{"gene":"ROR1","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2012,"finding":"ROR1 interacts with casein kinase 1ε (CK1ε) to activate PI3K-mediated AKT phosphorylation and CREB, promoting breast cancer cell growth; Wnt5a-induced ROR1 signaling enhances this effect.","method":"Co-immunoprecipitation, siRNA silencing, in vitro/in vivo growth assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional KD assay in single lab, two orthogonal methods","pmids":["22403610"],"is_preprint":false},{"year":2016,"finding":"Wnt5a induces ROR1 to oligomerize with ROR2 and recruit guanine nucleotide exchange factors (GEFs), activating Rac1 and RhoA to enhance CLL cell chemotaxis and proliferation; 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.","method":"Co-immunoprecipitation, siRNA silencing, ectopic expression of truncated/domain-deleted ROR1 constructs, Rac1/RhoA activation assays, in vivo engraftment","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (domain-deletion, Co-IP, GTPase assays, in vivo), rigorous domain mapping in single lab","pmids":["26690702"],"is_preprint":false},{"year":2017,"finding":"ROR1 phosphorylates HER3 at Tyr1307 following neuregulin stimulation, independently of other 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 breast cancer bone metastasis.","method":"Biochemical phosphorylation assays, site-directed mutagenesis, mass spectrometry, Co-IP, in vivo bone metastasis models","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — identification of novel phosphorylation site by mutagenesis + MS, reconstituted signaling cascade, in vivo validation, multiple orthogonal methods","pmids":["28114269"],"is_preprint":false},{"year":2011,"finding":"ROR1 is a pseudokinase devoid of intrinsic catalytic activity; in cancer cell lines with Met oncogene amplification, Met transphosphorylates ROR1; ROR1 suppression impairs proliferation in vitro and tumorigenesis in vivo in Met-amplified cells.","method":"Biochemical kinase assays, RNAi, Met inhibitor treatment, in vivo tumorigenesis assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay directly demonstrating lack of catalytic activity plus trans-phosphorylation by Met, multiple cell-line models, in vivo confirmation","pmids":["21487037"],"is_preprint":false},{"year":2013,"finding":"ROR1 can complex with TCL1 in CLL cells (identified by immunoprecipitation and mass spectrometry); ROR1×TCL1 double-transgenic mice develop leukemia earlier with higher phospho-AKT, increased proliferation, and reduced apoptosis compared to TCL1 alone, demonstrating that ROR1 cooperates with TCL1 to enhance AKT signaling and leukemogenesis.","method":"Immunoprecipitation and mass spectrometry, transgenic mouse model, phospho-AKT measurement, adoptive transfer","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP/MS identification of complex plus in vivo genetic epistasis in transgenic model, replicated in adoptive transfer","pmids":["24379361"],"is_preprint":false},{"year":2018,"finding":"Wnt5a induces ROR1 to complex with DOCK2 via the cytoplasmic proline-rich domain (PRD) of ROR1, activating Rac1/2; single amino acid substitution ROR1-P808A abolishes DOCK2 recruitment and Rac1/2 activation and abrogates the Wnt5a-driven growth advantage.","method":"Co-immunoprecipitation, truncation/point-mutagenesis of ROR1, siRNA silencing of DOCK2, Rac1/2 activation assays, cell proliferation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise point-mutagenesis mapping binding site, multiple orthogonal assays (Co-IP, GTPase, growth), in single rigorous study","pmids":["29678828"],"is_preprint":false},{"year":2020,"finding":"Wnt5a induces ERK1/2 phosphorylation and CLL cell proliferation via a ROR1/DOCK2-dependent mechanism; ROR1 PRD (specifically P808) is required for Wnt5a-induced ERK1/2 and DOCK2 phosphorylation; ibrutinib cannot inhibit this Wnt5a-induced, ROR1-dependent ERK1/2 activation.","method":"siRNA silencing, ROR1 mutant (ROR1ΔPRD, ROR1P808A) transfection, ERK1/2 phosphorylation assays, pharmacological inhibition","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-deletion and point-mutant approaches plus pharmacological controls, multiple orthogonal methods in single lab","pmids":["33097837"],"is_preprint":false},{"year":2016,"finding":"ROR1 functions as a scaffold protein for cavin-1 and caveolin-1 (CAV1) at the plasma membrane, independently of its kinase activity; this scaffold function prevents lysosomal degradation of CAV1, maintains caveolae structures, and sustains pro-survival AKT signaling from multiple RTKs (EGFR, MET, IGF-IR), contributing to EGFR-TKI resistance.","method":"Co-immunoprecipitation, ROR1 kinase-dead mutant analysis, immunofluorescence/electron microscopy of caveolae, AKT signaling assays, siRNA knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, kinase-dead mutant, structural imaging of caveolae, functional signaling assays), mechanistically rigorous","pmids":["26725982"],"is_preprint":false},{"year":2019,"finding":"ROR1 possesses an additional scaffold function: it binds CAVIN3 at a site distinct from sites for CAV1 and CAVIN1, which is required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis; this ROR1-CAVIN3 interaction links caveolae trafficking to RTK-mediated pro-survival AKT signaling in early endosomes in lung adenocarcinoma cells.","method":"Co-immunoprecipitation, domain-binding mapping, subcellular fractionation, functional endocytosis assay, AKT signaling assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — binding site distinct from CAV1/CAVIN1 shown by domain mapping, functional endocytosis and signaling assays, single lab with multiple orthogonal methods","pmids":["30894682"],"is_preprint":false},{"year":2011,"finding":"ROR1 undergoes N-linked glycosylation (producing ~100, 115, and 130 kDa variants) and mono-ubiquitination; glycosylation is required for cell surface localization of the mature 130-kDa isoform and for Ror1-induced filopodia formation; inhibition of glycosylation prevents cell surface trafficking.","method":"N-glycosidase treatment, glycosylation inhibitors, ubiquitination assay, immunocytochemistry, flow cytometry of surface proteins","journal":"Acta physiologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical removal of glycosylation plus functional localization assay, single lab with multiple orthogonal methods","pmids":["21481194"],"is_preprint":false},{"year":2012,"finding":"In t(1;19) ALL, ROR1 and pre-B cell receptor (pre-BCR) define distinct but counterbalancing downstream signaling pathways that both converge on AKT phosphorylation; inhibition of pre-BCR signaling by dasatinib upregulates ROR1, partially restoring AKT phosphorylation, while silencing ROR1 accentuates dasatinib-induced killing.","method":"Genetic epistasis (siRNA silencing), dasatinib treatment, AKT phosphorylation assays, cell viability assays","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus pharmacological pathway analysis, single lab","pmids":["23153538"],"is_preprint":false},{"year":2013,"finding":"ROR1 expression is associated with EMT in breast cancer; silencing ROR1 reduces vimentin, SNAIL-1/2, ZEB1 and increases E-cadherin, CK-19, and ZO-1 expression, impairing migration/invasion in vitro and metastasis in vivo; ectopic ROR1 in MCF-7 cells reduces E-cadherin and increases SNAIL-1/2 and vimentin.","method":"siRNA knockdown, ectopic overexpression, EMT marker immunoblot, migration/invasion assays, in vivo metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function approaches with molecular readouts of EMT markers plus in vivo metastasis, single lab","pmids":["23771907"],"is_preprint":false},{"year":2011,"finding":"Nuclear-localized ROR1 activation promotes actin stress fiber formation and increased cellular migration; activated nuclear ROR1 upregulates cytoskeleton-related genes including radixin (RDX), ezrin (EZR), SOS2, and caldesmon 1 (CALD1).","method":"Inducible nuclear-homing FKBP-ROR1 fusion system with synthetic dimerizer AP20187, gene expression microarray, functional migration assays","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — engineered inducible system plus functional and transcriptomic readouts, single lab","pmids":["22199287"],"is_preprint":false},{"year":2019,"finding":"ROR1 is a client protein of HSP90α (but not HSP90β or GRP94); HSP90 inhibition (geldanamycin and derivatives) destabilizes and degrades ROR1 via the ubiquitin/proteasome pathway; the kinase domain of ROR1 (but not its kinase activity or N-glycosylation) is required for HSP90-dependent stabilization. A specific binding motif (ELHHPNIV) on ROR1 mediates HSP90 association.","method":"Co-immunoprecipitation, pharmacological HSP90 inhibition, proteasome inhibitor rescue, domain/motif analysis, cell proliferation assays","journal":"Cancer science / Pharmacological research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identification of specific HSP90 paralog, binding motif mapping, ubiquitin-proteasome mechanism confirmed by rescue, replicated across two independent studies (PMID 33370472 and 31726100)","pmids":["33370472","31726100"],"is_preprint":false},{"year":2017,"finding":"ROR1 expression in satellite cells (SCs) after muscle injury is induced by TNF-α and IL-1β via NF-κB activation; SC-specific depletion of Ror1 decreases the number of Pax7-positive SCs after injury, demonstrating that Ror1 is required for satellite cell proliferation during skeletal muscle regeneration.","method":"In vivo muscle injury model, neutralizing antibodies against TNF-α/IL-1β, conditional SC-specific Ror1 knockout, flow cytometry, C2C12 cell NF-κB reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic depletion with cellular phenotype, NF-κB pathway epistasis, multiple orthogonal methods in single study","pmids":["28790171"],"is_preprint":false},{"year":2019,"finding":"In esophageal squamous cell carcinoma, Wnt5a promotes cell invasion via ROR1 and ROR2 receptors through DAAM1 activation and downstream RhoA (but not Rac1/Rac2) signaling; ROR1 strongly associates with ROR2; DAAM1 and PI3Kα/Akt are parallel downstream pathways of ROR1/ROR2 in Wnt5a-induced migration.","method":"Anti-ROR1 mAb, ROR2 shRNA, RhoA/DAAM1 activity assays, immunoprecipitation, fluorescent phalloidin staining, invasion assays","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus RhoA/DAAM1 activity assays and rescue with wild-type DAAM1, single lab","pmids":["31114334"],"is_preprint":false},{"year":2023,"finding":"IGFBP5 is identified as a ligand for ROR1; IGFBP5 binding facilitates ROR1/HER2 heterodimer formation, inducing CREB-mediated expression of ETV5 and FBXW9, thereby promoting glioblastoma stem cell invasion and tumorigenesis.","method":"Co-immunoprecipitation (IGFBP5-ROR1 binding), siRNA knockdown and ectopic overexpression of IGFBP5, patient-derived xenograft model, CRISPR/Cas9 gene editing, RNA sequencing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand-receptor binding demonstrated by Co-IP, signaling cascade validated by multiple orthogonal methods including CRISPR KO and in vivo PDX models","pmids":["36949068"],"is_preprint":false},{"year":2023,"finding":"ROR1 transcriptional expression in pancreatic cancer is dependent on YAP/BRD4 binding at an enhancer region; ROR1 promotes PDAC proliferation by activating E2F through c-Myc to induce Aurora kinase B (AURKB) expression; ROR1-high cells serve as tumor-initiating cells.","method":"ChIP/epigenomic analysis, ROR1 depletion, gene expression analysis, functional tumor recurrence/metastasis assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenomic ChIP plus mechanistic signaling delineation, single lab with multiple methods","pmids":["37096681"],"is_preprint":false},{"year":2022,"finding":"In metastatic castration-resistant prostate cancer, canonical Wnt/β-catenin signaling transcriptionally upregulates ROR1, which then enhances non-canonical responses to Wnt5a; APC genomic loss (but not epigenetic downregulation) is strongly associated with Wnt/β-catenin pathway activation and downstream ROR1 upregulation.","method":"IHC correlation, patient-derived xenograft treatment with Wnt synthesis inhibitor, transcriptomic analysis of clinical samples","journal":"Cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — transcriptomic plus IHC with limited direct mechanistic validation of the ROR1 upregulation mechanism specifically","pmids":["35131873"],"is_preprint":false},{"year":2020,"finding":"MSC-derived CXCL16 upregulates ROR1 expression in MKN45 gastric cancer cells via CXCR6/STAT3 activation; ROR1 induction downstream of STAT3 promotes gastric cancer cell proliferation and migration in vitro and tumor formation in vivo.","method":"siRNA knockdown of CXCL16 in MSC, recombinant CXCL16 treatment, STAT3 reporter/signaling assay, in vivo co-injection xenograft with CXCL16 neutralizing antibody","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway epistasis (STAT3-ROR1 axis) with in vitro and in vivo validation, single lab with multiple methods","pmids":["32012403"],"is_preprint":false},{"year":2023,"finding":"ROR1 activates a positive feedback loop with STAT3 in osteoarthritis chondrocytes: Wnt5a-induced ROR1 promotes STAT3 nuclear translocation, and STAT3 in turn binds the ROR1 promoter to upregulate ROR1 expression; this ROR1/STAT3 loop activates NF-κB signaling, causing catabolic imbalance and cartilage degeneration.","method":"siRNA knockdown, STAT3 luciferase reporter assay, ChIP of STAT3 at ROR1 promoter, immunofluorescence, in vivo DMM surgical OA model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating STAT3 binding to ROR1 promoter plus functional in vivo KD, single lab","pmids":["37343369"],"is_preprint":false},{"year":2022,"finding":"Notch and hypoxia signaling pathways transcriptionally activate Ror1 in glioblastoma stem-like cells (GSCs); NICD and HIF-1α bind upstream regions of the Ror1 gene more efficiently under spheroid conditions; upregulated Ror1 then promotes Wnt5a-driven spheroid formation (stem cell-like properties) in GSCs.","method":"Notch/hypoxia pathway inhibition, NICD forced expression, ChIP of NICD/HIF-1α at Ror1 promoter, spheroid formation assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating transcription factor binding at Ror1 locus plus functional sphere assay, single lab","pmids":["36314076"],"is_preprint":false},{"year":2021,"finding":"ROR1 physically interacts with HSP90α (identified by Co-IP); a specific binding motif on ROR1 (ELHHPNIV) is necessary for HSP90-facilitated stabilization; HSP90 inhibition leads to ROR1 degradation via ubiquitin/proteasome pathway, attenuating ROR1-dependent pro-survival signaling in CLL.","method":"Mass spectrometry-based screen for ROR1 partners, Co-IP validation, binding motif mapping, ubiquitin-proteasome pathway assay","journal":"Pharmacological research","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS identification of interaction, Co-IP validation, motif mapping, proteasome rescue assay — replicated across two independent labs (also PMID 33370472)","pmids":["31726100"],"is_preprint":false},{"year":2019,"finding":"In TCF3-PBX1 BCP-ALL, Wnt5a-ROR1 signaling activates RhoA/Rac1 GTPases and upregulates STAT3, enhancing cell proliferation; Wnt16b also activates this RhoA/Rac1 cascade but Wnt16 does not interact with ROR1 in TCF3-PBX1 cells.","method":"RhoA/Rac1 activation assays, Co-IP (Wnt16/ROR1 interaction tested), siRNA knockdown of ROR1, STAT3 measurement, high-throughput drug sensitivity","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GTPase assays plus Co-IP for ligand specificity, single lab","pmids":["30631148"],"is_preprint":false},{"year":2017,"finding":"Targeting ROR1 in mantle cell lymphoma downregulates NF-κB p65; NF-κB pathway activation can antagonize ROR1-mediated apoptotic responses, identifying NF-κB as a resistance mechanism to ROR1 targeting.","method":"ROR1 silencing, NF-κB pathway analysis, high-throughput drug sensitivity testing, synergy analysis","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ROR1 KD with downstream NF-κB readout plus pharmacological epistasis, single lab","pmids":["29296874"],"is_preprint":false},{"year":2021,"finding":"ROR1 expression in Alzheimer's disease cell models is reduced by Aβ1-42 treatment; overexpressed ROR1 preserves the actin network, abrogates cytoskeletal protein degradation, and promotes neuritogenesis even in the presence of Aβ1-42; miR-146a and miR-34a repress ROR1 and are themselves regulated by lncRNA NEAT1.","method":"ROR1 overexpression in Aβ1-42 cell model, actin cytoskeleton imaging, RNA immunoprecipitation (NEAT1-miRNA interaction), miRNA overexpression","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression with functional readout but single lab, single method per finding, limited mechanistic depth","pmids":["34584188"],"is_preprint":false}],"current_model":"ROR1 is a transmembrane receptor tyrosine kinase (classified as a pseudokinase lacking intrinsic catalytic activity) that acts as a Wnt5a (and IGFBP5) receptor, signaling through Wnt5a-induced hetero-oligomerization with ROR2, recruitment of GEFs (DOCK2) via its cytoplasmic proline-rich domain, and activation of Rac1/RhoA and ERK1/2 to promote cancer cell proliferation and migration; it also phosphorylates HER3 at Tyr1307 (a kinase-independent-of-ErbB mechanism) to engage the MAYA/NSUN6-MST1/YAP axis for bone metastasis, and functions as a scaffold for cavin-1, CAV1, and CAVIN3 to maintain caveolae integrity and sustain multi-RTK pro-survival AKT signaling; its stability is maintained by HSP90α and its surface expression requires N-linked glycosylation, while it can complex with TCL1 to amplify AKT-driven leukemogenesis."},"narrative":{"mechanistic_narrative":"ROR1 is a cell-surface receptor tyrosine kinase-like molecule that drives proliferation, migration, and pro-survival signaling in cancer and tissue regeneration, primarily as a non-canonical Wnt5a receptor [PMID:26690702, PMID:29678828]. Although it adopts a kinase fold, ROR1 is a pseudokinase devoid of intrinsic catalytic activity and is instead transphosphorylated by partner kinases such as Met in oncogene-amplified cells [PMID:21487037]. Upon Wnt5a stimulation, ROR1 hetero-oligomerizes with ROR2 through its extracellular Kringle domain and recruits guanine nucleotide exchange factors via its cytoplasmic proline-rich domain (PRD), with the single residue P808 being essential for DOCK2 binding and the downstream activation of Rac1/RhoA GTPases and ERK1/2 that promote chemotaxis and proliferation [PMID:26690702, PMID:29678828, PMID:33097837]. ROR1 converges on AKT survival signaling through multiple routes: it complexes with casein kinase 1ε to activate PI3K-AKT-CREB [PMID:22403610], cooperates with TCL1 to accelerate leukemogenesis [PMID:24379361], and acts as a kinase-independent scaffold that stabilizes caveolin-1 and CAVIN proteins to maintain caveolae and sustain pro-survival AKT output from EGFR, MET, and IGF-IR [PMID:26725982, PMID:30894682]. ROR1 can also directly phosphorylate HER3 at Tyr1307 to engage the LLGL2-MAYA-NSUN6/MST1-YAP axis driving breast cancer bone metastasis [PMID:28114269], and it promotes epithelial-mesenchymal transition through regulation of SNAIL, vimentin, and E-cadherin [PMID:23771907]. ROR1 itself is regulated at multiple levels: N-linked glycosylation is required for cell-surface trafficking of the mature receptor [PMID:21481194], HSP90α binds a specific ELHHPNIV motif to protect ROR1 from ubiquitin-proteasome degradation [PMID:33370472, PMID:31726100], and its transcription is induced by Wnt/β-catenin, STAT3, Notch/HIF-1α, and inflammatory NF-κB inputs across diverse tissues [PMID:28790171, PMID:37096681, PMID:37343369, PMID:36314076]. Beyond cancer, ROR1 is required for satellite cell proliferation during skeletal muscle regeneration downstream of TNF-α/IL-1β-NF-κB signaling [PMID:28790171].","teleology":[{"year":2011,"claim":"Established that ROR1 is catalytically inactive, reframing it from an autonomous kinase to a pseudokinase dependent on partner kinases for phosphorylation events.","evidence":"In vitro kinase assays and Met-inhibitor/RNAi experiments in Met-amplified cancer cell lines with in vivo tumorigenesis","pmids":["21487037"],"confidence":"High","gaps":["Whether transphosphorylation by Met is required in non-Met-amplified contexts","Functional consequence of the phosphorylated state on downstream signaling not defined"]},{"year":2011,"claim":"Showed that ROR1 surface display depends on post-translational maturation, linking glycosylation to its functional localization and cytoskeletal effects.","evidence":"N-glycosidase treatment, glycosylation inhibitors, ubiquitination assays, and surface flow cytometry","pmids":["21481194"],"confidence":"Medium","gaps":["Glycosylation sites not mapped","Functional role of mono-ubiquitination unresolved"]},{"year":2012,"claim":"Connected ROR1 to PI3K-AKT survival signaling by identifying CK1ε as a partner amplifying Wnt5a-driven growth, providing an early mechanistic link to a major oncogenic pathway.","evidence":"Reciprocal Co-IP, siRNA silencing, and in vitro/in vivo breast cancer growth assays","pmids":["22403610"],"confidence":"Medium","gaps":["Direct CK1ε-ROR1 phosphorylation relationship not established","Mechanism connecting CK1ε to PI3K activation undefined"]},{"year":2013,"claim":"Demonstrated genetically that ROR1 cooperates with TCL1 to enhance AKT signaling and accelerate leukemia, moving beyond correlation to in vivo epistasis.","evidence":"Co-IP/MS identification of the ROR1-TCL1 complex and ROR1×TCL1 double-transgenic mice with adoptive transfer","pmids":["24379361"],"confidence":"High","gaps":["Direct biochemical mechanism by which TCL1 binding enhances AKT phosphorylation unclear","Whether the interaction is direct or bridged not resolved"]},{"year":2016,"claim":"Defined the core non-canonical Wnt5a signaling architecture by mapping the domains required for ROR1/ROR2 hetero-oligomerization and GEF-driven Rac1/RhoA activation.","evidence":"Domain-deletion/truncation constructs, Co-IP, GTPase activation assays, and in vivo engraftment in CLL","pmids":["26690702"],"confidence":"High","gaps":["Identity of the GEFs not specified at this stage","Stoichiometry of the ROR1/ROR2 oligomer unknown"]},{"year":2016,"claim":"Revealed a kinase-independent scaffolding role for ROR1 in stabilizing caveolin-1 and maintaining caveolae, broadening its function beyond Wnt signaling to multi-RTK survival.","evidence":"Co-IP, kinase-dead mutants, EM/IF of caveolae, and AKT signaling assays in lung cancer with EGFR-TKI resistance readouts","pmids":["26725982"],"confidence":"High","gaps":["How the same molecule partitions between Wnt-signaling and scaffolding pools is unknown","Structural basis of cavin-1/CAV1 binding not defined"]},{"year":2017,"claim":"Showed that despite being a pseudokinase, ROR1 can phosphorylate HER3 at Tyr1307 to drive a methylation-dependent YAP axis for bone metastasis, defining a distinct ErbB-independent effector mechanism.","evidence":"Phosphorylation assays, site-directed mutagenesis, MS, Co-IP, and in vivo bone metastasis models","pmids":["28114269"],"confidence":"High","gaps":["Reconciliation with the catalytically-dead designation requires definition of how transphosphorylation enables this activity","Generality of the MAYA/NSUN6 axis across tumor types untested"]},{"year":2017,"claim":"Extended ROR1 function to physiological tissue regeneration, showing it is an NF-κB-induced effector required for satellite cell proliferation after muscle injury.","evidence":"Conditional SC-specific Ror1 knockout, cytokine-neutralizing antibodies, and NF-κB reporter assays in vivo","pmids":["28790171"],"confidence":"High","gaps":["Downstream signaling driving satellite cell proliferation not mapped","Ligand context in regenerating muscle not identified"]},{"year":2018,"claim":"Pinpointed DOCK2 as the proline-rich-domain effector GEF and identified P808 as the single critical residue, providing precise molecular resolution to the Wnt5a-Rac axis.","evidence":"Point-mutagenesis (P808A), Co-IP, DOCK2 siRNA, Rac1/2 activation, and growth assays in CLL","pmids":["29678828"],"confidence":"High","gaps":["Whether other GEFs use the same PRD site untested","How Wnt5a triggers PRD availability for DOCK2 unclear"]},{"year":2019,"claim":"Established HSP90α as a specific chaperone protecting ROR1 from proteasomal degradation, defining a druggable dependency for ROR1 stability.","evidence":"Co-IP/MS, paralog-specific analysis, ELHHPNIV motif mapping, and proteasome-rescue assays across two independent studies","pmids":["33370472","31726100"],"confidence":"High","gaps":["Co-chaperones in the ROR1-HSP90 complex not identified","E3 ligase mediating ROR1 ubiquitination unknown"]},{"year":2019,"claim":"Added a second scaffolding function in which ROR1 binds CAVIN3 at a distinct site to control caveolae endocytosis and endosomal AKT signaling.","evidence":"Co-IP, domain-binding mapping, subcellular fractionation, and endocytosis/AKT assays in lung adenocarcinoma","pmids":["30894682"],"confidence":"High","gaps":["Coordination between the CAV1, CAVIN1 and CAVIN3 binding events not resolved","Whether these scaffolding roles operate in the same cells as Wnt signaling unclear"]},{"year":2020,"claim":"Extended the DOCK2/P808 mechanism to ERK1/2 activation and showed it bypasses ibrutinib, explaining a route to therapy resistance.","evidence":"ROR1ΔPRD and P808A mutants, ERK1/2 phosphorylation assays, and pharmacological inhibition in CLL","pmids":["33097837"],"confidence":"High","gaps":["Direct kinase linking DOCK2/Rac to ERK not defined","Clinical relevance of ibrutinib bypass not validated"]},{"year":2019,"claim":"Demonstrated tissue- and ligand-specific wiring of the Wnt5a-ROR1 GTPase output, with RhoA/DAAM1 dominating in esophageal cancer and Wnt16 ligand specificity in ALL.","evidence":"RhoA/DAAM1 activity assays, Co-IP ligand-specificity tests, and invasion assays in ESCC and TCF3-PBX1 ALL","pmids":["31114334","30631148"],"confidence":"Medium","gaps":["Determinants selecting RhoA versus Rac branches not defined","Reconciliation with the canonical DOCK2/Rac model incomplete"]},{"year":2023,"claim":"Identified IGFBP5 as a second ROR1 ligand that drives ROR1/HER2 heterodimerization and CREB-mediated transcription, expanding ROR1's ligand repertoire beyond Wnt5a.","evidence":"Co-IP binding, IGFBP5 knockdown/overexpression, CRISPR editing, RNA-seq, and PDX models in glioblastoma","pmids":["36949068"],"confidence":"High","gaps":["Structural basis of IGFBP5-ROR1 binding undefined","Whether IGFBP5 and Wnt5a compete or cooperate untested"]},{"year":2023,"claim":"Placed ROR1 within transcriptional feed-forward circuits, showing YAP/BRD4-driven ROR1 expression sustains tumor-initiating cell programs through c-Myc/E2F/AURKB.","evidence":"ChIP/epigenomic analysis, ROR1 depletion, and tumor recurrence/metastasis assays in PDAC","pmids":["37096681"],"confidence":"Medium","gaps":["Whether ROR1 signaling reciprocally reinforces YAP not established","Direct versus indirect c-Myc induction unresolved"]},{"year":null,"claim":"How a catalytically-dead pseudokinase reconciles its documented transphosphorylation of HER3 and HER2 partners with its scaffolding and Wnt5a-GEF functions in a single structural and regulatory framework remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of liganded ROR1 signaling complexes","Mechanism partitioning ROR1 among Wnt-signaling, scaffolding, and transcriptionally-driven pools unknown","In vivo requirement of distinct functions in normal versus malignant tissue not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,5,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[1,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,4,11,17]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13,22]}],"complexes":["caveolae"],"partners":["ROR2","DOCK2","CAV1","CAVIN1","CAVIN3","TCL1","HSP90AA1","CSNK1E"],"other_free_text":[]}},"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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Lymphoma (MCL) Cells.","date":"2022","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/36297673","citation_count":16,"is_preprint":false},{"pmid":"37343369","id":"PMC_37343369","title":"ROR1/STAT3 positive feedback loop facilitates cartilage degeneration in Osteoarthritis through activation of NF-κB signaling pathway.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37343369","citation_count":16,"is_preprint":false},{"pmid":"30801848","id":"PMC_30801848","title":"Genetic interactions between Ror2 and Wnt9a, Ror1 and Wnt9a and Ror2 and Ror1: Phenotypic analysis of the limb skeleton and palate in compound mutants.","date":"2019","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/30801848","citation_count":16,"is_preprint":false},{"pmid":"33370472","id":"PMC_33370472","title":"Inhibition of heat shock protein 90 destabilizes receptor tyrosine kinase ROR1 in lung adenocarcinoma.","date":"2021","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/33370472","citation_count":15,"is_preprint":false},{"pmid":"34599596","id":"PMC_34599596","title":"SETD8 induces stemness and epithelial-mesenchymal transition of pancreatic cancer cells by regulating ROR1 expression.","date":"2021","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/34599596","citation_count":15,"is_preprint":false},{"pmid":"37400436","id":"PMC_37400436","title":"ROR1-STAT3 signaling contributes to ovarian cancer intra-tumor heterogeneity.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37400436","citation_count":14,"is_preprint":false},{"pmid":"15702250","id":"PMC_15702250","title":"Identification and characterization of rat Ror1 and Ror2 genes in silico.","date":"2005","source":"International journal of molecular 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Wnt5a-induced ROR1 signaling enhances this effect.\",\n      \"method\": \"Co-immunoprecipitation, siRNA silencing, in vitro/in vivo growth assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional KD assay in single lab, two orthogonal methods\",\n      \"pmids\": [\"22403610\"],\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 to enhance CLL cell chemotaxis and proliferation; 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, ectopic expression of truncated/domain-deleted ROR1 constructs, Rac1/RhoA activation assays, in vivo engraftment\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (domain-deletion, Co-IP, GTPase assays, in vivo), rigorous domain mapping in single lab\",\n      \"pmids\": [\"26690702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ROR1 phosphorylates HER3 at Tyr1307 following neuregulin stimulation, independently of other 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 breast cancer bone metastasis.\",\n      \"method\": \"Biochemical phosphorylation assays, site-directed mutagenesis, mass spectrometry, Co-IP, in vivo bone metastasis models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — identification of novel phosphorylation site by mutagenesis + MS, reconstituted signaling cascade, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"28114269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ROR1 is a pseudokinase devoid of intrinsic catalytic activity; in cancer cell lines with Met oncogene amplification, Met transphosphorylates ROR1; ROR1 suppression impairs proliferation in vitro and tumorigenesis in vivo in Met-amplified cells.\",\n      \"method\": \"Biochemical kinase assays, RNAi, Met inhibitor treatment, in vivo tumorigenesis assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay directly demonstrating lack of catalytic activity plus trans-phosphorylation by Met, multiple cell-line models, in vivo confirmation\",\n      \"pmids\": [\"21487037\"],\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 develop leukemia earlier with higher phospho-AKT, increased proliferation, and reduced apoptosis compared to TCL1 alone, demonstrating that ROR1 cooperates with TCL1 to enhance AKT signaling and leukemogenesis.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry, transgenic mouse model, phospho-AKT measurement, adoptive transfer\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP/MS identification of complex plus in vivo genetic epistasis in transgenic model, replicated in adoptive transfer\",\n      \"pmids\": [\"24379361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Wnt5a induces ROR1 to complex with DOCK2 via the cytoplasmic proline-rich domain (PRD) of ROR1, activating Rac1/2; single amino acid substitution ROR1-P808A abolishes DOCK2 recruitment and Rac1/2 activation and abrogates the Wnt5a-driven growth advantage.\",\n      \"method\": \"Co-immunoprecipitation, truncation/point-mutagenesis of ROR1, siRNA silencing of DOCK2, Rac1/2 activation assays, cell proliferation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise point-mutagenesis mapping binding site, multiple orthogonal assays (Co-IP, GTPase, growth), in single rigorous study\",\n      \"pmids\": [\"29678828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wnt5a induces ERK1/2 phosphorylation and CLL cell proliferation via a ROR1/DOCK2-dependent mechanism; ROR1 PRD (specifically P808) is required for Wnt5a-induced ERK1/2 and DOCK2 phosphorylation; ibrutinib cannot inhibit this Wnt5a-induced, ROR1-dependent ERK1/2 activation.\",\n      \"method\": \"siRNA silencing, ROR1 mutant (ROR1ΔPRD, ROR1P808A) transfection, ERK1/2 phosphorylation assays, pharmacological inhibition\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion and point-mutant approaches plus pharmacological controls, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"33097837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ROR1 functions as a scaffold protein for cavin-1 and caveolin-1 (CAV1) at the plasma membrane, independently of its kinase activity; this scaffold function prevents lysosomal degradation of CAV1, maintains caveolae structures, and sustains pro-survival AKT signaling from multiple RTKs (EGFR, MET, IGF-IR), contributing to EGFR-TKI resistance.\",\n      \"method\": \"Co-immunoprecipitation, ROR1 kinase-dead mutant analysis, immunofluorescence/electron microscopy of caveolae, AKT signaling assays, siRNA knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, kinase-dead mutant, structural imaging of caveolae, functional signaling assays), mechanistically rigorous\",\n      \"pmids\": [\"26725982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ROR1 possesses an additional scaffold function: it binds CAVIN3 at a site distinct from sites for CAV1 and CAVIN1, which is required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis; this ROR1-CAVIN3 interaction links caveolae trafficking to RTK-mediated pro-survival AKT signaling in early endosomes in lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, domain-binding mapping, subcellular fractionation, functional endocytosis assay, AKT signaling assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding site distinct from CAV1/CAVIN1 shown by domain mapping, functional endocytosis and signaling assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30894682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ROR1 undergoes N-linked glycosylation (producing ~100, 115, and 130 kDa variants) and mono-ubiquitination; glycosylation is required for cell surface localization of the mature 130-kDa isoform and for Ror1-induced filopodia formation; inhibition of glycosylation prevents cell surface trafficking.\",\n      \"method\": \"N-glycosidase treatment, glycosylation inhibitors, ubiquitination assay, immunocytochemistry, flow cytometry of surface proteins\",\n      \"journal\": \"Acta physiologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical removal of glycosylation plus functional localization assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21481194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In t(1;19) ALL, ROR1 and pre-B cell receptor (pre-BCR) define distinct but counterbalancing downstream signaling pathways that both converge on AKT phosphorylation; inhibition of pre-BCR signaling by dasatinib upregulates ROR1, partially restoring AKT phosphorylation, while silencing ROR1 accentuates dasatinib-induced killing.\",\n      \"method\": \"Genetic epistasis (siRNA silencing), dasatinib treatment, AKT phosphorylation assays, cell viability assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus pharmacological pathway analysis, single lab\",\n      \"pmids\": [\"23153538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ROR1 expression is associated with EMT in breast cancer; silencing ROR1 reduces vimentin, SNAIL-1/2, ZEB1 and increases E-cadherin, CK-19, and ZO-1 expression, impairing migration/invasion in vitro and metastasis in vivo; ectopic ROR1 in MCF-7 cells reduces E-cadherin and increases SNAIL-1/2 and vimentin.\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, EMT marker immunoblot, migration/invasion assays, in vivo metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function approaches with molecular readouts of EMT markers plus in vivo metastasis, single lab\",\n      \"pmids\": [\"23771907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nuclear-localized ROR1 activation promotes actin stress fiber formation and increased cellular migration; activated nuclear ROR1 upregulates cytoskeleton-related genes including radixin (RDX), ezrin (EZR), SOS2, and caldesmon 1 (CALD1).\",\n      \"method\": \"Inducible nuclear-homing FKBP-ROR1 fusion system with synthetic dimerizer AP20187, gene expression microarray, functional migration assays\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered inducible system plus functional and transcriptomic readouts, single lab\",\n      \"pmids\": [\"22199287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ROR1 is a client protein of HSP90α (but not HSP90β or GRP94); HSP90 inhibition (geldanamycin and derivatives) destabilizes and degrades ROR1 via the ubiquitin/proteasome pathway; the kinase domain of ROR1 (but not its kinase activity or N-glycosylation) is required for HSP90-dependent stabilization. A specific binding motif (ELHHPNIV) on ROR1 mediates HSP90 association.\",\n      \"method\": \"Co-immunoprecipitation, pharmacological HSP90 inhibition, proteasome inhibitor rescue, domain/motif analysis, cell proliferation assays\",\n      \"journal\": \"Cancer science / Pharmacological research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identification of specific HSP90 paralog, binding motif mapping, ubiquitin-proteasome mechanism confirmed by rescue, replicated across two independent studies (PMID 33370472 and 31726100)\",\n      \"pmids\": [\"33370472\", \"31726100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ROR1 expression in satellite cells (SCs) after muscle injury is induced by TNF-α and IL-1β via NF-κB activation; SC-specific depletion of Ror1 decreases the number of Pax7-positive SCs after injury, demonstrating that Ror1 is required for satellite cell proliferation during skeletal muscle regeneration.\",\n      \"method\": \"In vivo muscle injury model, neutralizing antibodies against TNF-α/IL-1β, conditional SC-specific Ror1 knockout, flow cytometry, C2C12 cell NF-κB reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic depletion with cellular phenotype, NF-κB pathway epistasis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"28790171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In esophageal squamous cell carcinoma, Wnt5a promotes cell invasion via ROR1 and ROR2 receptors through DAAM1 activation and downstream RhoA (but not Rac1/Rac2) signaling; ROR1 strongly associates with ROR2; DAAM1 and PI3Kα/Akt are parallel downstream pathways of ROR1/ROR2 in Wnt5a-induced migration.\",\n      \"method\": \"Anti-ROR1 mAb, ROR2 shRNA, RhoA/DAAM1 activity assays, immunoprecipitation, fluorescent phalloidin staining, invasion assays\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus RhoA/DAAM1 activity assays and rescue with wild-type DAAM1, single lab\",\n      \"pmids\": [\"31114334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IGFBP5 is identified as a ligand for ROR1; IGFBP5 binding facilitates ROR1/HER2 heterodimer formation, inducing CREB-mediated expression of ETV5 and FBXW9, thereby promoting glioblastoma stem cell invasion and tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation (IGFBP5-ROR1 binding), siRNA knockdown and ectopic overexpression of IGFBP5, patient-derived xenograft model, CRISPR/Cas9 gene editing, RNA sequencing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand-receptor binding demonstrated by Co-IP, signaling cascade validated by multiple orthogonal methods including CRISPR KO and in vivo PDX models\",\n      \"pmids\": [\"36949068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ROR1 transcriptional expression in pancreatic cancer is dependent on YAP/BRD4 binding at an enhancer region; ROR1 promotes PDAC proliferation by activating E2F through c-Myc to induce Aurora kinase B (AURKB) expression; ROR1-high cells serve as tumor-initiating cells.\",\n      \"method\": \"ChIP/epigenomic analysis, ROR1 depletion, gene expression analysis, functional tumor recurrence/metastasis assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenomic ChIP plus mechanistic signaling delineation, single lab with multiple methods\",\n      \"pmids\": [\"37096681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In metastatic castration-resistant prostate cancer, canonical Wnt/β-catenin signaling transcriptionally upregulates ROR1, which then enhances non-canonical responses to Wnt5a; APC genomic loss (but not epigenetic downregulation) is strongly associated with Wnt/β-catenin pathway activation and downstream ROR1 upregulation.\",\n      \"method\": \"IHC correlation, patient-derived xenograft treatment with Wnt synthesis inhibitor, transcriptomic analysis of clinical samples\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — transcriptomic plus IHC with limited direct mechanistic validation of the ROR1 upregulation mechanism specifically\",\n      \"pmids\": [\"35131873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MSC-derived CXCL16 upregulates ROR1 expression in MKN45 gastric cancer cells via CXCR6/STAT3 activation; ROR1 induction downstream of STAT3 promotes gastric cancer cell proliferation and migration in vitro and tumor formation in vivo.\",\n      \"method\": \"siRNA knockdown of CXCL16 in MSC, recombinant CXCL16 treatment, STAT3 reporter/signaling assay, in vivo co-injection xenograft with CXCL16 neutralizing antibody\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway epistasis (STAT3-ROR1 axis) with in vitro and in vivo validation, single lab with multiple methods\",\n      \"pmids\": [\"32012403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ROR1 activates a positive feedback loop with STAT3 in osteoarthritis chondrocytes: Wnt5a-induced ROR1 promotes STAT3 nuclear translocation, and STAT3 in turn binds the ROR1 promoter to upregulate ROR1 expression; this ROR1/STAT3 loop activates NF-κB signaling, causing catabolic imbalance and cartilage degeneration.\",\n      \"method\": \"siRNA knockdown, STAT3 luciferase reporter assay, ChIP of STAT3 at ROR1 promoter, immunofluorescence, in vivo DMM surgical OA model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating STAT3 binding to ROR1 promoter plus functional in vivo KD, single lab\",\n      \"pmids\": [\"37343369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Notch and hypoxia signaling pathways transcriptionally activate Ror1 in glioblastoma stem-like cells (GSCs); NICD and HIF-1α bind upstream regions of the Ror1 gene more efficiently under spheroid conditions; upregulated Ror1 then promotes Wnt5a-driven spheroid formation (stem cell-like properties) in GSCs.\",\n      \"method\": \"Notch/hypoxia pathway inhibition, NICD forced expression, ChIP of NICD/HIF-1α at Ror1 promoter, spheroid formation assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating transcription factor binding at Ror1 locus plus functional sphere assay, single lab\",\n      \"pmids\": [\"36314076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ROR1 physically interacts with HSP90α (identified by Co-IP); a specific binding motif on ROR1 (ELHHPNIV) is necessary for HSP90-facilitated stabilization; HSP90 inhibition leads to ROR1 degradation via ubiquitin/proteasome pathway, attenuating ROR1-dependent pro-survival signaling in CLL.\",\n      \"method\": \"Mass spectrometry-based screen for ROR1 partners, Co-IP validation, binding motif mapping, ubiquitin-proteasome pathway assay\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS identification of interaction, Co-IP validation, motif mapping, proteasome rescue assay — replicated across two independent labs (also PMID 33370472)\",\n      \"pmids\": [\"31726100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In TCF3-PBX1 BCP-ALL, Wnt5a-ROR1 signaling activates RhoA/Rac1 GTPases and upregulates STAT3, enhancing cell proliferation; Wnt16b also activates this RhoA/Rac1 cascade but Wnt16 does not interact with ROR1 in TCF3-PBX1 cells.\",\n      \"method\": \"RhoA/Rac1 activation assays, Co-IP (Wnt16/ROR1 interaction tested), siRNA knockdown of ROR1, STAT3 measurement, high-throughput drug sensitivity\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GTPase assays plus Co-IP for ligand specificity, single lab\",\n      \"pmids\": [\"30631148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Targeting ROR1 in mantle cell lymphoma downregulates NF-κB p65; NF-κB pathway activation can antagonize ROR1-mediated apoptotic responses, identifying NF-κB as a resistance mechanism to ROR1 targeting.\",\n      \"method\": \"ROR1 silencing, NF-κB pathway analysis, high-throughput drug sensitivity testing, synergy analysis\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ROR1 KD with downstream NF-κB readout plus pharmacological epistasis, single lab\",\n      \"pmids\": [\"29296874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ROR1 expression in Alzheimer's disease cell models is reduced by Aβ1-42 treatment; overexpressed ROR1 preserves the actin network, abrogates cytoskeletal protein degradation, and promotes neuritogenesis even in the presence of Aβ1-42; miR-146a and miR-34a repress ROR1 and are themselves regulated by lncRNA NEAT1.\",\n      \"method\": \"ROR1 overexpression in Aβ1-42 cell model, actin cytoskeleton imaging, RNA immunoprecipitation (NEAT1-miRNA interaction), miRNA overexpression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression with functional readout but single lab, single method per finding, limited mechanistic depth\",\n      \"pmids\": [\"34584188\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ROR1 is a transmembrane receptor tyrosine kinase (classified as a pseudokinase lacking intrinsic catalytic activity) that acts as a Wnt5a (and IGFBP5) receptor, signaling through Wnt5a-induced hetero-oligomerization with ROR2, recruitment of GEFs (DOCK2) via its cytoplasmic proline-rich domain, and activation of Rac1/RhoA and ERK1/2 to promote cancer cell proliferation and migration; it also phosphorylates HER3 at Tyr1307 (a kinase-independent-of-ErbB mechanism) to engage the MAYA/NSUN6-MST1/YAP axis for bone metastasis, and functions as a scaffold for cavin-1, CAV1, and CAVIN3 to maintain caveolae integrity and sustain multi-RTK pro-survival AKT signaling; its stability is maintained by HSP90α and its surface expression requires N-linked glycosylation, while it can complex with TCL1 to amplify AKT-driven leukemogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ROR1 is a cell-surface receptor tyrosine kinase-like molecule that drives proliferation, migration, and pro-survival signaling in cancer and tissue regeneration, primarily as a non-canonical Wnt5a receptor [#1, #5]. Although it adopts a kinase fold, ROR1 is a pseudokinase devoid of intrinsic catalytic activity and is instead transphosphorylated by partner kinases such as Met in oncogene-amplified cells [#3]. Upon Wnt5a stimulation, ROR1 hetero-oligomerizes with ROR2 through its extracellular Kringle domain and recruits guanine nucleotide exchange factors via its cytoplasmic proline-rich domain (PRD), with the single residue P808 being essential for DOCK2 binding and the downstream activation of Rac1/RhoA GTPases and ERK1/2 that promote chemotaxis and proliferation [#1, #5, #6]. ROR1 converges on AKT survival signaling through multiple routes: it complexes with casein kinase 1\\u03b5 to activate PI3K-AKT-CREB [#0], cooperates with TCL1 to accelerate leukemogenesis [#4], and acts as a kinase-independent scaffold that stabilizes caveolin-1 and CAVIN proteins to maintain caveolae and sustain pro-survival AKT output from EGFR, MET, and IGF-IR [#7, #8]. ROR1 can also directly phosphorylate HER3 at Tyr1307 to engage the LLGL2-MAYA-NSUN6/MST1-YAP axis driving breast cancer bone metastasis [#2], and it promotes epithelial-mesenchymal transition through regulation of SNAIL, vimentin, and E-cadherin [#11]. ROR1 itself is regulated at multiple levels: N-linked glycosylation is required for cell-surface trafficking of the mature receptor [#9], HSP90\\u03b1 binds a specific ELHHPNIV motif to protect ROR1 from ubiquitin-proteasome degradation [#13, #22], and its transcription is induced by Wnt/\\u03b2-catenin, STAT3, Notch/HIF-1\\u03b1, and inflammatory NF-\\u03baB inputs across diverse tissues [#14, #17, #20, #21]. Beyond cancer, ROR1 is required for satellite cell proliferation during skeletal muscle regeneration downstream of TNF-\\u03b1/IL-1\\u03b2-NF-\\u03baB signaling [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that ROR1 is catalytically inactive, reframing it from an autonomous kinase to a pseudokinase dependent on partner kinases for phosphorylation events.\",\n      \"evidence\": \"In vitro kinase assays and Met-inhibitor/RNAi experiments in Met-amplified cancer cell lines with in vivo tumorigenesis\",\n      \"pmids\": [\"21487037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether transphosphorylation by Met is required in non-Met-amplified contexts\", \"Functional consequence of the phosphorylated state on downstream signaling not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that ROR1 surface display depends on post-translational maturation, linking glycosylation to its functional localization and cytoskeletal effects.\",\n      \"evidence\": \"N-glycosidase treatment, glycosylation inhibitors, ubiquitination assays, and surface flow cytometry\",\n      \"pmids\": [\"21481194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Glycosylation sites not mapped\", \"Functional role of mono-ubiquitination unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected ROR1 to PI3K-AKT survival signaling by identifying CK1\\u03b5 as a partner amplifying Wnt5a-driven growth, providing an early mechanistic link to a major oncogenic pathway.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA silencing, and in vitro/in vivo breast cancer growth assays\",\n      \"pmids\": [\"22403610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CK1\\u03b5-ROR1 phosphorylation relationship not established\", \"Mechanism connecting CK1\\u03b5 to PI3K activation undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated genetically that ROR1 cooperates with TCL1 to enhance AKT signaling and accelerate leukemia, moving beyond correlation to in vivo epistasis.\",\n      \"evidence\": \"Co-IP/MS identification of the ROR1-TCL1 complex and ROR1\\u00d7TCL1 double-transgenic mice with adoptive transfer\",\n      \"pmids\": [\"24379361\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism by which TCL1 binding enhances AKT phosphorylation unclear\", \"Whether the interaction is direct or bridged not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the core non-canonical Wnt5a signaling architecture by mapping the domains required for ROR1/ROR2 hetero-oligomerization and GEF-driven Rac1/RhoA activation.\",\n      \"evidence\": \"Domain-deletion/truncation constructs, Co-IP, GTPase activation assays, and in vivo engraftment in CLL\",\n      \"pmids\": [\"26690702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the GEFs not specified at this stage\", \"Stoichiometry of the ROR1/ROR2 oligomer unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a kinase-independent scaffolding role for ROR1 in stabilizing caveolin-1 and maintaining caveolae, broadening its function beyond Wnt signaling to multi-RTK survival.\",\n      \"evidence\": \"Co-IP, kinase-dead mutants, EM/IF of caveolae, and AKT signaling assays in lung cancer with EGFR-TKI resistance readouts\",\n      \"pmids\": [\"26725982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same molecule partitions between Wnt-signaling and scaffolding pools is unknown\", \"Structural basis of cavin-1/CAV1 binding not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that despite being a pseudokinase, ROR1 can phosphorylate HER3 at Tyr1307 to drive a methylation-dependent YAP axis for bone metastasis, defining a distinct ErbB-independent effector mechanism.\",\n      \"evidence\": \"Phosphorylation assays, site-directed mutagenesis, MS, Co-IP, and in vivo bone metastasis models\",\n      \"pmids\": [\"28114269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with the catalytically-dead designation requires definition of how transphosphorylation enables this activity\", \"Generality of the MAYA/NSUN6 axis across tumor types untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended ROR1 function to physiological tissue regeneration, showing it is an NF-\\u03baB-induced effector required for satellite cell proliferation after muscle injury.\",\n      \"evidence\": \"Conditional SC-specific Ror1 knockout, cytokine-neutralizing antibodies, and NF-\\u03baB reporter assays in vivo\",\n      \"pmids\": [\"28790171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling driving satellite cell proliferation not mapped\", \"Ligand context in regenerating muscle not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Pinpointed DOCK2 as the proline-rich-domain effector GEF and identified P808 as the single critical residue, providing precise molecular resolution to the Wnt5a-Rac axis.\",\n      \"evidence\": \"Point-mutagenesis (P808A), Co-IP, DOCK2 siRNA, Rac1/2 activation, and growth assays in CLL\",\n      \"pmids\": [\"29678828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other GEFs use the same PRD site untested\", \"How Wnt5a triggers PRD availability for DOCK2 unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established HSP90\\u03b1 as a specific chaperone protecting ROR1 from proteasomal degradation, defining a druggable dependency for ROR1 stability.\",\n      \"evidence\": \"Co-IP/MS, paralog-specific analysis, ELHHPNIV motif mapping, and proteasome-rescue assays across two independent studies\",\n      \"pmids\": [\"33370472\", \"31726100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-chaperones in the ROR1-HSP90 complex not identified\", \"E3 ligase mediating ROR1 ubiquitination unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added a second scaffolding function in which ROR1 binds CAVIN3 at a distinct site to control caveolae endocytosis and endosomal AKT signaling.\",\n      \"evidence\": \"Co-IP, domain-binding mapping, subcellular fractionation, and endocytosis/AKT assays in lung adenocarcinoma\",\n      \"pmids\": [\"30894682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between the CAV1, CAVIN1 and CAVIN3 binding events not resolved\", \"Whether these scaffolding roles operate in the same cells as Wnt signaling unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the DOCK2/P808 mechanism to ERK1/2 activation and showed it bypasses ibrutinib, explaining a route to therapy resistance.\",\n      \"evidence\": \"ROR1\\u0394PRD and P808A mutants, ERK1/2 phosphorylation assays, and pharmacological inhibition in CLL\",\n      \"pmids\": [\"33097837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase linking DOCK2/Rac to ERK not defined\", \"Clinical relevance of ibrutinib bypass not validated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated tissue- and ligand-specific wiring of the Wnt5a-ROR1 GTPase output, with RhoA/DAAM1 dominating in esophageal cancer and Wnt16 ligand specificity in ALL.\",\n      \"evidence\": \"RhoA/DAAM1 activity assays, Co-IP ligand-specificity tests, and invasion assays in ESCC and TCF3-PBX1 ALL\",\n      \"pmids\": [\"31114334\", \"30631148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants selecting RhoA versus Rac branches not defined\", \"Reconciliation with the canonical DOCK2/Rac model incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified IGFBP5 as a second ROR1 ligand that drives ROR1/HER2 heterodimerization and CREB-mediated transcription, expanding ROR1's ligand repertoire beyond Wnt5a.\",\n      \"evidence\": \"Co-IP binding, IGFBP5 knockdown/overexpression, CRISPR editing, RNA-seq, and PDX models in glioblastoma\",\n      \"pmids\": [\"36949068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IGFBP5-ROR1 binding undefined\", \"Whether IGFBP5 and Wnt5a compete or cooperate untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed ROR1 within transcriptional feed-forward circuits, showing YAP/BRD4-driven ROR1 expression sustains tumor-initiating cell programs through c-Myc/E2F/AURKB.\",\n      \"evidence\": \"ChIP/epigenomic analysis, ROR1 depletion, and tumor recurrence/metastasis assays in PDAC\",\n      \"pmids\": [\"37096681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ROR1 signaling reciprocally reinforces YAP not established\", \"Direct versus indirect c-Myc induction unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a catalytically-dead pseudokinase reconciles its documented transphosphorylation of HER3 and HER2 partners with its scaffolding and Wnt5a-GEF functions in a single structural and regulatory framework remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of liganded ROR1 signaling complexes\", \"Mechanism partitioning ROR1 among Wnt-signaling, scaffolding, and transcriptionally-driven pools unknown\", \"In vivo requirement of distinct functions in normal versus malignant tissue not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 5, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [1, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 4, 11, 17]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13, 22]}\n    ],\n    \"complexes\": [\"caveolae\"],\n    \"partners\": [\"ROR2\", \"DOCK2\", \"CAV1\", \"CAVIN1\", \"CAVIN3\", \"TCL1\", \"HSP90AA1\", \"CSNK1E\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}