:15569154, PMID:22344299, PMID:28851822, PMID:32394892, PMID:33323370]. ROR2 mutations underlie brachydactyly type B1 and Robinow syndrome, where mutant protein stability and plasma-membrane localization correlate with phenotype severity [PMID:19640924]. ROR2-Wnt complexes can also be loaded onto cytonemes and transferred between cells to activate signaling in recipients independent of their own ROR2 status [PMID:38123680, PMID:37722040].","teleology":[{"year":2003,"claim":"Established ROR2 as a receptor/co-receptor for non-canonical Wnt signaling by showing Wnt5a binds its CRD and that ROR2 partners with Frizzled to activate JNK and control morphogenetic movements.","evidence":"In vitro CRD-Wnt5a binding, Ror2-Fz2 co-IP, JNK assay, Xenopus convergent extension, and Ror2/Wnt5a knockout mouse comparison","pmids":["12839624"],"confidence":"High","gaps":["Did not resolve the intracellular signaling chain linking ROR2 to JNK","Catalytic status of the ROR2 kinase domain not addressed"]},{"year":2004,"claim":"Defined how ROR2 is activated despite its non-canonical mechanism by showing CKIε-mediated serine/threonine phosphorylation of the ST domain drives ROR2 tyrosine autophosphorylation within the PRD rather than the kinase domain.","evidence":"Co-IP, deletion mapping, and site-directed mutagenesis of autophosphorylation sites in cells","pmids":["15375164"],"confidence":"High","gaps":["Physiological ligand trigger for CKIε recruitment not established here","Functional consequence of GRK2 phosphorylation downstream unclear"]},{"year":2004,"claim":"Showed ROR2 integrates with BMP/GDF5 signaling by forming a ligand-independent complex with BMPR1B that modulates Smad pathways during chondrogenesis, broadening ROR2 beyond Wnt.","evidence":"Co-IP, transphosphorylation assay, Smad1/5 reporter, ATDC5 differentiation, and triple-mutant mouse epistasis","pmids":["15569154"],"confidence":"High","gaps":["Identity of the Smad-independent pathway not defined","Direct relevance to human skeletal disease not tested"]},{"year":2006,"claim":"Linked ROR2 to actin cytoskeletal remodeling by identifying filamin A as a PRD-binding partner required for Wnt5a-induced filopodia and migration.","evidence":"Reciprocal Co-IP, domain mapping, siRNA of ROR2/filamin A, and filopodia/migration assays","pmids":["17101698"],"confidence":"High","gaps":["GTPase intermediaries between ROR2 and actin not yet placed","Filamin A recruitment dynamics upon ligand binding not resolved"]},{"year":2007,"claim":"Dissected the cytoplasmic cascade by showing ROR2 signals through PI3K/Cdc42 to JNK/ATF2/c-Jun to transcribe PAPC, independent of β-catenin, defining a discrete non-canonical branch.","evidence":"Xenopus morpholino loss-of-function, pharmacological/dominant-negative epistasis, and reporter/rescue assays","pmids":["17488628"],"confidence":"High","gaps":["How PI3K is activated by ROR2 not defined","Mammalian conservation of this exact branch not tested here"]},{"year":2007,"claim":"Identified GSK-3α as a kinase that directly phosphorylates ROR2 upon Wnt5a stimulation and is required for ROR2-driven migration, adding another priming kinase upstream of ROR2 activation.","evidence":"In vitro kinase reconstitution on immunoprecipitated ROR2, GSK-3 inhibitors, siRNA, and phospho-blots","pmids":["17986005"],"confidence":"High","gaps":["Phosphosites on ROR2 not mapped","Interplay between GSK-3α and CKIε/TAK1 priming unresolved"]},{"year":2008,"claim":"Demonstrated classic RTK-like behavior by showing Wnt5a, but not Wnt3a, induces ROR2 homodimerization, tyrosine autophosphorylation, and substrate (14-3-3β) phosphorylation, and defined TAK1 as an additional intracellular kinase regulated by ligand-dependent displacement.","evidence":"Co-IP dimerization, phosphotyrosine/substrate blots, osteoblast siRNA assays, and Wnt ligand displacement experiments","pmids":["18615587","18762249"],"confidence":"Medium","gaps":["Whether tyrosine phosphorylation reflects intrinsic versus heterologous kinase activity not settled","PRTB role mechanistically thin"]},{"year":2009,"claim":"Established that ROR2 inhibits canonical Wnt/β-catenin signaling in vivo and that its kinase function is required for transduction of Wnt5a signals.","evidence":"Kinase-dead/deletion mutants, β-catenin-TCF reporters, and Axin2-LacZ reporter in Ror2-null mice","pmids":["19720827"],"confidence":"High","gaps":["Apparent kinase requirement later reconciled with pseudokinase status","Mechanism of β-catenin antagonism not fully defined"]},{"year":2009,"claim":"Connected ROR2 to cancer by showing Wnt5a drives PKC-dependent clathrin-mediated ROR2 internalization that is required for melanoma metastasis.","evidence":"siRNA, in vitro/in vivo metastasis assays, and pharmacological inhibition of PKC and clathrin","pmids":["19802008"],"confidence":"Medium","gaps":["Signaling consequence of internalization versus surface signaling not separated","Single-lab in vivo model"]},{"year":2009,"claim":"Provided a mechanistic basis for ROR2 disease genotype-phenotype correlation by showing BDB1 mutants reach the membrane while Robinow mutants are unstable and intracellularly retained.","evidence":"Stable mutant cell lines, membrane fractionation/stability blots, and compound heterozygous mouse crosses","pmids":["19640924"],"confidence":"High","gaps":["Signaling defects of each mutant class not directly measured","How retention maps to specific developmental defects unclear"]},{"year":2010,"claim":"Resolved the receptor architecture and effector chain for AP-1 activation, showing ROR2-Fz7 complexes drive Dishevelled polymerization and Rac1-dependent AP-1, with the ROR2 cytoplasmic region dispensable for Dvl regulation.","evidence":"Co-IP, Dvl polymerization and AP-1 reporter assays, domain deletions, and Rac1 co-localization imaging","pmids":["20457807"],"confidence":"High","gaps":["Reconciling cytoplasm-independent Dvl signaling with PRD-dependent migration not addressed","Stoichiometry of the ROR2-Fz-Dvl complex unknown"]},{"year":2010,"claim":"Added ShcA as an SH2-domain effector recruited to phospho-ROR2 upon Wnt5a-induced clustering, required for PAPC induction.","evidence":"Co-IP with domain mapping, live imaging of ROR2 clustering, and Xenopus morpholino/PAPC assays","pmids":["20732301"],"confidence":"Medium","gaps":["Downstream connection from ShcA to transcription not detailed","Single-lab finding"]},{"year":2012,"claim":"Defined a transcriptional output of ROR2-JNK signaling in bone, where c-Jun upregulates RANK to enhance osteoclastogenesis, and demonstrated therapeutic potential of soluble ROR2 as a Wnt5a decoy.","evidence":"Osteoclast-specific conditional KO, c-Jun ChIP on RANK promoter, JNK inhibitor, and decoy ROR2 in a mouse arthritis model","pmids":["22344299"],"confidence":"High","gaps":["Other JNK target genes in osteoclasts not surveyed","Decoy specificity for Wnt5a versus other ligands not exhaustively tested"]},{"year":2014,"claim":"Reconciled prior 'kinase' claims by demonstrating human ROR1/ROR2 kinase domains are pseudokinases and that the extracellular domain alone suppresses canonical Wnt, shifting emphasis to scaffolding/receptor functions.","evidence":"In vitro kinase assays of purified domains, consensus-residue mutagenesis, deletion constructs, and Wnt reporters across orthologs","pmids":["25029443"],"confidence":"High","gaps":["How tyrosine phosphorylation occurs without intrinsic activity not fully mapped","Whether trace activity matters physiologically unresolved"]},{"year":2014,"claim":"Extended ROR2 ligand repertoire by showing it binds Wnt11 and signals via Dishevelled and RhoA, with specific intracellular residues (Y647, S863) essential for transduction.","evidence":"Co-IP, site-directed mutagenesis, dominant-negative ROR2, and zebrafish convergence/extension epistasis","pmids":["24928507"],"confidence":"High","gaps":["Whether Wnt11 uses the same co-receptors as Wnt5a not addressed","Functional role of the specific residues in mammals not tested"]},{"year":2015,"claim":"Identified PTK7 as a ROR2 co-receptor in the Wnt5a-JNK migration pathway, with ROR2 kinase function required for rescue of PTK7 loss, independently confirmed by two groups.","evidence":"Reciprocal Co-IP, JNK assays, kinase-dead Xenopus rescue, and live imaging","pmids":["26499793","26680417"],"confidence":"High","gaps":["Mechanism by which a pseudokinase ROR2 is required for rescue unclear","Hierarchy among PTK7/Fz/ROR1 co-receptors not defined"]},{"year":2015,"claim":"Broadened ROR2 function into the nervous system, showing it maintains NMDAR-mediated synaptic transmission through PKC and JNK in hippocampal neurons.","evidence":"Electrophysiology with ROR2 knockdown and PKC/JNK inhibitors plus Wnt ligand application","pmids":["25825749"],"confidence":"Medium","gaps":["Direct ROR2 substrates at the synapse not identified here","Specific Wnt ligand in neurons not defined"]},{"year":2016,"claim":"Showed Wnt5a-induced ROR1/ROR2 heterooligomerization recruits GEFs to activate Rac1 and RhoA driving leukemia cell proliferation and migration, with domain-specific roles mapped.","evidence":"Co-IP, domain deletions, GTPase activation assays, siRNA, and xenograft","pmids":["26690702"],"confidence":"High","gaps":["Identity of the recruited GEFs not specified","Relative contribution of homo- versus heterooligomers unclear"]},{"year":2017,"claim":"Connected ROR2 to RhoA-Pkn3-cSrc signaling for actin-ring formation in osteoclast bone resorption, establishing pathway order via constitutively active RhoA rescue.","evidence":"Osteoclast-specific and global KO mice, co-IP, c-Src kinase assay, actin ring assays, bone morphometry, and RhoA rescue","pmids":["28851822"],"confidence":"High","gaps":["How ROR2 activates RhoA upstream not detailed","Generalizability of Pkn3-cSrc axis to other cell types untested"]},{"year":2017,"claim":"Revealed a ROR2 mechanism for tumor invasiveness via IFT20-dependent Golgi ribbon organization and polarized secretion, linking ROR2 to membrane trafficking.","evidence":"siRNA of ROR2/IFT20, GM130-AKAP450 complex and Golgi imaging, microtubule nucleation, and invasion assays","pmids":["28127051"],"confidence":"Medium","gaps":["How ROR2 regulates IFT20 expression not defined","Single-lab mechanism"]},{"year":2017,"claim":"Demonstrated ROR2's morphogenetic role in mammary epithelium, controlling branching and differentiation through actin/RhoA programs while antagonizing canonical Wnt.","evidence":"In vivo lentiviral shRNA, microarray, branching morphogenesis assays, and RhoA pathway analysis","pmids":["25624393"],"confidence":"Medium","gaps":["Direct ROR2 effectors driving branching not pinpointed","Ligand source in mammary tissue not defined"]},{"year":2020,"claim":"Linked ROR2 to Hippo/YAP mechanotransduction in cartilage, showing ROR2 signaling drives Rho/G-protein-dependent nuclear YAP and that ROR2 blockade promotes chondrogenesis independent of Wnt.","evidence":"siRNA/overexpression, YAP imaging, Rho/G-protein inhibitors, ADAMTS assays, mouse OA model, and human organoids","pmids":["32938794"],"confidence":"High","gaps":["Ligand driving Wnt-independent ROR2 signaling unclear","How ROR2 couples to G-proteins not defined"]},{"year":2020,"claim":"Established a Wnt5a-Ror2-Vangl2 PCP cascade controlling cytoskeleton and PDGF secretion during alveologenesis, ordering the pathway genetically.","evidence":"Cell-type-specific conditional KO mice, cytoskeletal imaging, PDGF/migration assays, and epistasis","pmids":["32394892"],"confidence":"High","gaps":["Molecular link between ROR2 and Vangl2 not biochemically resolved","Direct effectors of cytoskeletal change not identified"]},{"year":2020,"claim":"Reported ROR2-dependent prostate cancer metastasis suppression via a miR-199a-5p-PIAS3-AKT2 axis, indicating context-dependent tumor-suppressive roles.","evidence":"ROR2 overexpression, miRNA/protein profiling, orthotopic xenograft, and tissue microarray IHC","pmids":["32415173"],"confidence":"Medium","gaps":["Mechanism by which ROR2 regulates miR-199a-5p unclear","Reconciliation with pro-metastatic roles in other cancers not addressed"]},{"year":2020,"claim":"Implicated ROR2 in inflammatory signaling, linking the Wnt5a/ROR2 axis to NF-κB activation and cytokine release in bronchial epithelium.","evidence":"siRNA of ROR2/Wnt5a, NF-κB translocation, cytokine ELISA, and PM2.5 stimulation","pmids":["33122903"],"confidence":"Low","gaps":["Single siRNA experiment with limited mechanistic depth","Direct ROR2-to-NF-κB link not established","Not independently confirmed"]},{"year":2021,"claim":"Defined ROR2's developmental role in tooth root formation through Cdc42-dependent mesenchymal proliferation, confirmed by activated-Cdc42 rescue.","evidence":"Dental mesenchyme conditional KO, Cdc42 activity assays, BrdU proliferation, and Cdc42 rescue","pmids":["33323370"],"confidence":"High","gaps":["Upstream link from ROR2 to Cdc42 not biochemically defined","Ligand source in dental mesenchyme not identified"]},{"year":2021,"claim":"Connected ROR2 to lipid metabolism and senescence, showing it represses SMS1 via STK4/FOXO1 to sustain sphingomyelin and prevent stem cell senescence.","evidence":"ROR2 knockdown/overexpression, STK4 phospho-assay, FOXO1 imaging, ChIP on SMS1, lipid measurement, and senescence assays","pmids":["34278704"],"confidence":"Medium","gaps":["How ROR2 regulates STK4 phosphorylation unclear","Relationship to canonical Wnt5a signaling not defined"]},{"year":2022,"claim":"Showed ROR2 supports hair follicle stem cell activation and long-term maintenance, acting through PKC as a compensatory pathway in β-catenin-null cells and sustaining ATM/ATR DNA damage responses.","evidence":"Conditional KO, β-catenin KO HFSCs, ATM/ATR assays, PKC inhibitors, and hair cycle analysis","pmids":["35915068"],"confidence":"High","gaps":["Mechanism linking ROR2 to DNA damage response unresolved","Direct ROR2-PKC coupling not biochemically mapped"]},{"year":2023,"claim":"Established that ROR2 expression status dictates whether Wnt5a activates or suppresses Hippo, with ROR2 driving MST1/2-LATS1-mediated suppression of YAP1 and a YAP-ROR2 feedback loop in prostate cancer.","evidence":"ROR2 and MST1/2 KO, phospho-assays of Hippo components, NF2 phosphorylation, and organoid/xenograft models","pmids":["36622276"],"confidence":"High","gaps":["Biochemical link from ROR2 to MST1/2 not defined","Reconciliation with ROR2-driven nuclear YAP in cartilage unaddressed"]},{"year":2023,"claim":"Identified an ROR2-ERK/CREB-ASCL1 axis driving lineage plasticity in prostate cancer after AR inhibition, broadening ROR2's role in therapy resistance.","evidence":"ROR2 overexpression/knockdown, ERK/CREB phospho-assays, ASCL1 expression, and chromatin/lineage marker analysis","pmids":["37552603"],"confidence":"Medium","gaps":["How ROR2 engages ERK/CREB upstream unclear","Single-lab finding"]},{"year":2023,"claim":"Revealed a paracrine mode of ROR2 action, demonstrating that active Wnt5b-ROR2 complexes are loaded onto cytonemes and transferred to recipient cells to activate PCP signaling independent of recipient ROR2 status.","evidence":"Live imaging of tagged Wnt5b-ROR2 on cytonemes, transplantation/mosaic experiments, and convergence/extension assays in zebrafish","pmids":["38123680"],"confidence":"High","gaps":["Molecular machinery loading complexes onto cytonemes unknown","How transferred complexes engage recipient signaling components unclear"]},{"year":2023,"claim":"Extended cytoneme-mediated ROR2 transfer to cancer, showing CAFs deliver ROR2 to gastric cancer cells to activate Wnt/JNK and promote migration.","evidence":"High-resolution live imaging of ROR2 transfer, JNK reporters in recipients, ROR2 blockade in CAFs, and zebrafish migration assays","pmids":["37722040"],"confidence":"High","gaps":["Receptor/machinery in recipient cells receiving ROR2 not defined","In vivo mammalian tumor validation pending"]},{"year":null,"claim":"How a catalytically deficient pseudokinase ROR2 produces context-opposite outputs (YAP activation versus suppression, tumor promotion versus suppression) and how it couples to diverse downstream kinases and GTPases remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying biochemical model linking ROR2 conformation to effector choice","Cell-context determinants of opposing outputs undefined","Structural basis of ROR2 co-receptor selectivity unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,11,21,31]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,10,28]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,25,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,17,31]}],"complexes":["ROR2-Frizzled (Fz2/Fz7) Wnt receptor complex","ROR1/ROR2 heterooligomer","PTK7-ROR2 heterodimer","ROR2-BMPR1B (BRI-b) complex"],"partners":["WNT5A","FZD7","PTK7","ROR1","FLNA","CSNK1E","SHC1","MAP3K7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01974","full_name":"Tyrosine-protein kinase transmembrane receptor ROR2","aliases":["Neurotrophic tyrosine kinase, receptor-related 2"],"length_aa":943,"mass_kda":104.8,"function":"Tyrosine-protein kinase receptor which may be involved in the early formation of the chondrocytes. It seems to be required for cartilage and growth plate development (By similarity). Phosphorylates YWHAB, leading to induction of osteogenesis and bone formation (PubMed:17717073). In contrast, has also been shown to have very little tyrosine kinase activity in vitro. May act as a receptor for wnt ligand WNT5A which may result in the inhibition of WNT3A-mediated signaling (PubMed:25029443)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q01974/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ROR2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ROR2","total_profiled":1310},"omim":[{"mim_id":"618529","title":"ROBINOW SYNDROME, AUTOSOMAL RECESSIVE 2; RRS2","url":"https://www.omim.org/entry/618529"},{"mim_id":"614790","title":"WT1-INTERACTING PROTEIN; WTIP","url":"https://www.omim.org/entry/614790"},{"mim_id":"614684","title":"HYPERTELORISM AND OTHER FACIAL DYSMORPHISM, BRACHYDACTYLY, GENITAL ABNORMALITIES, IMPAIRED INTELLECTUAL DEVELOPMENT, AND RECURRENT INFLAMMATORY EPISODES","url":"https://www.omim.org/entry/614684"},{"mim_id":"611377","title":"BRACHYDACTYLY, TYPE B2; BDB2","url":"https://www.omim.org/entry/611377"},{"mim_id":"610713","title":"BRACHYDACTYLY-SYNDACTYLY SYNDROME; BDSD","url":"https://www.omim.org/entry/610713"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ROR2"},"hgnc":{"alias_symbol":[],"prev_symbol":["NTRKR2","BDB","BDB1"]},"alphafold":{"accession":"Q01974","domains":[{"cath_id":"2.60.40.10","chopping":"62-154","consensus_level":"high","plddt":86.7045,"start":62,"end":154},{"cath_id":"1.10.2000.10","chopping":"174-298","consensus_level":"medium","plddt":78.9974,"start":174,"end":298},{"cath_id":"3.30.200.20","chopping":"463-556","consensus_level":"medium","plddt":87.1693,"start":463,"end":556},{"cath_id":"1.10.510.10","chopping":"560-574_586-755","consensus_level":"medium","plddt":89.0862,"start":560,"end":755}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01974","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01974-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01974-F1-predicted_aligned_error_v6.png","plddt_mean":68.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ROR2","jax_strain_url":"https://www.jax.org/strain/search?query=ROR2"},"sequence":{"accession":"Q01974","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01974.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01974/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01974"}},"corpus_meta":[{"pmid":"28127051","id":"PMC_28127051","title":"Ror2 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Wnt5a and Ror2 together activate the non-canonical JNK pathway and inhibit convergent extension movements in Xenopus, placing Ror2 as a receptor/co-receptor for Wnt5a in non-canonical Wnt signaling.\",\n      \"method\": \"In vitro binding assay (CRD-Wnt5a), co-immunoprecipitation (Ror2-rFz2), JNK activation assay in cultured cells, Xenopus convergent extension assay, Ror2-/- and Wnt5a-/- mouse phenotypic comparison\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, functional JNK activation, in vivo Xenopus rescue, replicated across mouse and frog models in single study with multiple orthogonal methods\",\n      \"pmids\": [\"12839624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ror2 associates with casein kinase Iε (CKIε) primarily via its cytoplasmic C-terminal proline-rich domain (PRD). CKIε phosphorylates Ror2 on serine/threonine residues in its ST2 domain, which in turn induces Ror2 autophosphorylation on tyrosine residues within the PRD (not the kinase domain). This CKIε-mediated activation of Ror2 then leads to tyrosine phosphorylation of GRK2 downstream.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of tyrosine residues, in-cell phosphorylation assays, deletion mapping of Ror2 domains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — co-IP, mutagenesis of autophosphorylation sites, domain deletion mapping, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15375164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Ror2 physically interacts with BRI-b (BMPR1B) in a ligand-independent heteromeric complex requiring Ror2's CRD domain, and Ror2 is transphosphorylated by BRI-b within this complex. Ror2 modulates GDF5 signaling by inhibiting Smad1/5 and activating a Smad-independent pathway, both required for chondrogenic differentiation.\",\n      \"method\": \"Co-immunoprecipitation, transphosphorylation assay, Smad1/5 reporter assay, ATDC5 chondrogenic differentiation, genetic epistasis in Ror2/BRI-b/Gdf5 compound mutant mice\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical co-IP, in vitro transphosphorylation, functional reporter assays, confirmed by in vivo genetic epistasis in triple mutant mice\",\n      \"pmids\": [\"15569154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Ror2 mediates Wnt5a-induced cell migration via its extracellular CRD (required for Wnt5a binding) and its cytoplasmic PRD. Ror2 drives filopodia formation through actin reorganization by associating with filamin A via the PRD. Disruption of filopodia by knockdown of either Ror2 or filamin A inhibits Wnt5a-induced migration.\",\n      \"method\": \"Co-immunoprecipitation (Ror2-filamin A), domain deletion/mutation, siRNA knockdown of Ror2 and filamin A, cell migration assays, filopodia quantification by fluorescence imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, domain mapping, multiple cell lines with siRNA and rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17101698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"XWnt-5A/Xror2 signals through PI3-kinase and Cdc42 to activate the JNK cascade (via ATF2 and c-Jun) to transcriptionally upregulate XPAPC, independent of the canonical β-catenin pathway. This represents an alternative non-canonical Wnt branch controlling convergent extension in Xenopus gastrulation.\",\n      \"method\": \"Xenopus loss-of-function (morpholino), epistasis analysis (PI3K inhibitors, dominant-negative Cdc42), reporter assays for ATF2/c-Jun, XPAPC expression rescue\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in Xenopus, pharmacological pathway dissection, functional rescue experiments, multiple orthogonal methods in one study\",\n      \"pmids\": [\"17488628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Wnt5a induces serine/threonine phosphorylation of Ror2 in a GSK-3α-dependent manner. GSK-3 inhibitors (LiCl, SB216763) or GSK-3α siRNA block Wnt5a-induced Ror2 phosphorylation and cell migration. Purified GSK-3α/β can directly phosphorylate immunoprecipitated Ror2 in vitro.\",\n      \"method\": \"In vitro kinase assay (purified GSK-3 on immunoprecipitated Ror2), GSK-3 inhibitors, siRNA knockdown of GSK-3α/β, western blot for phospho-Ror2\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase reconstitution plus cellular pharmacological and siRNA validation, single lab but multiple methods\",\n      \"pmids\": [\"17986005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Wnt5a induces Ror2 homodimerization and tyrosine autophosphorylation in osteoblastic cells, and increases phosphorylation of the Ror2 substrate 14-3-3β, demonstrating classical RTK signaling activation. Wnt3a binds Ror2 but does not induce homodimerization or tyrosine phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation for homodimerization, phosphotyrosine western blot, substrate phosphorylation assay (14-3-3β), Ror2 siRNA knockdown in osteoblast differentiation assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for dimerization, phosphorylation assays, functional osteoblast readout; single lab with multiple methods\",\n      \"pmids\": [\"18615587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TAK1 (MAP3K) interacts with the intracellular domain of Ror2 and phosphorylates its C-terminal STP domain. This TAK1-dependent serine/threonine phosphorylation induces subsequent tyrosine phosphorylation of Ror2 (including a MAPK-like TGY motif) independent of Ror2's own kinase domain. A second cytosolic factor, PRTB, also interacts with Ror2 and TAK1 to enhance this phosphorylation. Wnt1 binding displaces TAK1 from Ror2, while Wnt3a and Wnt5a do not, providing ligand-dependent regulation.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, domain deletion analysis, Wnt ligand displacement assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and phosphorylation experiments with domain mapping, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18762249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ror2 tyrosine kinase activity is required for transduction of Wnt5a non-canonical signaling. Mutation/deletion analysis showed kinase-dead Ror2 cannot mediate Wnt5a inhibition of β-catenin signaling. Loss of Ror2 in vivo (Ror2 null mice) results in increased Axin2-LacZ canonical Wnt reporter activity, confirming that Ror2 inhibits Wnt/β-catenin signaling in intact tissue.\",\n      \"method\": \"Kinase-dead and deletion mutants, Wnt reporter assays (β-catenin-TCF), in vivo Axin2-LacZ reporter in Ror2 null mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis of kinase domain plus in vivo reporter validation in knockout mice, multiple orthogonal approaches\",\n      \"pmids\": [\"19720827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ROR2 mediates Wnt5A-dependent melanoma metastasis. Wnt5A increases ROR2 expression and induces PKC-dependent, clathrin-mediated internalization of ROR2. ROR2 knockdown decreases Wnt5A downstream signaling and inhibits Wnt5A-mediated metastasis in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown of ROR2, in vitro and in vivo metastasis assays, pharmacological inhibition of PKC and clathrin, western blot for downstream signaling\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with in vivo xenograft validation, pharmacological dissection of internalization, single lab\",\n      \"pmids\": [\"19802008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ror2 associates with Frizzled7 (Fz7) via its extracellular CRD to form a receptor complex required for Wnt5a-induced Dishevelled (Dvl) polymerization and AP-1 activation. The cytoplasmic region of Ror2 is not required for Dvl regulation. Polymerized Dvl co-localizes with Rac1, and suppression of Rac1 inhibits Wnt5a-induced AP-1 activation. Both DIX and DEP domains of Dvl are indispensable for polymerization and AP-1 activation.\",\n      \"method\": \"Co-immunoprecipitation (Ror2-Fz7), Dvl polymerization assay, AP-1 reporter assay, siRNA knockdown, domain deletions, Rac1 co-localization imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with domain mapping, functional AP-1 reporter, Dvl polymerization assay, Rac1 localization, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20457807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ShcA is an intracellular binding partner of Ror2, interacting via its SH2 domain with a conserved phospho-tyrosine binding motif in Ror2. Wnt5a induces clustering of Ror2 at the cell membrane and recruitment of ShcA to the Ror2 receptor complex. ShcA is required for Wnt5a/Ror2-mediated upregulation of xPAPC in Xenopus.\",\n      \"method\": \"Co-immunoprecipitation (Ror2-ShcA), live imaging of Ror2 clustering, morpholino knockdown in Xenopus, PAPC expression assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP with domain mapping, functional in vivo Xenopus assay, single lab\",\n      \"pmids\": [\"20732301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Wnt5a-Ror2 signaling in osteoclast precursors enhances osteoclastogenesis by activating JNK, which recruits c-Jun to the RANK promoter to increase RANK expression, thereby enhancing RANKL-induced osteoclastogenesis. Osteoclast precursor-specific Ror2 deficiency impairs osteoclastogenesis. A soluble form of Ror2 acts as a Wnt5a decoy receptor and abrogates bone destruction in arthritis.\",\n      \"method\": \"Conditional knockout mice (osteoclast-specific Ror2 KO), c-Jun ChIP on RANK promoter, JNK inhibitor, soluble Ror2 decoy in mouse arthritis model\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout, ChIP assay, in vivo arthritis model with decoy receptor, multiple orthogonal approaches, high-impact journal\",\n      \"pmids\": [\"22344299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ROR2 kinase domains of human ROR1 and ROR2 are catalytically deficient (pseudokinases), in contrast to the active C. elegans ortholog CAM-1. Non-consensus residues in ROR1/2 reduce kinase activity, and restoring consensus residues does not restore robust kinase function. The membrane-bound extracellular domain alone of ROR1 or ROR2 is sufficient to suppress canonical Wnt3a signaling and enhance Wnt5a suppression of Wnt3a.\",\n      \"method\": \"In vitro kinase activity assays of purified kinase domains, site-directed mutagenesis of non-consensus residues, domain deletion constructs, Wnt reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution with mutagenesis, functional Wnt reporter assays, comparative evolutionary analysis across orthologs\",\n      \"pmids\": [\"25029443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ror2 physically interacts with Wnt11 and mediates Wnt11 signaling in zebrafish. Intracellular Tyr-647 and Ser-863 of Ror2 are essential for Wnt11 signal transduction. Dishevelled and RhoA act downstream of Wnt11-Ror2 to regulate convergence and extension movements.\",\n      \"method\": \"Co-immunoprecipitation (Ror2-Wnt11), site-directed mutagenesis of Ror2 (Y647, S863), dominant-negative Ror2, zebrafish morpholino and convergence/extension assays, epistasis with RhoA and Dvl\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — co-IP, mutagenesis of key residues, in vivo zebrafish epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"24928507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTK7 associates with ROR2 to form a heterodimeric complex in mammalian cells. PTK7 and ROR2 physically and functionally interact with WNT5A leading to JNK activation and cell movements. In Xenopus, Ror2 can rescue PTK7 loss-of-function migration defects, but a kinase-dead Ror2 mutant cannot, indicating Ror2 kinase activity is required for this rescue.\",\n      \"method\": \"Co-immunoprecipitation (PTK7-ROR2), JNK activation assay, Xenopus PTK7 morpholino rescue with Ror2, kinase-dead Ror2 mutant rescue experiment, live cell imaging\",\n      \"journal\": \"The Journal of biological chemistry / PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, functional rescue experiments with kinase-dead mutant, in vivo Xenopus validation, independently reported by two groups (PMID 26499793 and 26680417)\",\n      \"pmids\": [\"26499793\", \"26680417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ROR2 functions as a Wnt receptor required to maintain basal NMDAR-mediated synaptic transmission. ROR2 activation by non-canonical Wnt ligand activates PKC and JNK and acutely enhances NMDAR synaptic responses in hippocampal neurons.\",\n      \"method\": \"Electrophysiology (NMDAR-mediated synaptic currents), ROR2 knockdown, PKC and JNK inhibitors, Wnt ligand application to neurons\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with pharmacological pathway dissection, single lab, functional KD phenotype\",\n      \"pmids\": [\"25825749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wnt5a induces ROR1/ROR2 heterooligomerization, which recruits guanine exchange factors (GEFs) to activate Rac1 and RhoA, promoting CLL cell proliferation and migration. The extracellular Kringle domain of ROR1 is required for ROR1/ROR2 heterooligomerization; the CRD or intracellular PRD of ROR1 is required for GEF recruitment. siRNA silencing of either ROR1 or ROR2 blocks these effects.\",\n      \"method\": \"Co-immunoprecipitation, siRNA silencing of ROR1 and ROR2, domain deletion mutants (Kringle, CRD, PRD), Rac1/RhoA GTPase activation assays, in vivo xenograft in immune-deficient mice\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with domain mapping, GTPase activation assays, siRNA validation, in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"26690702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ror2 signaling promotes tumor invasiveness by upregulating IFT20, which regulates Golgi ribbon formation by affecting the GM130-AKAP450 complex (promoting Golgi-derived microtubule nucleation) and enhances transport efficiency through the Golgi complex, enabling polarized secretion for cell migration and invasion.\",\n      \"method\": \"siRNA knockdown of IFT20 and Ror2, GM130-AKAP450 complex analysis, Golgi morphology imaging, microtubule nucleation assay, invasion assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with mechanistic follow-up on Golgi complex, single lab, multiple functional assays\",\n      \"pmids\": [\"28127051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Wnt5a-Ror2 signaling in osteoclasts promotes bone resorption via Rho activation followed by Pkn3 binding to and enhancement of c-Src kinase activity, which is critical for actin ring formation. Osteoclast-specific Ror2 KO mice show increased bone mass, impaired bone resorption, and reduced c-Src/Pkn3 interaction. This phenotype is rescued by constitutively active RhoA.\",\n      \"method\": \"Osteoclast-specific Ror2 conditional KO mice, Pkn3-/- mice, co-immunoprecipitation (Pkn3-c-Src), c-Src kinase assay, actin ring formation assay, bone morphometry, constitutively active RhoA rescue\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mice, global KO mice, co-IP, kinase assay, in vivo rescue with constitutively active RhoA, multiple orthogonal methods\",\n      \"pmids\": [\"28851822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ror2 depletion in mammary epithelium increases branching and alters differentiation; loss of Ror2 causes marked changes in actin cytoskeleton-related genes and RhoA pathway alterations in in vitro branching morphogenesis models. Ror2 also antagonizes canonical Wnt/β-catenin signaling in vivo in mammary tissue.\",\n      \"method\": \"Lentiviral shRNA knockdown of Ror2 in vivo (mammary gland), microarray gene expression analysis, in vitro branching morphogenesis assay with cytoskeletal imaging, RhoA pathway analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo lentiviral KD with microarray, functional branching morphogenesis assay, pathway analysis, single lab\",\n      \"pmids\": [\"25624393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CK1ε associates with Ror2 (independent of p120-catenin, unlike its association with canonical Wnt receptors), stabilizes Ror2 protein, and is activated by Wnt5a via Fz-associated PP2A within the Ror2-Fz complex. p120-catenin maintains Ror2 at the plasma membrane; depletion of p120-catenin causes rapid clathrin-dependent internalization of Ror2. Both CK1ε and p120-catenin regulate downstream Wnt5a responses (SIAH2 transcription, cell invasion, actin polarization).\",\n      \"method\": \"Co-immunoprecipitation (CK1ε-Ror2, p120-Ror2), PP2A activity assay, clathrin inhibitor, siRNA knockdown, cell fractionation, SIAH2 reporter, invasion assay, actin imaging\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple co-IPs, mechanistic pathway dissection, functional assays, single lab\",\n      \"pmids\": [\"29465811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Lrp4 interacts with and activates Ror2 in hippocampal neural stem/progenitor cells; Ror2 mutation impairs NSPC proliferation downstream of Agrin-Lrp4 signaling.\",\n      \"method\": \"Co-immunoprecipitation (Lrp4-Ror2), Ror2 conditional knockout in NSPCs, BrdU/EdU proliferation assays, genetic epistasis (Lrp4 mutation blocks Ror2 activity)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus conditional KO, functional NSPC proliferation readout, single lab\",\n      \"pmids\": [\"31268420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ROR2 signaling induces G-protein and Rho-dependent nuclear accumulation of YAP (mechanotransducer), and YAP inhibition is required but not sufficient for ROR2 blockade-induced chondrogenesis in OA. ROR2 blockade suppresses ADAMTS-4 and ADAMTS-5 expression and promotes chondrogenic differentiation, independent of Wnt signaling.\",\n      \"method\": \"ROR2 siRNA/overexpression, YAP nuclear translocation imaging, Rho and G-protein inhibitors, ADAMTS enzyme expression assay, mouse instability OA model with ROR2 siRNA, human chondrocyte organoids\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell models, in vivo mouse OA model, human organoid model, pharmacological pathway dissection, multiple orthogonal methods\",\n      \"pmids\": [\"32938794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ROR2 in the Wnt5a/Ror2 axis promotes Wnt5a-induced NF-κB nuclear translocation and inflammatory cytokine (IL-6, IL-8, IL-1β) secretion in bronchial epithelial cells; ROR2 siRNA blocks NF-κB activity and cytokine release.\",\n      \"method\": \"siRNA knockdown of Ror2 and Wnt5a, NF-κB nuclear translocation assay, ELISA for cytokines, PM2.5 stimulation model\",\n      \"journal\": \"International journal of chronic obstructive pulmonary disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA experiment, single lab, limited mechanistic depth\",\n      \"pmids\": [\"33122903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A mammalian Wnt5a-Ror2-Vangl2 cascade controls the cytoskeleton in alveolar epithelial cells and myofibroblasts to regulate PDGF secretion, type I cell shape changes, and myofibroblast migration for alveologenesis.\",\n      \"method\": \"Conditional knockout mice (cell-type specific), cytoskeletal imaging, PDGF secretion assay, cell migration assay, genetic epistasis (Wnt5a-Ror2-Vangl2)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO models, functional cellular assays, genetic epistasis establishing pathway order, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32394892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ror2-mediated non-canonical Wnt signaling in dental mesenchyme regulates cell proliferation during tooth root development via Cdc42 as a downstream mediator; activation of Cdc42 rescues cell proliferation and root development size defects in Ror2 mutant mice.\",\n      \"method\": \"Dental mesenchyme-specific Ror2 conditional KO mice, Cdc42 activity assays, cell proliferation (BrdU), constitutively active Cdc42 rescue experiment\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with functional readout and genetic rescue via activated Cdc42, in vivo model\",\n      \"pmids\": [\"33323370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ROR2 in hair follicle stem cells (HFSCs) is required for Wnt-activated signaling needed for HFSC activation and self-renewal, and also maintains ATM/ATR-dependent DNA damage response for long-term HFSC maintenance. In β-catenin-null HFSCs, ROR2-PKC signaling acts as a compensatory pathway to protect the stem cell pool.\",\n      \"method\": \"Ror2-depleted HFSC analysis (conditional KO), β-catenin KO HFSCs, ATM/ATR DNA damage assays, PKC inhibitor experiments, hair cycle analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, multiple functional readouts, PKC pathway dissection, genetic interaction with β-catenin KO, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35915068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WNT5a signaling through ROR2 activates the Hippo pathway (increasing phosphorylation of MST1/2, LATS1, MOB1, YAP1) to suppress YAP1 activity and tumor growth. Deletion of MST1/2 abrogates the WNT5a response. In ROR2-negative cells, WNT5a suppresses Hippo (via NF2/Merlin phosphorylation), revealing that ROR2 expression status determines whether WNT5a activates or suppresses Hippo. YAP1 activity also feeds back to stimulate ROR2 and WNT5a expression.\",\n      \"method\": \"ROR2 knockout/knockdown, MST1/2 deletion, phosphorylation assays (MST1/2, LATS1, MOB1, YAP1), prostate cancer organoid and xenograft models, NF2/Merlin phosphorylation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO of pathway components, phosphoprotein assays, in vivo organoid and xenograft models, multiple orthogonal methods establishing pathway order\",\n      \"pmids\": [\"36622276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Active Wnt5b-Ror2 complexes form in producing cells and are loaded onto cytonemes (long signaling filopodia) for transfer to receiving cells in zebrafish. The transferred Ror2 complexes can activate Wnt-PCP signaling in receiving cells independently of the receiving cell's own Ror2 receptor status. Cytoneme-mediated Wnt5b-Ror2 complex spreading affects convergence and extension in zebrafish gastrula.\",\n      \"method\": \"Live fluorescence imaging of Wnt5b-Ror2 fluorescent fusions on cytonemes, cell transplantation experiments, convergence/extension assays in zebrafish, Ror2 loss-of-function receiving cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging of tagged complexes, transplantation/mosaic experiments in zebrafish, loss-of-function validation, multiple orthogonal approaches in high-impact journal\",\n      \"pmids\": [\"38123680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cancer-associated fibroblasts (CAFs) transfer ROR2 to gastric cancer cells via cytonemes (signaling filopodia), and the transferred ROR2 activates Wnt/JNK signaling in receiving cells, promoting their polarization and migration. Blockage of ROR2 function in CAFs reduces paracrine Wnt/JNK signaling and migration of gastric cancer cells.\",\n      \"method\": \"High-resolution live imaging of fluorescent ROR2 transfer, JNK signaling reporter in receiving cells, ROR2 blockade in CAFs, zebrafish in vivo migration assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct imaging of receptor transfer, functional signaling readout in receiving cells, in vivo zebrafish validation, multiple orthogonal methods\",\n      \"pmids\": [\"37722040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Differential protein stability and membrane localization of ROR2 mutants underlies the distinct phenotypes of BDB1 vs. Robinow syndrome: BDB1 mutant proteins are stable and reach the cell membrane, while RRS mutant proteins are less abundant and retained intracellularly. A gradient of membrane-associated ROR2 correlates with clinical phenotype severity, confirmed in compound heterozygous mice.\",\n      \"method\": \"Stably transfected cell lines expressing BDB1 and RRS mutants, cell fractionation, western blot for protein stability, membrane protein fraction quantification, compound heterozygous mouse crosses\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative membrane fractionation across multiple mutants, in vivo genetic confirmation in compound mouse models, mechanistic model validated by multiple approaches\",\n      \"pmids\": [\"19640924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ROR2 activates the ERK/CREB signaling pathway to upregulate the transcription factor ASCL1, which drives lineage plasticity (stem-cell-like and neuronal programs) in prostate cancer following AR pathway inhibition.\",\n      \"method\": \"ROR2 overexpression/knockdown in PCa cells, ERK/CREB phosphorylation assays, ASCL1 expression assay, chromatin assays, functional lineage marker analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation assays, transcription factor expression analysis with genetic manipulation, single lab, functional lineage readout\",\n      \"pmids\": [\"37552603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ROR2 suppresses prostate cancer metastasis via upregulation of PIAS3 (through suppression of miR-199a-5p), which decreases AKT2 phosphorylation, inhibiting EMT and migration/invasion in vitro and in orthotopic xenograft models.\",\n      \"method\": \"ROR2 overexpression in PCa cell lines, miRNA array and western blot, PIAS3 and AKT2 expression analysis, orthotopic xenograft model, tissue microarray IHC\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional validation with molecular mechanism (miR-199a-5p-PIAS3-AKT2), single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"32415173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ROR2 promotes sphingomyelin biosynthesis by inhibiting STK4 phosphorylation, which promotes FOXO1 nuclear translocation where it represses SMS1 transcription; loss of ROR2 in DPSCs reduces sphingomyelin levels and promotes cellular senescence.\",\n      \"method\": \"ROR2 knockdown/overexpression, STK4 phosphorylation assay, FOXO1 nuclear localization imaging, ChIP for FOXO1 on SMS1 promoter, sphingomyelin measurement, senescence assays\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, phosphorylation assays, functional lipid biochemistry, single lab with multiple methods\",\n      \"pmids\": [\"34278704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ROR2 in spinal neurons modulates neuropathic pain by phosphorylating GluN2B (NMDAR subunit) at Ser1303 and Tyr1472 via PKC and Src family kinase pathways. Intrathecal Wnt5a injection induces pain behaviors that are blocked by GluN2B, PKC, or Src inhibitors. CCI-induced spinal ROR2 upregulation involves CpG demethylation of the ROR2 promoter.\",\n      \"method\": \"Immunoprecipitation for GluN2B phosphorylation, siRNA knockdown of ROR2, intrathecal Wnt5a injection, pharmacological inhibitors (PKC, Src, GluN2B), CCI mouse model, bisulfite sequencing of ROR2 promoter\",\n      \"journal\": \"British journal of anaesthesia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for substrate phosphorylation, pharmacological pathway dissection, functional pain behavior readout, single lab\",\n      \"pmids\": [\"30916039\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ROR2 is a transmembrane receptor tyrosine kinase (with largely pseudokinase activity in humans) that acts as a receptor and co-receptor for non-canonical Wnt ligands (principally Wnt5a, and also Wnt5b, Wnt11): Wnt5a binding to the extracellular CRD induces Ror2 homodimerization/heterodimerization (with Frizzled, PTK7, or ROR1), recruits intracellular effectors including CKIε, GSK-3α, TAK1, and filamin A via its cytoplasmic proline-rich domain, and activates downstream cascades including JNK/AP-1, Rac1, RhoA-Pkn3-cSrc, PI3K/AKT, Hippo/YAP, and PKC, while simultaneously inhibiting canonical β-catenin/TCF signaling; Ror2-Wnt5a complexes can also be transferred intercellularly via cytonemes to activate signaling in recipient cells regardless of their own ROR2 status.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ROR2 is a single-pass transmembrane receptor for non-canonical Wnt ligands that governs cell polarity, migration, and tissue morphogenesis while antagonizing canonical Wnt/\\u03b2-catenin signaling [#0, #8]. Wnt5a binds directly to the extracellular cysteine-rich domain (CRD), which also mediates assembly of ROR2 into receptor complexes with Frizzled, PTK7, and ROR1, and into ligand-independent complexes with BMPR1B [#0, #2, #15, #17]. Although the human ROR2 kinase domain is catalytically deficient (a pseudokinase), ligand engagement still drives ROR2 phosphorylation: serine/threonine priming by CKI\\u03b5, GSK-3\\u03b1, and TAK1 within its ST/STP/STP motifs precedes tyrosine autophosphorylation in the cytoplasmic proline-rich domain (PRD) rather than the kinase domain, and the membrane-bound extracellular domain alone suffices to suppress canonical Wnt3a signaling [#1, #5, #7, #13]. Through its PRD, ROR2 recruits intracellular effectors\\u2014including filamin A, ShcA, and CKI\\u03b5\\u2014to reorganize the actin cytoskeleton and form filopodia for Wnt5a-induced migration [#1, #3, #11]. Downstream, ROR2 activates a branching set of cascades: PI3K/Cdc42 and Dishevelled-Rac1 feeding JNK/AP-1 transcription, RhoA-Pkn3-cSrc actin-ring assembly, and Hippo-dependent control of YAP [#4, #10, #19, #28]. These activities place ROR2 at the center of skeletal and connective-tissue development\\u2014chondrogenesis, osteoclastogenesis, tooth root, alveolar, and mammary morphogenesis\\u2014and of disease processes in cancer invasion and metastasis [#2, #12, #19, #25, #26]. ROR2 mutations underlie brachydactyly type B1 and Robinow syndrome, where mutant protein stability and plasma-membrane localization correlate with phenotype severity [#31]. ROR2-Wnt complexes can also be loaded onto cytonemes and transferred between cells to activate signaling in recipients independent of their own ROR2 status [#29, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established ROR2 as a receptor/co-receptor for non-canonical Wnt signaling by showing Wnt5a binds its CRD and that ROR2 partners with Frizzled to activate JNK and control morphogenetic movements.\",\n      \"evidence\": \"In vitro CRD-Wnt5a binding, Ror2-Fz2 co-IP, JNK assay, Xenopus convergent extension, and Ror2/Wnt5a knockout mouse comparison\",\n      \"pmids\": [\"12839624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the intracellular signaling chain linking ROR2 to JNK\", \"Catalytic status of the ROR2 kinase domain not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined how ROR2 is activated despite its non-canonical mechanism by showing CKI\\u03b5-mediated serine/threonine phosphorylation of the ST domain drives ROR2 tyrosine autophosphorylation within the PRD rather than the kinase domain.\",\n      \"evidence\": \"Co-IP, deletion mapping, and site-directed mutagenesis of autophosphorylation sites in cells\",\n      \"pmids\": [\"15375164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological ligand trigger for CKI\\u03b5 recruitment not established here\", \"Functional consequence of GRK2 phosphorylation downstream unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed ROR2 integrates with BMP/GDF5 signaling by forming a ligand-independent complex with BMPR1B that modulates Smad pathways during chondrogenesis, broadening ROR2 beyond Wnt.\",\n      \"evidence\": \"Co-IP, transphosphorylation assay, Smad1/5 reporter, ATDC5 differentiation, and triple-mutant mouse epistasis\",\n      \"pmids\": [\"15569154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the Smad-independent pathway not defined\", \"Direct relevance to human skeletal disease not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked ROR2 to actin cytoskeletal remodeling by identifying filamin A as a PRD-binding partner required for Wnt5a-induced filopodia and migration.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mapping, siRNA of ROR2/filamin A, and filopodia/migration assays\",\n      \"pmids\": [\"17101698\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GTPase intermediaries between ROR2 and actin not yet placed\", \"Filamin A recruitment dynamics upon ligand binding not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Dissected the cytoplasmic cascade by showing ROR2 signals through PI3K/Cdc42 to JNK/ATF2/c-Jun to transcribe PAPC, independent of \\u03b2-catenin, defining a discrete non-canonical branch.\",\n      \"evidence\": \"Xenopus morpholino loss-of-function, pharmacological/dominant-negative epistasis, and reporter/rescue assays\",\n      \"pmids\": [\"17488628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PI3K is activated by ROR2 not defined\", \"Mammalian conservation of this exact branch not tested here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified GSK-3\\u03b1 as a kinase that directly phosphorylates ROR2 upon Wnt5a stimulation and is required for ROR2-driven migration, adding another priming kinase upstream of ROR2 activation.\",\n      \"evidence\": \"In vitro kinase reconstitution on immunoprecipitated ROR2, GSK-3 inhibitors, siRNA, and phospho-blots\",\n      \"pmids\": [\"17986005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosites on ROR2 not mapped\", \"Interplay between GSK-3\\u03b1 and CKI\\u03b5/TAK1 priming unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated classic RTK-like behavior by showing Wnt5a, but not Wnt3a, induces ROR2 homodimerization, tyrosine autophosphorylation, and substrate (14-3-3\\u03b2) phosphorylation, and defined TAK1 as an additional intracellular kinase regulated by ligand-dependent displacement.\",\n      \"evidence\": \"Co-IP dimerization, phosphotyrosine/substrate blots, osteoblast siRNA assays, and Wnt ligand displacement experiments\",\n      \"pmids\": [\"18615587\", \"18762249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether tyrosine phosphorylation reflects intrinsic versus heterologous kinase activity not settled\", \"PRTB role mechanistically thin\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that ROR2 inhibits canonical Wnt/\\u03b2-catenin signaling in vivo and that its kinase function is required for transduction of Wnt5a signals.\",\n      \"evidence\": \"Kinase-dead/deletion mutants, \\u03b2-catenin-TCF reporters, and Axin2-LacZ reporter in Ror2-null mice\",\n      \"pmids\": [\"19720827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent kinase requirement later reconciled with pseudokinase status\", \"Mechanism of \\u03b2-catenin antagonism not fully defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected ROR2 to cancer by showing Wnt5a drives PKC-dependent clathrin-mediated ROR2 internalization that is required for melanoma metastasis.\",\n      \"evidence\": \"siRNA, in vitro/in vivo metastasis assays, and pharmacological inhibition of PKC and clathrin\",\n      \"pmids\": [\"19802008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling consequence of internalization versus surface signaling not separated\", \"Single-lab in vivo model\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided a mechanistic basis for ROR2 disease genotype-phenotype correlation by showing BDB1 mutants reach the membrane while Robinow mutants are unstable and intracellularly retained.\",\n      \"evidence\": \"Stable mutant cell lines, membrane fractionation/stability blots, and compound heterozygous mouse crosses\",\n      \"pmids\": [\"19640924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling defects of each mutant class not directly measured\", \"How retention maps to specific developmental defects unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the receptor architecture and effector chain for AP-1 activation, showing ROR2-Fz7 complexes drive Dishevelled polymerization and Rac1-dependent AP-1, with the ROR2 cytoplasmic region dispensable for Dvl regulation.\",\n      \"evidence\": \"Co-IP, Dvl polymerization and AP-1 reporter assays, domain deletions, and Rac1 co-localization imaging\",\n      \"pmids\": [\"20457807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling cytoplasm-independent Dvl signaling with PRD-dependent migration not addressed\", \"Stoichiometry of the ROR2-Fz-Dvl complex unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Added ShcA as an SH2-domain effector recruited to phospho-ROR2 upon Wnt5a-induced clustering, required for PAPC induction.\",\n      \"evidence\": \"Co-IP with domain mapping, live imaging of ROR2 clustering, and Xenopus morpholino/PAPC assays\",\n      \"pmids\": [\"20732301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream connection from ShcA to transcription not detailed\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a transcriptional output of ROR2-JNK signaling in bone, where c-Jun upregulates RANK to enhance osteoclastogenesis, and demonstrated therapeutic potential of soluble ROR2 as a Wnt5a decoy.\",\n      \"evidence\": \"Osteoclast-specific conditional KO, c-Jun ChIP on RANK promoter, JNK inhibitor, and decoy ROR2 in a mouse arthritis model\",\n      \"pmids\": [\"22344299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other JNK target genes in osteoclasts not surveyed\", \"Decoy specificity for Wnt5a versus other ligands not exhaustively tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Reconciled prior 'kinase' claims by demonstrating human ROR1/ROR2 kinase domains are pseudokinases and that the extracellular domain alone suppresses canonical Wnt, shifting emphasis to scaffolding/receptor functions.\",\n      \"evidence\": \"In vitro kinase assays of purified domains, consensus-residue mutagenesis, deletion constructs, and Wnt reporters across orthologs\",\n      \"pmids\": [\"25029443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How tyrosine phosphorylation occurs without intrinsic activity not fully mapped\", \"Whether trace activity matters physiologically unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended ROR2 ligand repertoire by showing it binds Wnt11 and signals via Dishevelled and RhoA, with specific intracellular residues (Y647, S863) essential for transduction.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis, dominant-negative ROR2, and zebrafish convergence/extension epistasis\",\n      \"pmids\": [\"24928507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Wnt11 uses the same co-receptors as Wnt5a not addressed\", \"Functional role of the specific residues in mammals not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified PTK7 as a ROR2 co-receptor in the Wnt5a-JNK migration pathway, with ROR2 kinase function required for rescue of PTK7 loss, independently confirmed by two groups.\",\n      \"evidence\": \"Reciprocal Co-IP, JNK assays, kinase-dead Xenopus rescue, and live imaging\",\n      \"pmids\": [\"26499793\", \"26680417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a pseudokinase ROR2 is required for rescue unclear\", \"Hierarchy among PTK7/Fz/ROR1 co-receptors not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Broadened ROR2 function into the nervous system, showing it maintains NMDAR-mediated synaptic transmission through PKC and JNK in hippocampal neurons.\",\n      \"evidence\": \"Electrophysiology with ROR2 knockdown and PKC/JNK inhibitors plus Wnt ligand application\",\n      \"pmids\": [\"25825749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ROR2 substrates at the synapse not identified here\", \"Specific Wnt ligand in neurons not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed Wnt5a-induced ROR1/ROR2 heterooligomerization recruits GEFs to activate Rac1 and RhoA driving leukemia cell proliferation and migration, with domain-specific roles mapped.\",\n      \"evidence\": \"Co-IP, domain deletions, GTPase activation assays, siRNA, and xenograft\",\n      \"pmids\": [\"26690702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the recruited GEFs not specified\", \"Relative contribution of homo- versus heterooligomers unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected ROR2 to RhoA-Pkn3-cSrc signaling for actin-ring formation in osteoclast bone resorption, establishing pathway order via constitutively active RhoA rescue.\",\n      \"evidence\": \"Osteoclast-specific and global KO mice, co-IP, c-Src kinase assay, actin ring assays, bone morphometry, and RhoA rescue\",\n      \"pmids\": [\"28851822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ROR2 activates RhoA upstream not detailed\", \"Generalizability of Pkn3-cSrc axis to other cell types untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a ROR2 mechanism for tumor invasiveness via IFT20-dependent Golgi ribbon organization and polarized secretion, linking ROR2 to membrane trafficking.\",\n      \"evidence\": \"siRNA of ROR2/IFT20, GM130-AKAP450 complex and Golgi imaging, microtubule nucleation, and invasion assays\",\n      \"pmids\": [\"28127051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ROR2 regulates IFT20 expression not defined\", \"Single-lab mechanism\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated ROR2's morphogenetic role in mammary epithelium, controlling branching and differentiation through actin/RhoA programs while antagonizing canonical Wnt.\",\n      \"evidence\": \"In vivo lentiviral shRNA, microarray, branching morphogenesis assays, and RhoA pathway analysis\",\n      \"pmids\": [\"25624393\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ROR2 effectors driving branching not pinpointed\", \"Ligand source in mammary tissue not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked ROR2 to Hippo/YAP mechanotransduction in cartilage, showing ROR2 signaling drives Rho/G-protein-dependent nuclear YAP and that ROR2 blockade promotes chondrogenesis independent of Wnt.\",\n      \"evidence\": \"siRNA/overexpression, YAP imaging, Rho/G-protein inhibitors, ADAMTS assays, mouse OA model, and human organoids\",\n      \"pmids\": [\"32938794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand driving Wnt-independent ROR2 signaling unclear\", \"How ROR2 couples to G-proteins not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a Wnt5a-Ror2-Vangl2 PCP cascade controlling cytoskeleton and PDGF secretion during alveologenesis, ordering the pathway genetically.\",\n      \"evidence\": \"Cell-type-specific conditional KO mice, cytoskeletal imaging, PDGF/migration assays, and epistasis\",\n      \"pmids\": [\"32394892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between ROR2 and Vangl2 not biochemically resolved\", \"Direct effectors of cytoskeletal change not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reported ROR2-dependent prostate cancer metastasis suppression via a miR-199a-5p-PIAS3-AKT2 axis, indicating context-dependent tumor-suppressive roles.\",\n      \"evidence\": \"ROR2 overexpression, miRNA/protein profiling, orthotopic xenograft, and tissue microarray IHC\",\n      \"pmids\": [\"32415173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ROR2 regulates miR-199a-5p unclear\", \"Reconciliation with pro-metastatic roles in other cancers not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated ROR2 in inflammatory signaling, linking the Wnt5a/ROR2 axis to NF-\\u03baB activation and cytokine release in bronchial epithelium.\",\n      \"evidence\": \"siRNA of ROR2/Wnt5a, NF-\\u03baB translocation, cytokine ELISA, and PM2.5 stimulation\",\n      \"pmids\": [\"33122903\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single siRNA experiment with limited mechanistic depth\", \"Direct ROR2-to-NF-\\u03baB link not established\", \"Not independently confirmed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined ROR2's developmental role in tooth root formation through Cdc42-dependent mesenchymal proliferation, confirmed by activated-Cdc42 rescue.\",\n      \"evidence\": \"Dental mesenchyme conditional KO, Cdc42 activity assays, BrdU proliferation, and Cdc42 rescue\",\n      \"pmids\": [\"33323370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream link from ROR2 to Cdc42 not biochemically defined\", \"Ligand source in dental mesenchyme not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected ROR2 to lipid metabolism and senescence, showing it represses SMS1 via STK4/FOXO1 to sustain sphingomyelin and prevent stem cell senescence.\",\n      \"evidence\": \"ROR2 knockdown/overexpression, STK4 phospho-assay, FOXO1 imaging, ChIP on SMS1, lipid measurement, and senescence assays\",\n      \"pmids\": [\"34278704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ROR2 regulates STK4 phosphorylation unclear\", \"Relationship to canonical Wnt5a signaling not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed ROR2 supports hair follicle stem cell activation and long-term maintenance, acting through PKC as a compensatory pathway in \\u03b2-catenin-null cells and sustaining ATM/ATR DNA damage responses.\",\n      \"evidence\": \"Conditional KO, \\u03b2-catenin KO HFSCs, ATM/ATR assays, PKC inhibitors, and hair cycle analysis\",\n      \"pmids\": [\"35915068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking ROR2 to DNA damage response unresolved\", \"Direct ROR2-PKC coupling not biochemically mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that ROR2 expression status dictates whether Wnt5a activates or suppresses Hippo, with ROR2 driving MST1/2-LATS1-mediated suppression of YAP1 and a YAP-ROR2 feedback loop in prostate cancer.\",\n      \"evidence\": \"ROR2 and MST1/2 KO, phospho-assays of Hippo components, NF2 phosphorylation, and organoid/xenograft models\",\n      \"pmids\": [\"36622276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical link from ROR2 to MST1/2 not defined\", \"Reconciliation with ROR2-driven nuclear YAP in cartilage unaddressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an ROR2-ERK/CREB-ASCL1 axis driving lineage plasticity in prostate cancer after AR inhibition, broadening ROR2's role in therapy resistance.\",\n      \"evidence\": \"ROR2 overexpression/knockdown, ERK/CREB phospho-assays, ASCL1 expression, and chromatin/lineage marker analysis\",\n      \"pmids\": [\"37552603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ROR2 engages ERK/CREB upstream unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a paracrine mode of ROR2 action, demonstrating that active Wnt5b-ROR2 complexes are loaded onto cytonemes and transferred to recipient cells to activate PCP signaling independent of recipient ROR2 status.\",\n      \"evidence\": \"Live imaging of tagged Wnt5b-ROR2 on cytonemes, transplantation/mosaic experiments, and convergence/extension assays in zebrafish\",\n      \"pmids\": [\"38123680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery loading complexes onto cytonemes unknown\", \"How transferred complexes engage recipient signaling components unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended cytoneme-mediated ROR2 transfer to cancer, showing CAFs deliver ROR2 to gastric cancer cells to activate Wnt/JNK and promote migration.\",\n      \"evidence\": \"High-resolution live imaging of ROR2 transfer, JNK reporters in recipients, ROR2 blockade in CAFs, and zebrafish migration assays\",\n      \"pmids\": [\"37722040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/machinery in recipient cells receiving ROR2 not defined\", \"In vivo mammalian tumor validation pending\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a catalytically deficient pseudokinase ROR2 produces context-opposite outputs (YAP activation versus suppression, tumor promotion versus suppression) and how it couples to diverse downstream kinases and GTPases remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying biochemical model linking ROR2 conformation to effector choice\", \"Cell-context determinants of opposing outputs undefined\", \"Structural basis of ROR2 co-receptor selectivity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042813\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 11, 21, 31]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 10, 28]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 25, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 17, 31]}\n    ],\n    \"complexes\": [\n      \"ROR2-Frizzled (Fz2/Fz7) Wnt receptor complex\",\n      \"ROR1/ROR2 heterooligomer\",\n      \"PTK7-ROR2 heterodimer\",\n      \"ROR2-BMPR1B (BRI-b) complex\"\n    ],\n    \"partners\": [\n      \"WNT5A\",\n      \"FZD7\",\n      \"PTK7\",\n      \"ROR1\",\n      \"FLNA\",\n      \"CSNK1E\",\n      \"SHC1\",\n      \"MAP3K7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}