{"gene":"ROR1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2012,"finding":"ROR1 interacts with casein kinase 1 epsilon (CK1ε) to activate PI3K-mediated AKT phosphorylation and CREB, and Wnt5a acts as a ligand for ROR1 to induce this ROR1-dependent signaling and enhance cancer cell growth.","method":"Co-immunoprecipitation, siRNA knockdown, in vitro growth assays, xenograft mouse models","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 — reciprocal Co-IP and functional KD, single lab","pmids":["22403610"],"is_preprint":false},{"year":2012,"finding":"NKX2-1/TTF-1 transcriptionally induces ROR1 expression in lung adenocarcinoma; ROR1 sustains prosurvival PI3K-AKT over pro-apoptotic p38 signaling through both kinase-dependent c-Src activation and kinase-independent maintenance of the EGFR-ERBB3 association and ERBB3 phosphorylation.","method":"siRNA knockdown, phosphoprotein analysis, co-immunoprecipitation, lung cancer cell line functional assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (kinase-dependent and -independent mechanisms dissected), replicated across cell lines","pmids":["22439932"],"is_preprint":false},{"year":2013,"finding":"ROR1 expression promotes epithelial-mesenchymal transition (EMT), enhancing vimentin and SNAIL-1/2 expression while reducing E-cadherin; silencing ROR1 attenuates in vitro migration/invasion and in vivo metastasis of breast cancer cells.","method":"siRNA/shRNA knockdown, overexpression in MCF-7 cells, Western blot for EMT markers, in vivo metastasis assay in immunodeficient mice, anti-ROR1 mAb treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function with defined molecular markers, in vitro and in vivo validation","pmids":["23771907"],"is_preprint":false},{"year":2013,"finding":"ROR1 complexes with TCL1 in CLL cells as revealed by immunoprecipitation and mass spectrometry; ROR1×TCL1 double-transgenic mice develop leukemia earlier than single-transgenic animals, with higher phospho-AKT levels, establishing ROR1 as an enhancer of TCL1-driven AKT signaling in leukemogenesis.","method":"Co-immunoprecipitation, mass spectrometry, transgenic mouse crosses, phospho-AKT analysis, adoptive transfer","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — MS-confirmed complex, genetic epistasis in vivo, multiple readouts","pmids":["24379361"],"is_preprint":false},{"year":2014,"finding":"Human ROR1 and ROR2 kinase domains are catalytically deficient (pseudokinases), whereas the C. elegans ortholog CAM-1 has active tyrosine kinase activity; substitution of non-consensus residues from ROR1/ROR2 into active kinases reduces activity, and restoration of consensus residues in ROR does not rescue kinase function. Additionally, the extracellular domain alone of ROR1 is sufficient to suppress canonical Wnt3a signaling.","method":"In vitro kinase assay with recombinant proteins, mutagenesis, Wnt reporter assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical assays with mutagenesis, clear demonstration of pseudokinase nature","pmids":["25029443"],"is_preprint":false},{"year":2001,"finding":"The frizzled (FRZ) module of rat Ror1 contains 10 conserved cysteines forming disulfide bonds in a 1-5, 2-4, 3-8, 6-10, 7-9 pattern; the isolated domain forms a compact, stable folding unit with both alpha-helices and beta-strands.","method":"Recombinant protein expression in Pichia pastoris, proteolytic digestion, amino acid sequencing, circular dichroism, differential scanning calorimetry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical structural characterization with mutagenesis-equivalent disulfide mapping","pmids":["11279007"],"is_preprint":false},{"year":2011,"finding":"ROR1 is extensively modified by N-linked glycosylation, producing isoforms of ~100, 115, and 130 kDa; glycosylation is required for cell-surface localization of the 130 kDa isoform and for ROR1-induced filopodia formation. ROR1 is also mono-ubiquitinated.","method":"Glycosylation inhibitors, N-glycosidase treatment, immunohistochemistry, cell surface protein analysis, ubiquitination assay","journal":"Acta physiologica","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and enzymatic perturbation of glycosylation with functional readout, single lab","pmids":["21481194"],"is_preprint":false},{"year":2016,"finding":"Wnt5a induces ROR1 to oligomerize with ROR2 and recruit guanine nucleotide exchange factors (GEFs), activating Rac1 and RhoA in CLL cells; the extracellular Kringle domain of ROR1 is required for ROR1/ROR2 heterooligomerization, and the cysteine-rich domain or intracellular proline-rich domain is required for GEF recruitment.","method":"Co-immunoprecipitation, siRNA silencing of ROR1/ROR2, domain truncation/mutation analysis, GTPase activation assays, xenograft mouse model","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — domain mapping with multiple truncation mutants, reciprocal Co-IP, functional GTPase assays, in vivo validation","pmids":["26690702"],"is_preprint":false},{"year":2016,"finding":"ROR1 functions as a scaffold protein for cavin-1 (CAVIN1) and caveolin-1 (CAV1), facilitating their interaction at the plasma membrane in a kinase-independent manner; this prevents lysosomal degradation of CAV1, maintains caveolae structure, and sustains prosurvival AKT signaling through multiple RTKs including EGFR, MET, and IGF-IR.","method":"Co-immunoprecipitation, electron microscopy (caveolae structure), ROR1 kinase-dead mutants, lysosome inhibitor assays, lung cancer cell lines","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — kinase-independent scaffold function established by kinase-dead mutants and structural (EM) analysis, multiple orthogonal methods","pmids":["26725982"],"is_preprint":false},{"year":2017,"finding":"ROR1 phosphorylates HER3 at a previously unidentified site Tyr1307 following neuregulin stimulation, independently of other ErbB family members; phospho-HER3 Tyr1307 recruits the LLGL2-MAYA-NSUN6 RNA-protein complex to methylate Hippo/MST1 at Lys59, leading to MST1 inactivation and YAP target gene activation, promoting osteoclast differentiation and bone metastasis.","method":"Phosphoproteomic analysis, mutagenesis, co-immunoprecipitation, RNA-protein complex purification, methylation assays, in vivo bone metastasis models","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — novel phosphorylation site identified by mass spectrometry, mechanistic chain validated by mutagenesis and complex reconstitution, in vivo validation","pmids":["28114269"],"is_preprint":false},{"year":2017,"finding":"Wnt5a induces ROR1 to associate with HS1 (hematopoietic lineage cell-specific protein 1) via the ROR1 proline-rich domain (PRD); this complex recruits ARHGEF1 and activates RhoA, enhancing CLL cell migration. The proline at position 841 of the PRD is specifically required for HS1 and ARHGEF1 recruitment.","method":"Co-immunoprecipitation, domain truncation mutants, single amino-acid substitution mutants (P→A), GTPase activation assay, CLL cell migration assay","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — precise residue-level mapping with panel of point mutants, functional migration assay","pmids":["28465529"],"is_preprint":false},{"year":2018,"finding":"Wnt5a induces ROR1 to recruit DOCK2 via the PRD (specifically Pro808), activating Rac1/2 and enhancing CLL cell proliferation. The ROR1P808A mutant cannot recruit DOCK2 or activate Rac1/2, and cells expressing it lack the proliferative advantage conferred by wild-type ROR1.","method":"Co-immunoprecipitation, siRNA silencing of DOCK2, single amino-acid substitution mutants (P808A), Rac1/2 activation assay, cell proliferation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — precise residue mapping, DOCK2-specific rescue experiments, functional proliferation readout","pmids":["29678828"],"is_preprint":false},{"year":2018,"finding":"Wnt5a causes ROR1 to bind cortactin and induce tyrosine phosphorylation of cortactin at Y421, which recruits ARHGEF1 and activates RhoA to enhance CLL cell migration; the proline at position 841 of the ROR1 PRD is required for cortactin and ARHGEF1 recruitment.","method":"Co-immunoprecipitation, ROR1 PRD mutants (P→A), cortactin phosphorylation assay, F-actin polymerization assay, CLL migration assay","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — precise residue mapping matching HS1 recruitment site, independent confirmation of PRD-841 requirement","pmids":["30568170"],"is_preprint":false},{"year":2019,"finding":"Wnt5a-ROR1 signaling induces CLL cell NF-κB activation within 30 minutes, which in turn drives autocrine expression of IL-6 and other cytokines that subsequently induce STAT3 phosphorylation; cirmtuzumab blocks both NF-κB phosphorylation and STAT3 activation in patients treated with the antibody.","method":"Time-course signaling assays, NF-κB inhibitors, cytokine measurement, patient sample analysis before/after cirmtuzumab treatment","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic dissection with inhibitors and patient samples, single lab","pmids":["31409670"],"is_preprint":false},{"year":2019,"finding":"Wnt5a induces ROR1 to recruit cortactin in breast cancer cells via PRD-Pro841; this complex phosphorylates cortactin at Y421, recruits ARHGEF1, activates RhoA, and promotes breast cancer cell migration and metastasis in vivo; cirmtuzumab inhibits cortactin phosphorylation in vivo.","method":"Co-immunoprecipitation, ROR1 point mutants, RhoA activation assay, in vivo xenograft metastasis model","journal":"NPJ breast cancer","confidence":"High","confidence_rationale":"Tier 2 — extends CLL finding to breast cancer with in vivo validation; consistent mechanism across two labs/papers","pmids":["31667337"],"is_preprint":false},{"year":2019,"finding":"ROR1 functions as a scaffold for CAVIN3, binding at a site distinct from CAV1 and CAVIN1 binding sites; this interaction is required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis, which links to RTK-mediated prosurvival AKT signaling in early endosomes.","method":"Co-immunoprecipitation, domain mapping, electron microscopy, endocytosis assays, lung adenocarcinoma cell lines","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — extends caveolae scaffold finding; distinct binding sites for CAVIN3 vs CAV1/CAVIN1 mapped, functional endocytosis assay","pmids":["30894682"],"is_preprint":false},{"year":2020,"finding":"Wnt5a induces activation of ERK1/2 and enhances CLL cell proliferation via a ROR1/DOCK2-dependent pathway; this pathway is independent of BTK, as ibrutinib does not block Wnt5a-induced, ROR1-dependent ERK1/2 or DOCK2 phosphorylation. The ROR1P808A and ROR1ΔPRD mutants cannot support ERK1/2 activation.","method":"ERK1/2 phosphorylation assays, siRNA DOCK2 silencing, ibrutinib treatment, ROR1 point mutants, MEC1 transfection model","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway placement via genetic constructs, pharmacological dissection, clear BTK-independence","pmids":["33097837"],"is_preprint":false},{"year":2011,"finding":"Mouse resistin interacts with specific extracellular domains of ROR1, inhibits ROR1 phosphorylation, modulates ERK1/2 phosphorylation, regulates SOCS3, GLUT4, and GLUT1 expression, and promotes adipogenesis while modulating glucose uptake in 3T3-L1 cells through ROR1.","method":"Co-immunoprecipitation/binding assays, phosphorylation analysis, gene expression analysis, glucose uptake assay, adipogenesis assay in 3T3-L1 cells","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, binding and downstream signaling measured but no structural or reconstitution-level validation","pmids":["22074948"],"is_preprint":false},{"year":2005,"finding":"Ror1 and Ror2 modulate neurite elongation and branching in hippocampal neurons; Ror depletion (antisense or RNAi) results in shorter, less-branched minor processes and longer but less-branched axons, while Ror overexpression promotes short, highly branched processes; these phenotypes are accompanied by changes in microtubule-associated proteins MAP1B and MAP2.","method":"Antisense oligonucleotides, RNAi knockdown, overexpression in neurons and non-neuronal cells, morphometric analysis, MAP1B/MAP2 protein analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss- and gain-of-function in neurons with molecular marker analysis, but mechanism not fully resolved","pmids":["15654020"],"is_preprint":false},{"year":2016,"finding":"Ror1-null mice display distinct skeletal and urogenital defects and postnatal growth retardation, demonstrating a non-redundant role for Ror1 in skeletal development and growth.","method":"Ror1 knockout mouse analysis, skeletal staining, anatomical phenotyping","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with defined skeletal/growth phenotype","pmids":["20593419"],"is_preprint":false},{"year":2016,"finding":"ROR1 is essential for spiral ganglion neuron innervation of auditory hair cells and hearing; a missense mutation (p.R736T) prevents ROR1 from reaching the plasma membrane and abrogates WNT5A-induced NF-κB activation; Ror1 mutant mice are severely deaf with fasciculation defects in spiral ganglion axons and impaired Type I neuron synapses with inner hair cells.","method":"Whole-exome sequencing, cell localization assay, NF-κB reporter assay, Ror1 mutant mouse phenotyping, auditory testing (otoacoustic emissions, ABR), spiral ganglion histology","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — human mutation linked to cellular mislocalization and loss of NF-κB signaling, validated in mouse model with detailed neuroanatomy","pmids":["27162350"],"is_preprint":false},{"year":2018,"finding":"The 3D crystal structure of an ROR1-targeting scFv (R11) in complex with the kringle domain of ROR1 was determined at 1.6 Å resolution, precisely mapping a membrane-proximal epitope conserved between human and mouse ROR1.","method":"X-ray crystallography at 1.6 Å resolution","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure directly determining epitope-receptor interaction geometry","pmids":["29844189"],"is_preprint":false},{"year":2018,"finding":"Twist transcription factor directly binds to and activates the ROR1 gene promoter, transcriptionally upregulating ROR1 expression; ROR1 silencing inhibits Twist-induced EMT, migration, invasion, and lung metastasis in basal-like breast cancer cells.","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), microarray transcriptomics, ROR1 siRNA knockdown, in vivo lung metastasis model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — direct transcriptional regulation demonstrated by ChIP and reporter assay, functional rescue experiment","pmids":["29774072"],"is_preprint":false},{"year":2023,"finding":"IGFBP5 is identified as a ligand for ROR1; IGFBP5 binding to ROR1 facilitates ROR1/HER2 heterodimer formation, leading to CREB-mediated expression of ETV5 and FBXW9, thereby promoting glioblastoma stem cell invasion and tumorigenesis.","method":"Co-immunoprecipitation, IGFBP5 knockdown/overexpression, patient-derived xenograft model, RNA sequencing, CRISPR/Cas9 gene editing, nanocapsule delivery in orthotopic mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — novel ligand identified by Co-IP, heterodimer formation shown, downstream pathway defined with rescue experiments, in vivo validation","pmids":["36949068"],"is_preprint":false},{"year":2023,"finding":"In pancreatic cancer, ROR1 induces expression of Aurora kinase B (AURKB) by activating E2F through c-Myc to enhance proliferation; ROR1 expression is transcriptionally dependent on YAP/BRD4 binding at an enhancer region.","method":"ROR1 depletion (siRNA/shRNA), ChIP-seq/epigenomic analysis, c-Myc and E2F pathway analysis, YAP/BRD4 inhibition, in vivo tumor growth and metastasis models","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — epigenomic and transcriptional circuit dissected with ChIP-seq and functional assays, single lab","pmids":["37096681"],"is_preprint":false},{"year":2020,"finding":"CXCL16 produced by mesenchymal stem cells upregulates Ror1 expression in gastric cancer cells through activation of the CXCR6-STAT3 pathway; Ror1 expression in tumor cells is required for MSC-promoted tumor formation in vivo.","method":"siRNA knockdown of CXCL16, recombinant CXCL16 treatment, STAT3 pathway analysis, co-injection xenograft model, anti-CXCL16 neutralizing antibody","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2–3 — pathway placed (CXCL16→CXCR6→STAT3→ROR1), in vivo validation, single lab","pmids":["32012403"],"is_preprint":false},{"year":2023,"finding":"ROR1 forms a positive feedback loop with STAT3 in osteoarthritis chondrocytes: Wnt5a-induced ROR1 activates NF-κB, and STAT3 binds the ROR1 promoter to upregulate ROR1 expression; ROR1 knockdown alleviates NF-κB activation and cartilage degradation in a surgical OA mouse model.","method":"Luciferase assay, immunofluorescence, Western blot, STAT3 ChIP on ROR1 promoter, DMM surgical OA mouse model, histological staining","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP confirms STAT3 binding to ROR1 promoter, in vivo OA model, single lab","pmids":["37343369"],"is_preprint":false},{"year":2022,"finding":"Canonical Wnt/β-catenin signaling transcriptionally upregulates ROR1 expression in prostate cancer, and increased ROR1 enhances noncanonical responses to Wnt5a; APC genomic loss (but not epigenetic downregulation) is the key upstream driver of this pathway.","method":"Gene expression analysis, Wnt/β-catenin reporter assays, patient sample IHC, patient-derived xenograft treatment with Wnt synthesis inhibitor","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic link between canonical and noncanonical Wnt through ROR1, validated in PDX model","pmids":["35131873"],"is_preprint":false},{"year":2019,"finding":"In esophageal squamous cell carcinoma, Wnt5a activates ROR1 (in complex with ROR2) to signal through DAAM1 and activate RhoA (but not Rac1/2), promoting actin filament reassembly and cell invasion; DAAM1 is positioned downstream of ROR1/ROR2 and upstream of RhoA in this pathway.","method":"Co-immunoprecipitation, DAAM1/ROR2 shRNA, Rho activation assay, immunofluorescence (phalloidin), cell invasion assay, DAAM1 rescue with wild-type overexpression","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2–3 — pathway ordering established by shRNA and rescue, single lab","pmids":["31114334"],"is_preprint":false},{"year":2017,"finding":"COBLL1 is identified as a novel interaction partner of ROR1 in CLL cells; high COBLL1 expression correlates with impaired motility and enhanced BCR signaling (increased PLCγ2 and SYK phosphorylation after IgM stimulation).","method":"Co-immunoprecipitation/interaction studies, CLL patient sample analysis, chemotaxis assays, BCR signaling phosphorylation assays","journal":"Haematologica","confidence":"Low","confidence_rationale":"Tier 3 — Co-IP for interaction, functional correlation but no mechanistic dissection of ROR1-COBLL1 complex function","pmids":["29122990"],"is_preprint":false}],"current_model":"ROR1 is a transmembrane pseudokinase (catalytically deficient in humans) that acts as a receptor for Wnt5a and IGFBP5, forming functional heterooligomers with ROR2 and heterodimers with HER2/HER3; upon ligand binding it recruits GEFs (DOCK2, ARHGEF1) and adaptor proteins (HS1, cortactin, COBLL1) through its intracellular proline-rich domain (notably Pro808 for DOCK2 and Pro841 for HS1/cortactin), activating Rac1/2, RhoA, ERK1/2, PI3K-AKT, NF-κB, and STAT3 signaling to drive cancer cell migration, EMT, and survival; in parallel, ROR1 functions as a kinase-independent scaffold for cavin-1/caveolin-1 and CAVIN3 to maintain caveolae integrity and RTK-mediated AKT signaling, and can phosphorylate HER3-Tyr1307 to recruit the LLGL2-MAYA-NSUN6 complex that methylates MST1-Lys59 and inactivates the Hippo pathway, promoting bone metastasis."},"narrative":{"teleology":[{"year":2001,"claim":"Structural characterization of the ROR1 frizzled domain established it as an autonomously folded Wnt-binding module with a defined disulfide bonding pattern, providing the first biochemical foundation for understanding how ROR1 engages extracellular ligands.","evidence":"Recombinant expression, disulfide mapping, circular dichroism, and differential scanning calorimetry of the rat Ror1 FRZ domain","pmids":["11279007"],"confidence":"High","gaps":["No ligand-bound structure determined","Binding affinity for Wnt ligands not measured","Contribution of other extracellular domains (Ig, Kringle) to ligand recognition not addressed"]},{"year":2005,"claim":"Demonstration that Ror1 (with Ror2) modulates neurite morphology and microtubule-associated protein expression in hippocampal neurons established a developmental neuronal function beyond the receptor's initial cloning as an orphan RTK.","evidence":"Antisense/RNAi knockdown and overexpression in hippocampal neurons with morphometric and MAP1B/MAP2 protein analysis","pmids":["15654020"],"confidence":"Medium","gaps":["Ror1- vs Ror2-specific contributions not resolved","Upstream ligand not identified in this context","Downstream signaling mechanism not dissected"]},{"year":2012,"claim":"Identification of Wnt5a as a functional ligand and CK1ε as an intracellular partner of ROR1, together with demonstration that ROR1 sustains PI3K-AKT signaling through both kinase-dependent (c-Src) and kinase-independent (EGFR-ERBB3 scaffolding) mechanisms, established the dual signaling mode of ROR1 in cancer.","evidence":"Co-immunoprecipitation, siRNA knockdown, phosphoprotein analysis across lung adenocarcinoma cell lines and xenograft models","pmids":["22403610","22439932"],"confidence":"High","gaps":["Direct kinase activity of human ROR1 not yet formally tested","Relative contributions of kinase-dependent vs -independent arms to in vivo tumor growth not quantified"]},{"year":2013,"claim":"ROR1 was shown to promote EMT (upregulating vimentin/SNAIL, downregulating E-cadherin) and to cooperate with TCL1 to enhance AKT-driven leukemogenesis in vivo, broadening the receptor's role from a signaling scaffold to a driver of tumor cell plasticity and oncogene cooperation.","evidence":"Gain/loss-of-function in breast cancer cells with in vivo metastasis assay; ROR1×TCL1 double-transgenic mice with accelerated leukemia and elevated phospho-AKT","pmids":["23771907","24379361"],"confidence":"High","gaps":["EMT transcription factor directly downstream of ROR1 not identified","Whether TCL1-ROR1 interaction is direct or bridged not resolved"]},{"year":2014,"claim":"Biochemical demonstration that human ROR1 (and ROR2) kinase domains are catalytically deficient pseudokinases resolved a longstanding ambiguity and redirected mechanistic focus toward scaffolding and co-receptor functions.","evidence":"In vitro kinase assays with recombinant proteins and systematic mutagenesis of non-consensus residues","pmids":["25029443"],"confidence":"High","gaps":["Conditions under which ROR1 might exhibit residual or context-dependent kinase activity not exhaustively tested","How the pseudokinase domain contributes structurally to signaling complex assembly not determined"]},{"year":2016,"claim":"Domain dissection revealed that Wnt5a-induced ROR1/ROR2 heterooligomerization requires the Kringle domain while GEF recruitment requires the cysteine-rich or proline-rich intracellular domain, defining a modular architecture for noncanonical Wnt signal transduction; separately, ROR1 was shown to scaffold cavin-1/caveolin-1 in a kinase-independent manner to maintain caveolae and RTK-AKT signaling; a causative ROR1 mutation (p.R736T) was linked to human deafness through loss of plasma membrane localization and NF-κB signaling.","evidence":"Truncation/mutation panels with Co-IP and GTPase assays; electron microscopy of caveolae with kinase-dead mutants; whole-exome sequencing of deaf patients with Ror1 mutant mouse phenotyping","pmids":["26690702","26725982","27162350"],"confidence":"High","gaps":["Stoichiometry of ROR1/ROR2 oligomers unknown","How caveolae scaffolding and Wnt5a signaling are coordinated or segregated not addressed","Additional human ROR1 disease-causing alleles not reported"]},{"year":2017,"claim":"Residue-level mapping of the proline-rich domain identified Pro841 as the site for HS1 and ARHGEF1 recruitment (activating RhoA and migration) and revealed that ROR1 phosphorylates HER3-Tyr1307 to recruit the LLGL2-MAYA-NSUN6 complex, methylating MST1-Lys59 to inactivate Hippo signaling and drive bone metastasis — establishing two distinct downstream effector arms.","evidence":"Point mutants (P841A) with Co-IP and migration assays in CLL; phosphoproteomics, mutagenesis, complex reconstitution, and in vivo bone metastasis models","pmids":["28465529","28114269"],"confidence":"High","gaps":["How ROR1 phosphorylates HER3 given its pseudokinase status is mechanistically unresolved — may require co-receptor kinase activity","Whether MST1 methylation pathway operates in non-metastatic contexts unknown","Structural basis for Pro841-mediated HS1 binding not determined"]},{"year":2018,"claim":"Pro808 of the PRD was mapped as the DOCK2-binding site required for Rac1/2 activation and proliferation, while cortactin was identified as a parallel PRD-Pro841-dependent effector whose Y421 phosphorylation recruits ARHGEF1 for RhoA-driven migration, establishing bifurcating signaling branches from distinct PRD residues.","evidence":"P808A point mutant with DOCK2 silencing and Rac activation assays; cortactin phosphorylation and F-actin assays in CLL cells","pmids":["29678828","30568170"],"confidence":"High","gaps":["Whether Pro808 and Pro841 pathways are activated simultaneously or sequentially not resolved","Kinase responsible for cortactin Y421 phosphorylation downstream of ROR1 not identified"]},{"year":2019,"claim":"Extension of the cortactin-ARHGEF1-RhoA pathway to breast cancer metastasis in vivo, identification of CAVIN3 as an additional ROR1-scaffolded caveolae component, and demonstration that ROR1 signals through NF-κB to drive autocrine IL-6/STAT3 activation in CLL broadened the tissue scope and downstream signaling repertoire of ROR1.","evidence":"Xenograft metastasis models with cirmtuzumab; CAVIN3 domain mapping and EM; time-course signaling with NF-κB inhibitors and patient samples pre/post cirmtuzumab","pmids":["31667337","30894682","31409670"],"confidence":"High","gaps":["Whether NF-κB activation requires GEF-Rho axis or is a parallel branch not determined","CAVIN3 binding site on ROR1 relative to cavin-1/CAV1 sites not mapped at residue level"]},{"year":2020,"claim":"Wnt5a-ROR1-DOCK2 signaling was shown to activate ERK1/2 independently of BTK, providing a mechanistic rationale for ibrutinib resistance in CLL and positioning the ROR1 pathway as a parallel survival axis.","evidence":"ERK1/2 phosphorylation assays with ibrutinib co-treatment, DOCK2 siRNA, and ROR1 P808A/ΔPRD mutants","pmids":["33097837"],"confidence":"High","gaps":["Intermediate kinase(s) between DOCK2-Rac and ERK1/2 not identified","Clinical impact of dual BTK/ROR1 targeting not established mechanistically"]},{"year":2023,"claim":"IGFBP5 was identified as a second ROR1 ligand that promotes ROR1/HER2 heterodimer formation and CREB-mediated transcription in glioblastoma, while canonical Wnt/β-catenin signaling was shown to transcriptionally upregulate ROR1, creating a feedforward loop between canonical and noncanonical Wnt pathways.","evidence":"Co-IP and CRISPR-based functional studies with patient-derived xenografts for IGFBP5; ChIP-seq and PDX models for Wnt/β-catenin-ROR1 axis","pmids":["36949068","35131873"],"confidence":"High","gaps":["Whether IGFBP5 and Wnt5a compete for ROR1 binding or engage different domains not tested","IGFBP5-ROR1 binding site not structurally resolved","Relative contributions of IGFBP5 vs Wnt5a signaling in physiological contexts unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis for ROR1 pseudokinase-domain-mediated scaffolding, how ROR1 catalyzes HER3-Tyr1307 phosphorylation despite being catalytically deficient, whether the multiple ligands (Wnt5a, IGFBP5, resistin) activate distinct or overlapping downstream pathways, and the full physiological role of ROR1 outside oncology (e.g., in skeletal development and auditory innervation).","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length ROR1 structure available","Trans-phosphorylation mechanism for HER3 undefined","Developmental signaling partners remain uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,7,10,11,13,23]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,15,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,9,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,7,8,20,21]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,7,9,10,11,13,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[18,19,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,14,24]}],"complexes":["ROR1/ROR2 heterooligomer","ROR1/cavin-1/caveolin-1/CAVIN3 caveolae complex","ROR1/HER2 heterodimer"],"partners":["ROR2","DOCK2","ARHGEF1","CTTN","HCLS1","CAV1","CAVIN1","ERBB2"],"other_free_text":[]},"mechanistic_narrative":"ROR1 is a transmembrane pseudokinase receptor that transduces noncanonical Wnt signals to drive cell migration, survival, and proliferation across developmental and oncogenic contexts. Wnt5a binding induces ROR1 heterooligomerization with ROR2 via its extracellular Kringle domain, recruiting guanine nucleotide exchange factors (DOCK2 via Pro808, ARHGEF1 via Pro841 of the proline-rich domain) and adaptors (HS1, cortactin) to activate Rac1/2, RhoA, ERK1/2, NF-κB, and PI3K-AKT signaling cascades that promote EMT, invasion, and leukemic cell proliferation [PMID:26690702, PMID:29678828, PMID:30568170, PMID:23771907, PMID:33097837]. Independent of its catalytically inactive kinase domain, ROR1 scaffolds cavin-1/caveolin-1 and CAVIN3 to maintain caveolae integrity and sustain RTK-mediated AKT signaling, and can phosphorylate HER3-Tyr1307 to recruit the LLGL2-MAYA-NSUN6 complex that inactivates the Hippo kinase MST1, promoting bone metastasis [PMID:26725982, PMID:30894682, PMID:28114269]. Loss-of-function mutations in ROR1 cause autosomal recessive deafness through defective spiral ganglion neuron innervation of auditory hair cells [PMID:27162350]."},"prefetch_data":{"uniprot":{"accession":"Q01973","full_name":"Inactive tyrosine-protein kinase transmembrane receptor ROR1","aliases":["Neurotrophic tyrosine kinase, receptor-related 1"],"length_aa":937,"mass_kda":104.3,"function":"Has very low kinase activity in vitro and is unlikely to function as a tyrosine kinase in vivo (PubMed:25029443). Receptor for ligand WNT5A which activate downstream NFkB signaling pathway and may result in the inhibition of WNT3A-mediated signaling (PubMed:25029443, PubMed:27162350). In inner ear, crucial for spiral ganglion neurons to innervate auditory hair cells (PubMed:27162350). 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ErbB family members. Phospho-HER3 Tyr1307 then recruits the LLGL2-MAYA-NSUN6 RNA-protein complex to methylate Hippo/MST1 at Lys59, leading to MST1 inactivation and YAP target gene activation, promoting osteoclast differentiation and bone metastasis.\",\n      \"method\": \"In vitro kinase assay, Co-IP, mass spectrometry, mutagenesis, RNA-protein complex characterization, xenograft mouse model\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vitro phosphorylation, Co-IP, mutagenesis, and in vivo validation in single rigorous study\",\n      \"pmids\": [\"28114269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ROR1 interacts with casein kinase 1 epsilon (CK1ε) to activate PI3K-mediated AKT phosphorylation and CREB, enhancing tumor cell growth. Wnt5a, a ligand of ROR1, induces ROR1-dependent signaling to enhance cell growth.\",\n      \"method\": \"Co-immunoprecipitation, siRNA silencing, immunoblotting, xenograft mouse model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and functional knockdown with defined readout, single lab\",\n      \"pmids\": [\"22403610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ROR1 sustains a favorable balance between pro-survival PI3K-AKT and pro-apoptotic p38 signaling through kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation in lung adenocarcinoma.\",\n      \"method\": \"ROR1 knockdown, kinase-dead mutant transfection, immunoblotting, co-immunoprecipitation, cell viability assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — kinase-dead mutagenesis plus Co-IP distinguishing kinase-dependent and -independent functions, multiple orthogonal methods\",\n      \"pmids\": [\"22439932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wnt5a induces ROR1 to oligomerize with ROR2, forming ROR1/ROR2 heterooligomers that recruit guanine exchange factors (GEFs), activating Rac1 and RhoA to enhance CLL cell proliferation and chemotaxis. The extracellular Kringle domain is required for ROR1/ROR2 heterooligomerization, and the cysteine-rich domain or intracellular proline-rich domain is required for Wnt5a-induced GEF recruitment.\",\n      \"method\": \"Co-immunoprecipitation, siRNA silencing, domain deletion/mutagenesis, Rac1/RhoA activation assays, xenograft engraftment in immune-deficient and immune-competent transgenic mice\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, domain mapping mutagenesis, GTPase activation assays, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"26690702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ROR1 functions as a scaffold for cavin-1 and caveolin-1 (CAV1), two essential structural components of caveolae. This kinase-independent scaffold function facilitates cavin-1/CAV1 interactions at the plasma membrane, preventing lysosomal degradation of CAV1 and sustaining caveolae structures and pro-survival AKT signaling through multiple RTKs.\",\n      \"method\": \"Co-immunoprecipitation, electron microscopy, domain mutagenesis, lysosomal inhibitor assays, immunofluorescence, ROR1 knockdown with functional readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Co-IP, EM, mutagenesis, rescue experiments) in single rigorous study\",\n      \"pmids\": [\"26725982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ROR1 can complex with TCL1 in CLL cells (identified by immunoprecipitation and mass spectrometry). ROR1 × TCL1 double-transgenic mice developed leukemia at younger age with higher phospho-AKT than TCL1 alone; anti-ROR1 mAb induced ROR1 downmodulation and reduced phospho-AKT.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, transgenic mouse model, immunoblotting\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — IP-MS identification of TCL1 complex plus in vivo genetic model with functional readout\",\n      \"pmids\": [\"24379361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Wnt5a induces ROR1 to associate with hematopoietic-lineage-cell-specific protein 1 (HS1), causing HS1 tyrosine phosphorylation at Y421, recruitment of ARHGEF1, and activation of RhoA to enhance CLL cell migration. The proline-rich domain (PRD) of ROR1 is required for HS1 association, and the proline at position 841 (ROR1-P841) in a potential SH3-binding motif is specifically required for HS1/ARHGEF1 recruitment.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (P→A substitutions), RhoA activation assay, cell migration assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, systematic mutagenesis, and functional migration readout with multiple domain mutants\",\n      \"pmids\": [\"28465529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt5a induces ROR1 to complex with DOCK2, activating Rac1/2. The cytoplasmic proline-rich domain (PRD) of ROR1 is required for DOCK2 recruitment, and the proline at position 808 (ROR1-P808A) is specifically required; MEC1 cells expressing ROR1-P808A do not gain proliferative advantage and fail to activate Rac1/2 upon Wnt5a stimulation.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis (P→A substitutions), siRNA silencing of DOCK2, Rac1/2 activation assay, proliferation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic domain mutagenesis, Co-IP, GTPase activation assay, and functional proliferation readout\",\n      \"pmids\": [\"29678828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt5a causes ROR1 to bind cortactin, inducing cortactin tyrosine phosphorylation at Y421, recruitment of ARHGEF1, and RhoA activation to enhance CLL cell migration. The proline at position 841 of ROR1's PRD is required for cortactin and ARHGEF1 recruitment.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (P→A), RhoA activation assay, F-actin polymerization assay, cell migration assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, systematic mutagenesis, and functional cytoskeletal/migration readout\",\n      \"pmids\": [\"30568170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wnt5a induces ROR1 to recruit cortactin and ARHGEF1, activating RhoA and promoting breast cancer cell migration and metastasis in vivo. The proline at position 841 of ROR1 is required for cortactin recruitment; cirmtuzumab inhibits cortactin phosphorylation in vivo and impairs metastatic development.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, RhoA activation assay, xenograft mouse model with anti-ROR1 mAb treatment, in vivo cortactin phosphorylation analysis\",\n      \"journal\": \"NPJ breast cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — extends cortactin mechanism from CLL to breast cancer with in vivo validation\",\n      \"pmids\": [\"31667337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wnt5a induces ROR1-dependent activation of ERK1/2 via a ROR1/DOCK2-dependent pathway. The PRD of ROR1 and specifically P808 are required for this effect, which is independent of BTK and cannot be blocked by ibrutinib.\",\n      \"method\": \"siRNA silencing of DOCK2, ROR1 mutants (ΔPRD, P808A), ERK1/2 phosphorylation assay, ibrutinib treatment comparison\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic mutagenesis and pharmacological dissection with defined mechanistic readout\",\n      \"pmids\": [\"33097837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wnt5a/ROR1 signaling induces NF-κB activation within 30 minutes, which drives autocrine expression of IL-6, IL-8, CCL2, CCL3, CCL4, and CXCL1, which in turn induces STAT3 phosphorylation (pSTAT3) in CLL cells. Cirmtuzumab blocks Wnt5a-induced NF-κB activation and downstream STAT3 activation.\",\n      \"method\": \"Time-course signaling assays, anti-Wnt5a antibody/cirmtuzumab blocking, NF-κB inhibitor treatment, transcriptomic analysis of patient samples pre/post therapy\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic pathway dissection with pharmacological inhibitors, time-course experiments, and in vivo patient sample validation\",\n      \"pmids\": [\"31409670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ROR1 and ROR2 kinase domains are catalytically deficient (pseudokinases) in vitro, while the C. elegans homolog CAM-1 has an active tyrosine kinase domain, indicating evolutionary divergence. The membrane-bound extracellular domain alone of ROR1 or ROR2 is sufficient for suppression of canonical Wnt3a signaling.\",\n      \"method\": \"In vitro kinase activity assays, mutagenesis of consensus kinase residues, Wnt signaling reporter assays with extracellular domain constructs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic assay with mutagenesis demonstrating pseudokinase nature\",\n      \"pmids\": [\"25029443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ROR1 undergoes extensive N-linked glycosylation producing variants of ~100, 115, and 130 kDa. Glycosylation is required for cell surface localization of the 130 kDa variant and for ROR1-induced filopodia formation. ROR1 is also mono-ubiquitinated.\",\n      \"method\": \"Glycosylation inhibitors, N-glycosidase treatment, ubiquitination assay, immunohistochemistry, cell surface protein analysis\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods (enzyme treatment, inhibitors, ubiquitination assay) with functional consequence (filopodia formation), single lab\",\n      \"pmids\": [\"21481194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ROR1 is constitutively phosphorylated at both tyrosine and serine residues in CLL cells. The 130 kDa mature glycosylated isoform shows higher phosphorylation in progressive disease. Anti-ROR1 mAbs against CRD or KNG domains induce specific ROR1 dephosphorylation. A 64 kDa C-terminal ROR1 fragment is located in the nucleus.\",\n      \"method\": \"Western blot with anti-phospho-ROR1 antibody (TK domain), flow cytometry, mAb-induced dephosphorylation assay, subcellular fractionation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — phosphorylation characterization by specific antibody with functional (apoptosis) link; single lab\",\n      \"pmids\": [\"24205204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The disulfide bond pattern of the frizzled (FRZ) module of Ror1 was determined: 10 conserved cysteines are connected in a 1-5, 2-4, 3-8, 6-10, and 7-9 pattern. The FRZ domain forms a compact, stable folding unit with both alpha-helices and beta-strands.\",\n      \"method\": \"Recombinant protein expression in Pichia pastoris, proteolytic digestion, amino acid sequencing, circular dichroism, differential scanning calorimetry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical structural determination with multiple orthogonal methods\",\n      \"pmids\": [\"11279007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The 3D crystal structure of anti-ROR1 scFv R11 in complex with the kringle domain of ROR1 was determined by X-ray crystallography at 1.6-Å resolution, identifying a membrane-proximal epitope conserved between human and mouse ROR1.\",\n      \"method\": \"X-ray crystallography at 1.6-Å resolution\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional validation of epitope\",\n      \"pmids\": [\"29844189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ror1-deficient mice are severely deaf with malformed cochleae; axons of spiral ganglion neurons show fasciculation defects, type I neurons have impaired synapses with inner hair cells, and type II neurons display aberrant projections. A human ROR1 mutation (p.R736T) prevents the protein from reaching the plasma membrane and fails to activate NF-κB in the presence of WNT5A.\",\n      \"method\": \"Mouse knockout model, auditory functional testing (otoacoustic emissions, ABR), histological/anatomical analysis, exome sequencing, NF-κB reporter assay with mutant ROR1\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mouse KO with defined neuroanatomical phenotype plus human mutation functional validation\",\n      \"pmids\": [\"27162350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ror1-null mice display distinct skeletal and urogenital phenotypic defects and postnatal growth retardation, consistent with a role in skeletogenesis and development.\",\n      \"method\": \"Mouse knockout model, skeletal analysis\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined anatomical phenotypes but limited molecular mechanism elucidation\",\n      \"pmids\": [\"20593419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ror1 modulates neurite growth and branching in hippocampal neurons; Ror1 suppression causes shorter, less branched minor processes and longer but less branched axons, while overexpression leads to enhanced short, highly branched processes, accompanied by changes in MAP1B and MAP2.\",\n      \"method\": \"Antisense oligonucleotides, RNA interference, overexpression in hippocampal neurons, morphological analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss- and gain-of-function with defined morphological phenotype; single lab\",\n      \"pmids\": [\"15654020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mouse resistin interacts with specific extracellular domains of ROR1 and functions as an inhibitory ligand, inhibiting ROR1 phosphorylation, modulating ERK1/2 phosphorylation, and regulating SOCS3, GLUT4, and GLUT1 expression, thereby modulating glucose uptake and promoting adipogenesis in 3T3-L1 cells.\",\n      \"method\": \"Co-immunoprecipitation, ROR1 domain binding studies, phosphorylation assays, siRNA knockdown, glucose uptake assay, adipogenesis assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional downstream readouts; single lab, novel ligand claim\",\n      \"pmids\": [\"22074948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ROR1 functions as a scaffold for CAVIN3, with a binding site distinct from those for CAV1 and CAVIN1. ROR1-CAVIN3 interaction is required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis (but not caveolae formation itself), and is mechanistically linked to RTK-mediated pro-survival AKT signaling in early endosomes.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, subcellular fractionation, endocytosis assays, AKT phosphorylation readout\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — domain-level Co-IP mapping, functional endocytosis and signaling readouts; extends prior caveolae scaffold findings\",\n      \"pmids\": [\"30894682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"COBLL1 was identified as a novel interaction partner of ROR1 by co-immunoprecipitation in CLL cells.\",\n      \"method\": \"Co-immunoprecipitation\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP identification of binding partner without mechanistic follow-up for the interaction itself\",\n      \"pmids\": [\"29122990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGFBP5 is a ligand for ROR1; IGFBP5 binding to ROR1 facilitates ROR1/HER2 heterodimer formation, inducing CREB-mediated expression of ETV5 and FBXW9 to promote glioblastoma stem cell invasion and tumorigenesis.\",\n      \"method\": \"Co-IP, IGFBP5 knockdown/overexpression, in vitro invasion assay, patient-derived xenograft model, CRISPR/Cas9 gene editing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP identification of ROR1-IGFBP5 interaction, functional rescue experiments, and in vivo xenograft validation with multiple orthogonal methods\",\n      \"pmids\": [\"36949068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Canonical Wnt/β-catenin signaling transcriptionally upregulates ROR1 expression in prostate cancer, and increased ROR1 then enhances noncanonical responses to Wnt5a, revealing a priming mechanism linking canonical to noncanonical Wnt signaling.\",\n      \"method\": \"Transcriptomic analysis, IHC, patient-derived xenograft model, Wnt synthesis inhibitor treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic pathway link supported by in vivo PDX and clinical correlates; single lab\",\n      \"pmids\": [\"35131873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ROR1 induces expression of Aurora kinase B (AURKB) by activating E2F through c-Myc to enhance PDAC proliferation. ROR1 transcription is dependent on YAP/BRD4 binding at an enhancer region in pancreatic cancer.\",\n      \"method\": \"ROR1 depletion, gene expression analysis, epigenomic (ChIP) analysis of YAP/BRD4 enhancer binding, xenograft/recurrence models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epigenomic ChIP and functional knockdown with defined pathway placement; single lab\",\n      \"pmids\": [\"37096681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In TCF3-PBX1 acute lymphoblastic leukemia cells, Wnt5a-ROR1 signaling enhances proliferation via RhoA/Rac1 GTPase activation and STAT3 upregulation.\",\n      \"method\": \"siRNA knockdown, RhoA/Rac1 activation assay, STAT3 phosphorylation assay, high-throughput drug sensitivity testing\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ROR1 knockdown with defined GTPase/STAT3 pathway readout, single lab\",\n      \"pmids\": [\"30631148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In esophageal squamous cell carcinoma cells, Wnt5a promotes invasion via ROR1 and ROR2 receptors through DAAM1 activation and downstream RhoA signaling. ROR1 was found strongly associated with ROR2 by immunoprecipitation in these cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/shRNA knockdown, RhoA/DAAM1 activation assay, cell invasion assay, actin staining\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and functional assays; single lab, moderate mechanistic depth\",\n      \"pmids\": [\"31114334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ROR1 forms a positive feedback loop with STAT3 in chondrocytes: Wnt5a-induced ROR1 activates NF-κB and promotes STAT3 nuclear translocation, while STAT3 binds to the ROR1 promoter to upregulate ROR1 expression. ROR1 knockdown reduces NF-κB activation and alleviates cartilage degradation in vivo.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay, immunofluorescence of STAT3 nuclear translocation, ChIP (STAT3 binding to ROR1 promoter), surgical OA mouse model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay establish STAT3-ROR1 promoter feedback, supported by in vivo model\",\n      \"pmids\": [\"37343369\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ROR1 is a Wnt5a receptor and pseudokinase that signals through its cytoplasmic proline-rich domain (PRD) to recruit scaffold partners (HS1, cortactin, DOCK2, ARHGEF1, GEFs) and activate RhoA/Rac GTPases and downstream PI3K-AKT, NF-κB, STAT3, ERK, and Hippo-YAP pathways; it forms ROR1/ROR2 heterooligomers upon Wnt5a stimulation, functions kinase-independently as a caveolae scaffold (cavin-1/CAV1/CAVIN3), phosphorylates HER3 at Tyr1307 to drive a lncRNA-MST1 methylation cascade, is extensively N-glycosylated and monoubiquitinated (modifications that regulate its surface localization and signaling), and is essential for spiral ganglion neuron innervation of auditory hair cells during development.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"ROR1 interacts with casein kinase 1 epsilon (CK1ε) to activate PI3K-mediated AKT phosphorylation and CREB, and Wnt5a acts as a ligand for ROR1 to induce this ROR1-dependent signaling and enhance cancer cell growth.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, in vitro growth assays, xenograft mouse models\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — reciprocal Co-IP and functional KD, single lab\",\n      \"pmids\": [\"22403610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NKX2-1/TTF-1 transcriptionally induces ROR1 expression in lung adenocarcinoma; ROR1 sustains prosurvival PI3K-AKT over pro-apoptotic p38 signaling through both kinase-dependent c-Src activation and kinase-independent maintenance of the EGFR-ERBB3 association and ERBB3 phosphorylation.\",\n      \"method\": \"siRNA knockdown, phosphoprotein analysis, co-immunoprecipitation, lung cancer cell line functional assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (kinase-dependent and -independent mechanisms dissected), replicated across cell lines\",\n      \"pmids\": [\"22439932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ROR1 expression promotes epithelial-mesenchymal transition (EMT), enhancing vimentin and SNAIL-1/2 expression while reducing E-cadherin; silencing ROR1 attenuates in vitro migration/invasion and in vivo metastasis of breast cancer cells.\",\n      \"method\": \"siRNA/shRNA knockdown, overexpression in MCF-7 cells, Western blot for EMT markers, in vivo metastasis assay in immunodeficient mice, anti-ROR1 mAb treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with defined molecular markers, in vitro and in vivo validation\",\n      \"pmids\": [\"23771907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ROR1 complexes with TCL1 in CLL cells as revealed by immunoprecipitation and mass spectrometry; ROR1×TCL1 double-transgenic mice develop leukemia earlier than single-transgenic animals, with higher phospho-AKT levels, establishing ROR1 as an enhancer of TCL1-driven AKT signaling in leukemogenesis.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, transgenic mouse crosses, phospho-AKT analysis, adoptive transfer\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-confirmed complex, genetic epistasis in vivo, multiple readouts\",\n      \"pmids\": [\"24379361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human ROR1 and ROR2 kinase domains are catalytically deficient (pseudokinases), whereas the C. elegans ortholog CAM-1 has active tyrosine kinase activity; substitution of non-consensus residues from ROR1/ROR2 into active kinases reduces activity, and restoration of consensus residues in ROR does not rescue kinase function. Additionally, the extracellular domain alone of ROR1 is sufficient to suppress canonical Wnt3a signaling.\",\n      \"method\": \"In vitro kinase assay with recombinant proteins, mutagenesis, Wnt reporter assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assays with mutagenesis, clear demonstration of pseudokinase nature\",\n      \"pmids\": [\"25029443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The frizzled (FRZ) module of rat Ror1 contains 10 conserved cysteines forming disulfide bonds in a 1-5, 2-4, 3-8, 6-10, 7-9 pattern; the isolated domain forms a compact, stable folding unit with both alpha-helices and beta-strands.\",\n      \"method\": \"Recombinant protein expression in Pichia pastoris, proteolytic digestion, amino acid sequencing, circular dichroism, differential scanning calorimetry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical structural characterization with mutagenesis-equivalent disulfide mapping\",\n      \"pmids\": [\"11279007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ROR1 is extensively modified by N-linked glycosylation, producing isoforms of ~100, 115, and 130 kDa; glycosylation is required for cell-surface localization of the 130 kDa isoform and for ROR1-induced filopodia formation. ROR1 is also mono-ubiquitinated.\",\n      \"method\": \"Glycosylation inhibitors, N-glycosidase treatment, immunohistochemistry, cell surface protein analysis, ubiquitination assay\",\n      \"journal\": \"Acta physiologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and enzymatic perturbation of glycosylation with functional readout, single lab\",\n      \"pmids\": [\"21481194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Wnt5a induces ROR1 to oligomerize with ROR2 and recruit guanine nucleotide exchange factors (GEFs), activating Rac1 and RhoA in CLL cells; the extracellular Kringle domain of ROR1 is required for ROR1/ROR2 heterooligomerization, and the cysteine-rich domain or intracellular proline-rich domain is required for GEF recruitment.\",\n      \"method\": \"Co-immunoprecipitation, siRNA silencing of ROR1/ROR2, domain truncation/mutation analysis, GTPase activation assays, xenograft mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with multiple truncation mutants, reciprocal Co-IP, functional GTPase assays, in vivo validation\",\n      \"pmids\": [\"26690702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ROR1 functions as a scaffold protein for cavin-1 (CAVIN1) and caveolin-1 (CAV1), facilitating their interaction at the plasma membrane in a kinase-independent manner; this prevents lysosomal degradation of CAV1, maintains caveolae structure, and sustains prosurvival AKT signaling through multiple RTKs including EGFR, MET, and IGF-IR.\",\n      \"method\": \"Co-immunoprecipitation, electron microscopy (caveolae structure), ROR1 kinase-dead mutants, lysosome inhibitor assays, lung cancer cell lines\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — kinase-independent scaffold function established by kinase-dead mutants and structural (EM) analysis, multiple orthogonal methods\",\n      \"pmids\": [\"26725982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ROR1 phosphorylates HER3 at a previously unidentified site Tyr1307 following neuregulin stimulation, independently of other ErbB family members; phospho-HER3 Tyr1307 recruits the LLGL2-MAYA-NSUN6 RNA-protein complex to methylate Hippo/MST1 at Lys59, leading to MST1 inactivation and YAP target gene activation, promoting osteoclast differentiation and bone metastasis.\",\n      \"method\": \"Phosphoproteomic analysis, mutagenesis, co-immunoprecipitation, RNA-protein complex purification, methylation assays, in vivo bone metastasis models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — novel phosphorylation site identified by mass spectrometry, mechanistic chain validated by mutagenesis and complex reconstitution, in vivo validation\",\n      \"pmids\": [\"28114269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Wnt5a induces ROR1 to associate with HS1 (hematopoietic lineage cell-specific protein 1) via the ROR1 proline-rich domain (PRD); this complex recruits ARHGEF1 and activates RhoA, enhancing CLL cell migration. The proline at position 841 of the PRD is specifically required for HS1 and ARHGEF1 recruitment.\",\n      \"method\": \"Co-immunoprecipitation, domain truncation mutants, single amino-acid substitution mutants (P→A), GTPase activation assay, CLL cell migration assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — precise residue-level mapping with panel of point mutants, functional migration assay\",\n      \"pmids\": [\"28465529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt5a induces ROR1 to recruit DOCK2 via the PRD (specifically Pro808), activating Rac1/2 and enhancing CLL cell proliferation. The ROR1P808A mutant cannot recruit DOCK2 or activate Rac1/2, and cells expressing it lack the proliferative advantage conferred by wild-type ROR1.\",\n      \"method\": \"Co-immunoprecipitation, siRNA silencing of DOCK2, single amino-acid substitution mutants (P808A), Rac1/2 activation assay, cell proliferation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — precise residue mapping, DOCK2-specific rescue experiments, functional proliferation readout\",\n      \"pmids\": [\"29678828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt5a causes ROR1 to bind cortactin and induce tyrosine phosphorylation of cortactin at Y421, which recruits ARHGEF1 and activates RhoA to enhance CLL cell migration; the proline at position 841 of the ROR1 PRD is required for cortactin and ARHGEF1 recruitment.\",\n      \"method\": \"Co-immunoprecipitation, ROR1 PRD mutants (P→A), cortactin phosphorylation assay, F-actin polymerization assay, CLL migration assay\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — precise residue mapping matching HS1 recruitment site, independent confirmation of PRD-841 requirement\",\n      \"pmids\": [\"30568170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wnt5a-ROR1 signaling induces CLL cell NF-κB activation within 30 minutes, which in turn drives autocrine expression of IL-6 and other cytokines that subsequently induce STAT3 phosphorylation; cirmtuzumab blocks both NF-κB phosphorylation and STAT3 activation in patients treated with the antibody.\",\n      \"method\": \"Time-course signaling assays, NF-κB inhibitors, cytokine measurement, patient sample analysis before/after cirmtuzumab treatment\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic dissection with inhibitors and patient samples, single lab\",\n      \"pmids\": [\"31409670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wnt5a induces ROR1 to recruit cortactin in breast cancer cells via PRD-Pro841; this complex phosphorylates cortactin at Y421, recruits ARHGEF1, activates RhoA, and promotes breast cancer cell migration and metastasis in vivo; cirmtuzumab inhibits cortactin phosphorylation in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ROR1 point mutants, RhoA activation assay, in vivo xenograft metastasis model\",\n      \"journal\": \"NPJ breast cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — extends CLL finding to breast cancer with in vivo validation; consistent mechanism across two labs/papers\",\n      \"pmids\": [\"31667337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ROR1 functions as a scaffold for CAVIN3, binding at a site distinct from CAV1 and CAVIN1 binding sites; this interaction is required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis, which links to RTK-mediated prosurvival AKT signaling in early endosomes.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, electron microscopy, endocytosis assays, lung adenocarcinoma cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — extends caveolae scaffold finding; distinct binding sites for CAVIN3 vs CAV1/CAVIN1 mapped, functional endocytosis assay\",\n      \"pmids\": [\"30894682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wnt5a induces activation of ERK1/2 and enhances CLL cell proliferation via a ROR1/DOCK2-dependent pathway; this pathway is independent of BTK, as ibrutinib does not block Wnt5a-induced, ROR1-dependent ERK1/2 or DOCK2 phosphorylation. The ROR1P808A and ROR1ΔPRD mutants cannot support ERK1/2 activation.\",\n      \"method\": \"ERK1/2 phosphorylation assays, siRNA DOCK2 silencing, ibrutinib treatment, ROR1 point mutants, MEC1 transfection model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement via genetic constructs, pharmacological dissection, clear BTK-independence\",\n      \"pmids\": [\"33097837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mouse resistin interacts with specific extracellular domains of ROR1, inhibits ROR1 phosphorylation, modulates ERK1/2 phosphorylation, regulates SOCS3, GLUT4, and GLUT1 expression, and promotes adipogenesis while modulating glucose uptake in 3T3-L1 cells through ROR1.\",\n      \"method\": \"Co-immunoprecipitation/binding assays, phosphorylation analysis, gene expression analysis, glucose uptake assay, adipogenesis assay in 3T3-L1 cells\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, binding and downstream signaling measured but no structural or reconstitution-level validation\",\n      \"pmids\": [\"22074948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ror1 and Ror2 modulate neurite elongation and branching in hippocampal neurons; Ror depletion (antisense or RNAi) results in shorter, less-branched minor processes and longer but less-branched axons, while Ror overexpression promotes short, highly branched processes; these phenotypes are accompanied by changes in microtubule-associated proteins MAP1B and MAP2.\",\n      \"method\": \"Antisense oligonucleotides, RNAi knockdown, overexpression in neurons and non-neuronal cells, morphometric analysis, MAP1B/MAP2 protein analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss- and gain-of-function in neurons with molecular marker analysis, but mechanism not fully resolved\",\n      \"pmids\": [\"15654020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ror1-null mice display distinct skeletal and urogenital defects and postnatal growth retardation, demonstrating a non-redundant role for Ror1 in skeletal development and growth.\",\n      \"method\": \"Ror1 knockout mouse analysis, skeletal staining, anatomical phenotyping\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with defined skeletal/growth phenotype\",\n      \"pmids\": [\"20593419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ROR1 is essential for spiral ganglion neuron innervation of auditory hair cells and hearing; a missense mutation (p.R736T) prevents ROR1 from reaching the plasma membrane and abrogates WNT5A-induced NF-κB activation; Ror1 mutant mice are severely deaf with fasciculation defects in spiral ganglion axons and impaired Type I neuron synapses with inner hair cells.\",\n      \"method\": \"Whole-exome sequencing, cell localization assay, NF-κB reporter assay, Ror1 mutant mouse phenotyping, auditory testing (otoacoustic emissions, ABR), spiral ganglion histology\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human mutation linked to cellular mislocalization and loss of NF-κB signaling, validated in mouse model with detailed neuroanatomy\",\n      \"pmids\": [\"27162350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The 3D crystal structure of an ROR1-targeting scFv (R11) in complex with the kringle domain of ROR1 was determined at 1.6 Å resolution, precisely mapping a membrane-proximal epitope conserved between human and mouse ROR1.\",\n      \"method\": \"X-ray crystallography at 1.6 Å resolution\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure directly determining epitope-receptor interaction geometry\",\n      \"pmids\": [\"29844189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Twist transcription factor directly binds to and activates the ROR1 gene promoter, transcriptionally upregulating ROR1 expression; ROR1 silencing inhibits Twist-induced EMT, migration, invasion, and lung metastasis in basal-like breast cancer cells.\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), microarray transcriptomics, ROR1 siRNA knockdown, in vivo lung metastasis model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct transcriptional regulation demonstrated by ChIP and reporter assay, functional rescue experiment\",\n      \"pmids\": [\"29774072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGFBP5 is identified as a ligand for ROR1; IGFBP5 binding to ROR1 facilitates ROR1/HER2 heterodimer formation, leading to CREB-mediated expression of ETV5 and FBXW9, thereby promoting glioblastoma stem cell invasion and tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation, IGFBP5 knockdown/overexpression, patient-derived xenograft model, RNA sequencing, CRISPR/Cas9 gene editing, nanocapsule delivery in orthotopic mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — novel ligand identified by Co-IP, heterodimer formation shown, downstream pathway defined with rescue experiments, in vivo validation\",\n      \"pmids\": [\"36949068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In pancreatic cancer, ROR1 induces expression of Aurora kinase B (AURKB) by activating E2F through c-Myc to enhance proliferation; ROR1 expression is transcriptionally dependent on YAP/BRD4 binding at an enhancer region.\",\n      \"method\": \"ROR1 depletion (siRNA/shRNA), ChIP-seq/epigenomic analysis, c-Myc and E2F pathway analysis, YAP/BRD4 inhibition, in vivo tumor growth and metastasis models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epigenomic and transcriptional circuit dissected with ChIP-seq and functional assays, single lab\",\n      \"pmids\": [\"37096681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CXCL16 produced by mesenchymal stem cells upregulates Ror1 expression in gastric cancer cells through activation of the CXCR6-STAT3 pathway; Ror1 expression in tumor cells is required for MSC-promoted tumor formation in vivo.\",\n      \"method\": \"siRNA knockdown of CXCL16, recombinant CXCL16 treatment, STAT3 pathway analysis, co-injection xenograft model, anti-CXCL16 neutralizing antibody\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pathway placed (CXCL16→CXCR6→STAT3→ROR1), in vivo validation, single lab\",\n      \"pmids\": [\"32012403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ROR1 forms a positive feedback loop with STAT3 in osteoarthritis chondrocytes: Wnt5a-induced ROR1 activates NF-κB, and STAT3 binds the ROR1 promoter to upregulate ROR1 expression; ROR1 knockdown alleviates NF-κB activation and cartilage degradation in a surgical OA mouse model.\",\n      \"method\": \"Luciferase assay, immunofluorescence, Western blot, STAT3 ChIP on ROR1 promoter, DMM surgical OA mouse model, histological staining\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP confirms STAT3 binding to ROR1 promoter, in vivo OA model, single lab\",\n      \"pmids\": [\"37343369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Canonical Wnt/β-catenin signaling transcriptionally upregulates ROR1 expression in prostate cancer, and increased ROR1 enhances noncanonical responses to Wnt5a; APC genomic loss (but not epigenetic downregulation) is the key upstream driver of this pathway.\",\n      \"method\": \"Gene expression analysis, Wnt/β-catenin reporter assays, patient sample IHC, patient-derived xenograft treatment with Wnt synthesis inhibitor\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic link between canonical and noncanonical Wnt through ROR1, validated in PDX model\",\n      \"pmids\": [\"35131873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In esophageal squamous cell carcinoma, Wnt5a activates ROR1 (in complex with ROR2) to signal through DAAM1 and activate RhoA (but not Rac1/2), promoting actin filament reassembly and cell invasion; DAAM1 is positioned downstream of ROR1/ROR2 and upstream of RhoA in this pathway.\",\n      \"method\": \"Co-immunoprecipitation, DAAM1/ROR2 shRNA, Rho activation assay, immunofluorescence (phalloidin), cell invasion assay, DAAM1 rescue with wild-type overexpression\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pathway ordering established by shRNA and rescue, single lab\",\n      \"pmids\": [\"31114334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"COBLL1 is identified as a novel interaction partner of ROR1 in CLL cells; high COBLL1 expression correlates with impaired motility and enhanced BCR signaling (increased PLCγ2 and SYK phosphorylation after IgM stimulation).\",\n      \"method\": \"Co-immunoprecipitation/interaction studies, CLL patient sample analysis, chemotaxis assays, BCR signaling phosphorylation assays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP for interaction, functional correlation but no mechanistic dissection of ROR1-COBLL1 complex function\",\n      \"pmids\": [\"29122990\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ROR1 is a transmembrane pseudokinase (catalytically deficient in humans) that acts as a receptor for Wnt5a and IGFBP5, forming functional heterooligomers with ROR2 and heterodimers with HER2/HER3; upon ligand binding it recruits GEFs (DOCK2, ARHGEF1) and adaptor proteins (HS1, cortactin, COBLL1) through its intracellular proline-rich domain (notably Pro808 for DOCK2 and Pro841 for HS1/cortactin), activating Rac1/2, RhoA, ERK1/2, PI3K-AKT, NF-κB, and STAT3 signaling to drive cancer cell migration, EMT, and survival; in parallel, ROR1 functions as a kinase-independent scaffold for cavin-1/caveolin-1 and CAVIN3 to maintain caveolae integrity and RTK-mediated AKT signaling, and can phosphorylate HER3-Tyr1307 to recruit the LLGL2-MAYA-NSUN6 complex that methylates MST1-Lys59 and inactivates the Hippo pathway, promoting bone metastasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ROR1 is a type I transmembrane receptor tyrosine kinase-related protein that functions primarily as a Wnt5a-activated pseudokinase and signaling scaffold, coordinating noncanonical Wnt signaling through Rho-family GTPases and multiple pro-survival pathways. Upon Wnt5a stimulation, ROR1 oligomerizes with ROR2 via its extracellular Kringle domain and recruits guanine exchange factors (ARHGEF1, DOCK2) and actin-regulatory adaptors (HS1, cortactin) through specific proline residues (P808, P841) in its cytoplasmic proline-rich domain, activating Rac1/2 and RhoA to drive cell migration, proliferation, and downstream NF-κB, STAT3, and ERK signaling [PMID:26690702, PMID:28465529, PMID:29678828, PMID:30568170, PMID:31409670, PMID:33097837, PMID:31409670]. Independently of its catalytically deficient kinase domain, ROR1 scaffolds caveolae components (cavin-1, CAV1, CAVIN3), sustaining caveolae-dependent endocytosis and AKT signaling, and maintains EGFR–ERBB3 complexes to support PI3K activation; ROR1 can also phosphorylate HER3 at Tyr1307 to inactivate the Hippo kinase MST1 via an RNA-methyltransferase cascade, promoting YAP target gene expression [PMID:26725982, PMID:30894682, PMID:22439932, PMID:28114269, PMID:25029443]. Loss-of-function mutations in ROR1 cause deafness with cochlear malformation and spiral ganglion neuron innervation defects in mice, and a human ROR1 missense variant (p.R736T) fails to reach the plasma membrane and to activate NF-κB, establishing ROR1 as a deafness gene [PMID:27162350].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Determining the disulfide-bond architecture of the ROR1 frizzled domain established its structural basis as a compact, independently folded Wnt-binding module, addressing whether the extracellular CRD/FRZ region adopted a stable fold.\",\n      \"evidence\": \"Recombinant expression in Pichia pastoris with proteolytic mapping, amino acid sequencing, and biophysical characterization\",\n      \"pmids\": [\"11279007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand-bound structure was obtained\", \"No full-length ectodomain structure determined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that ROR1 modulates neurite growth and branching in hippocampal neurons established an early developmental signaling role, answering whether ROR1 had functional consequences in the nervous system.\",\n      \"evidence\": \"Antisense/RNAi loss-of-function and overexpression in cultured hippocampal neurons with morphometric analysis\",\n      \"pmids\": [\"15654020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream ligand not identified\", \"Downstream signaling pathway not delineated\", \"Single lab without independent replication\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Ror1-null mice revealed skeletal, urogenital, and growth defects, demonstrating that ROR1 has essential non-redundant roles in mammalian development beyond the nervous system.\",\n      \"evidence\": \"Mouse knockout model with skeletal and anatomical phenotyping\",\n      \"pmids\": [\"20593419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathways mediating skeletal phenotype not dissected\", \"Relationship to Wnt5a signaling in these tissues not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that ROR1 is extensively N-glycosylated and mono-ubiquitinated, and that glycosylation is required for surface localization and filopodia formation, revealed post-translational regulation of ROR1 trafficking and function.\",\n      \"evidence\": \"Glycosylation inhibitors, N-glycosidase treatment, ubiquitination assay, and cell surface protein analysis\",\n      \"pmids\": [\"21481194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific glycosylation sites not mapped\", \"Functional role of mono-ubiquitination not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of CK1ε as a ROR1 interactor linking Wnt5a stimulation to PI3K-AKT-CREB activation, and the parallel finding that ROR1 sustains EGFR-ERBB3 complexes and c-Src activation with both kinase-dependent and -independent modes, established ROR1 as a multifunctional signaling hub in cancer.\",\n      \"evidence\": \"Co-IP, siRNA, kinase-dead mutagenesis, and immunoblotting in CLL and lung adenocarcinoma cells\",\n      \"pmids\": [\"22403610\", \"22439932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase substrates of ROR1 not identified at this point\", \"Structural basis for kinase-dead-dependent scaffold function unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"In vitro kinase assays proved that mammalian ROR1 (and ROR2) kinase domains are catalytically deficient, resolving the long-standing question of whether ROR1 is a true kinase or a pseudokinase and redirecting the field toward scaffold functions.\",\n      \"evidence\": \"Purified kinase domain activity assay with consensus-site mutagenesis and Wnt reporter assays showing extracellular domain sufficiency for Wnt3a suppression\",\n      \"pmids\": [\"25029443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not exclude context-dependent kinase reactivation in vivo\", \"Contradicted by later report of HER3 phosphorylation activity\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"IP-MS identification of TCL1 as a ROR1 complex partner, coupled with accelerated leukemia in ROR1×TCL1 double-transgenic mice, demonstrated that ROR1 enhances AKT-dependent oncogenic signaling in a cooperative in vivo model.\",\n      \"evidence\": \"IP-mass spectrometry, transgenic mouse model, anti-ROR1 mAb treatment\",\n      \"pmids\": [\"24379361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"Whether TCL1 association is Wnt5a-dependent not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Three key advances consolidated ROR1's mechanism: (1) Wnt5a-induced ROR1/ROR2 heterooligomerization via the Kringle domain recruits GEFs to activate Rac1/RhoA; (2) ROR1 scaffolds cavin-1/CAV1 to maintain caveolae and AKT signaling kinase-independently; (3) Ror1-knockout mice are deaf with cochlear innervation defects, and a human ROR1 mutation (p.R736T) prevents surface expression.\",\n      \"evidence\": \"Reciprocal Co-IP with domain deletion mutagenesis and GTPase assays; electron microscopy of caveolae; mouse KO auditory phenotyping; human exome sequencing with functional rescue\",\n      \"pmids\": [\"26690702\", \"26725982\", \"27162350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ROR1/ROR2 oligomerization not resolved at atomic level\", \"How caveolae scaffold function relates to Wnt5a-GEF signaling not integrated\", \"Additional human deafness families not yet reported\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping of the PRD-dependent recruitment of HS1 (via P841) and ARHGEF1 for RhoA-driven CLL migration, and the separate finding that ROR1 phosphorylates HER3-Y1307 to inactivate MST1/Hippo via an lncRNA-methyltransferase cascade, revealed two distinct signaling arms — one scaffold-dependent, one kinase-dependent.\",\n      \"evidence\": \"Systematic P→A mutagenesis with Co-IP and migration assays; in vitro kinase assay with mass spectrometry, RNA-protein complex characterization, and xenograft bone metastasis model\",\n      \"pmids\": [\"28465529\", \"28114269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase activity toward HER3 is difficult to reconcile with pseudokinase data; no independent replication of ROR1 kinase activity\", \"HS1 phosphorylation kinase not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of DOCK2 as a PRD-dependent (P808) ROR1 partner activating Rac1/2 for CLL proliferation, and cortactin as a P841-dependent partner activating RhoA via ARHGEF1, delineated two discrete proline-docking sites on ROR1 that bifurcate Rac versus RhoA signaling.\",\n      \"evidence\": \"Systematic mutagenesis of individual prolines, Co-IP, GTPase activation assays, and proliferation/migration readouts\",\n      \"pmids\": [\"29678828\", \"30568170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DOCK2 and cortactin bind simultaneously or compete not tested\", \"Crystal structure of PRD-adaptor complexes not available\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Multiple studies consolidated the downstream signaling network: ROR1/DOCK2 activates ERK independently of BTK; Wnt5a/ROR1 triggers rapid NF-κB activation driving autocrine cytokine–STAT3 signaling; ROR1 scaffolds CAVIN3 for caveolae-dependent endocytosis and endosomal AKT signaling; and cortactin/ARHGEF1/RhoA signaling extends to breast cancer metastasis in vivo.\",\n      \"evidence\": \"Mutagenesis with pharmacological dissection (ibrutinib resistance), time-course NF-κB/cytokine measurements with cirmtuzumab blocking, domain-mapped CAVIN3 Co-IP with endocytosis assays, xenograft metastasis models\",\n      \"pmids\": [\"33097837\", \"31409670\", \"30894682\", \"31667337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of caveolae-endosomal pathway with GEF-GTPase pathway is unclear\", \"Whether NF-κB activation requires GTPase intermediates not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of IGFBP5 as a new ROR1 ligand promoting ROR1/HER2 heterodimerization and CREB-dependent transcription in glioblastoma, plus discovery of a STAT3-ROR1 positive transcriptional feedback loop in chondrocytes, expanded ROR1's ligand repertoire and revealed context-dependent signaling outputs beyond Wnt5a.\",\n      \"evidence\": \"Co-IP, CRISPR editing, PDX models for IGFBP5; ChIP of STAT3 on ROR1 promoter, OA mouse model for feedback loop\",\n      \"pmids\": [\"36949068\", \"37343369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IGFBP5 binding site on ROR1 ectodomain not mapped\", \"Whether IGFBP5 and Wnt5a compete or cooperate unknown\", \"STAT3-ROR1 feedback not validated outside chondrocytes\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of full-length ROR1/ROR2 heterooligomerization and Wnt5a engagement; reconciliation of pseudokinase status with reported HER3 phosphorylation activity; the interrelationship between caveolae scaffold, GEF-GTPase, and Hippo signaling arms; and how developmental roles (cochlear innervation, skeletogenesis) mechanistically connect to the Wnt5a-GTPase cascade.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length ROR1 structure available\", \"Kinase vs pseudokinase discrepancy unresolved\", \"Developmental signaling intermediates largely unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 21, 6, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7, 10, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 13, 17, 21]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3, 6, 7, 8, 10, 11, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 18, 19]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [17, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 25, 23]}\n    ],\n    \"complexes\": [\n      \"ROR1/ROR2 heterooligomer\",\n      \"ROR1/cavin-1/CAV1/CAVIN3 caveolae complex\",\n      \"ROR1/HER2 heterodimer\"\n    ],\n    \"partners\": [\n      \"ROR2\",\n      \"DOCK2\",\n      \"ARHGEF1\",\n      \"HCLS1\",\n      \"CTTN\",\n      \"CAV1\",\n      \"CAVIN1\",\n      \"CAVIN3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ROR1 is a transmembrane pseudokinase receptor that transduces noncanonical Wnt signals to drive cell migration, survival, and proliferation across developmental and oncogenic contexts. Wnt5a binding induces ROR1 heterooligomerization with ROR2 via its extracellular Kringle domain, recruiting guanine nucleotide exchange factors (DOCK2 via Pro808, ARHGEF1 via Pro841 of the proline-rich domain) and adaptors (HS1, cortactin) to activate Rac1/2, RhoA, ERK1/2, NF-κB, and PI3K-AKT signaling cascades that promote EMT, invasion, and leukemic cell proliferation [PMID:26690702, PMID:29678828, PMID:30568170, PMID:23771907, PMID:33097837]. Independent of its catalytically inactive kinase domain, ROR1 scaffolds cavin-1/caveolin-1 and CAVIN3 to maintain caveolae integrity and sustain RTK-mediated AKT signaling, and can phosphorylate HER3-Tyr1307 to recruit the LLGL2-MAYA-NSUN6 complex that inactivates the Hippo kinase MST1, promoting bone metastasis [PMID:26725982, PMID:30894682, PMID:28114269]. Loss-of-function mutations in ROR1 cause autosomal recessive deafness through defective spiral ganglion neuron innervation of auditory hair cells [PMID:27162350].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Structural characterization of the ROR1 frizzled domain established it as an autonomously folded Wnt-binding module with a defined disulfide bonding pattern, providing the first biochemical foundation for understanding how ROR1 engages extracellular ligands.\",\n      \"evidence\": \"Recombinant expression, disulfide mapping, circular dichroism, and differential scanning calorimetry of the rat Ror1 FRZ domain\",\n      \"pmids\": [\"11279007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand-bound structure determined\", \"Binding affinity for Wnt ligands not measured\", \"Contribution of other extracellular domains (Ig, Kringle) to ligand recognition not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that Ror1 (with Ror2) modulates neurite morphology and microtubule-associated protein expression in hippocampal neurons established a developmental neuronal function beyond the receptor's initial cloning as an orphan RTK.\",\n      \"evidence\": \"Antisense/RNAi knockdown and overexpression in hippocampal neurons with morphometric and MAP1B/MAP2 protein analysis\",\n      \"pmids\": [\"15654020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ror1- vs Ror2-specific contributions not resolved\", \"Upstream ligand not identified in this context\", \"Downstream signaling mechanism not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of Wnt5a as a functional ligand and CK1ε as an intracellular partner of ROR1, together with demonstration that ROR1 sustains PI3K-AKT signaling through both kinase-dependent (c-Src) and kinase-independent (EGFR-ERBB3 scaffolding) mechanisms, established the dual signaling mode of ROR1 in cancer.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, phosphoprotein analysis across lung adenocarcinoma cell lines and xenograft models\",\n      \"pmids\": [\"22403610\", \"22439932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase activity of human ROR1 not yet formally tested\", \"Relative contributions of kinase-dependent vs -independent arms to in vivo tumor growth not quantified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"ROR1 was shown to promote EMT (upregulating vimentin/SNAIL, downregulating E-cadherin) and to cooperate with TCL1 to enhance AKT-driven leukemogenesis in vivo, broadening the receptor's role from a signaling scaffold to a driver of tumor cell plasticity and oncogene cooperation.\",\n      \"evidence\": \"Gain/loss-of-function in breast cancer cells with in vivo metastasis assay; ROR1×TCL1 double-transgenic mice with accelerated leukemia and elevated phospho-AKT\",\n      \"pmids\": [\"23771907\", \"24379361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EMT transcription factor directly downstream of ROR1 not identified\", \"Whether TCL1-ROR1 interaction is direct or bridged not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Biochemical demonstration that human ROR1 (and ROR2) kinase domains are catalytically deficient pseudokinases resolved a longstanding ambiguity and redirected mechanistic focus toward scaffolding and co-receptor functions.\",\n      \"evidence\": \"In vitro kinase assays with recombinant proteins and systematic mutagenesis of non-consensus residues\",\n      \"pmids\": [\"25029443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conditions under which ROR1 might exhibit residual or context-dependent kinase activity not exhaustively tested\", \"How the pseudokinase domain contributes structurally to signaling complex assembly not determined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Domain dissection revealed that Wnt5a-induced ROR1/ROR2 heterooligomerization requires the Kringle domain while GEF recruitment requires the cysteine-rich or proline-rich intracellular domain, defining a modular architecture for noncanonical Wnt signal transduction; separately, ROR1 was shown to scaffold cavin-1/caveolin-1 in a kinase-independent manner to maintain caveolae and RTK-AKT signaling; a causative ROR1 mutation (p.R736T) was linked to human deafness through loss of plasma membrane localization and NF-κB signaling.\",\n      \"evidence\": \"Truncation/mutation panels with Co-IP and GTPase assays; electron microscopy of caveolae with kinase-dead mutants; whole-exome sequencing of deaf patients with Ror1 mutant mouse phenotyping\",\n      \"pmids\": [\"26690702\", \"26725982\", \"27162350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of ROR1/ROR2 oligomers unknown\", \"How caveolae scaffolding and Wnt5a signaling are coordinated or segregated not addressed\", \"Additional human ROR1 disease-causing alleles not reported\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Residue-level mapping of the proline-rich domain identified Pro841 as the site for HS1 and ARHGEF1 recruitment (activating RhoA and migration) and revealed that ROR1 phosphorylates HER3-Tyr1307 to recruit the LLGL2-MAYA-NSUN6 complex, methylating MST1-Lys59 to inactivate Hippo signaling and drive bone metastasis — establishing two distinct downstream effector arms.\",\n      \"evidence\": \"Point mutants (P841A) with Co-IP and migration assays in CLL; phosphoproteomics, mutagenesis, complex reconstitution, and in vivo bone metastasis models\",\n      \"pmids\": [\"28465529\", \"28114269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ROR1 phosphorylates HER3 given its pseudokinase status is mechanistically unresolved — may require co-receptor kinase activity\", \"Whether MST1 methylation pathway operates in non-metastatic contexts unknown\", \"Structural basis for Pro841-mediated HS1 binding not determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Pro808 of the PRD was mapped as the DOCK2-binding site required for Rac1/2 activation and proliferation, while cortactin was identified as a parallel PRD-Pro841-dependent effector whose Y421 phosphorylation recruits ARHGEF1 for RhoA-driven migration, establishing bifurcating signaling branches from distinct PRD residues.\",\n      \"evidence\": \"P808A point mutant with DOCK2 silencing and Rac activation assays; cortactin phosphorylation and F-actin assays in CLL cells\",\n      \"pmids\": [\"29678828\", \"30568170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Pro808 and Pro841 pathways are activated simultaneously or sequentially not resolved\", \"Kinase responsible for cortactin Y421 phosphorylation downstream of ROR1 not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extension of the cortactin-ARHGEF1-RhoA pathway to breast cancer metastasis in vivo, identification of CAVIN3 as an additional ROR1-scaffolded caveolae component, and demonstration that ROR1 signals through NF-κB to drive autocrine IL-6/STAT3 activation in CLL broadened the tissue scope and downstream signaling repertoire of ROR1.\",\n      \"evidence\": \"Xenograft metastasis models with cirmtuzumab; CAVIN3 domain mapping and EM; time-course signaling with NF-κB inhibitors and patient samples pre/post cirmtuzumab\",\n      \"pmids\": [\"31667337\", \"30894682\", \"31409670\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NF-κB activation requires GEF-Rho axis or is a parallel branch not determined\", \"CAVIN3 binding site on ROR1 relative to cavin-1/CAV1 sites not mapped at residue level\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Wnt5a-ROR1-DOCK2 signaling was shown to activate ERK1/2 independently of BTK, providing a mechanistic rationale for ibrutinib resistance in CLL and positioning the ROR1 pathway as a parallel survival axis.\",\n      \"evidence\": \"ERK1/2 phosphorylation assays with ibrutinib co-treatment, DOCK2 siRNA, and ROR1 P808A/ΔPRD mutants\",\n      \"pmids\": [\"33097837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intermediate kinase(s) between DOCK2-Rac and ERK1/2 not identified\", \"Clinical impact of dual BTK/ROR1 targeting not established mechanistically\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"IGFBP5 was identified as a second ROR1 ligand that promotes ROR1/HER2 heterodimer formation and CREB-mediated transcription in glioblastoma, while canonical Wnt/β-catenin signaling was shown to transcriptionally upregulate ROR1, creating a feedforward loop between canonical and noncanonical Wnt pathways.\",\n      \"evidence\": \"Co-IP and CRISPR-based functional studies with patient-derived xenografts for IGFBP5; ChIP-seq and PDX models for Wnt/β-catenin-ROR1 axis\",\n      \"pmids\": [\"36949068\", \"35131873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IGFBP5 and Wnt5a compete for ROR1 binding or engage different domains not tested\", \"IGFBP5-ROR1 binding site not structurally resolved\", \"Relative contributions of IGFBP5 vs Wnt5a signaling in physiological contexts unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for ROR1 pseudokinase-domain-mediated scaffolding, how ROR1 catalyzes HER3-Tyr1307 phosphorylation despite being catalytically deficient, whether the multiple ligands (Wnt5a, IGFBP5, resistin) activate distinct or overlapping downstream pathways, and the full physiological role of ROR1 outside oncology (e.g., in skeletal development and auditory innervation).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length ROR1 structure available\", \"Trans-phosphorylation mechanism for HER3 undefined\", \"Developmental signaling partners remain uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 7, 10, 11, 13, 23]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 15, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 9, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 7, 8, 20, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 7, 9, 10, 11, 13, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [18, 19, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 14, 24]}\n    ],\n    \"complexes\": [\n      \"ROR1/ROR2 heterooligomer\",\n      \"ROR1/cavin-1/caveolin-1/CAVIN3 caveolae complex\",\n      \"ROR1/HER2 heterodimer\"\n    ],\n    \"partners\": [\n      \"ROR2\",\n      \"DOCK2\",\n      \"ARHGEF1\",\n      \"CTTN\",\n      \"HCLS1\",\n      \"CAV1\",\n      \"CAVIN1\",\n      \"ERBB2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}