{"gene":"RYK","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":1992,"finding":"RYK encodes a receptor tyrosine kinase-related protein with unusual sequence idiosyncrasies in conserved kinase domain motifs (ATP-binding and phosphotransfer subdomains), calling into question its catalytic activity. The protein has a transmembrane domain, a small extracellular domain with N-linked glycosylation sites, and an intracellular kinase-related domain.","method":"cDNA cloning, sequence analysis, structural prediction","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 (sequence/structure) / Weak — single foundational cloning paper, no functional assay","pmids":["1334548"],"is_preprint":false},{"year":1993,"finding":"Human RYK protein contains a catalytic domain in which the conserved DFG motif is altered to DNA, and conserved residues in ATP-binding (subdomains I and II) and subdomain VI are changed, predicting catalytic inactivity. The gene maps to chromosome 3q22.","method":"cDNA cloning from ovarian cancer cell line, sequence analysis, chromosomal mapping","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 (sequence/structure) / Moderate — independently confirmed in two papers with consistent findings","pmids":["8386829","8390040"],"is_preprint":false},{"year":1999,"finding":"H-RYK has impaired catalytic activity: using a chimeric receptor approach, H-RYK fails to undergo autophosphorylation or phosphorylate substrates in vitro. Amino acid substitutions in the activation domain account for the loss of catalytic activity. Despite this, ligand stimulation activates the MAPK pathway, and this signaling is abolished by mutation of the invariant lysine K334A in subdomain II.","method":"Chimeric receptor assay, in vitro kinase assay, site-directed mutagenesis, homology modelling","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, chimeric receptor functional studies, multiple orthogonal methods in single study","pmids":["10454588"],"is_preprint":false},{"year":2000,"finding":"Murine Ryk physically associates with EphB2 and EphB3 receptors and with the PDZ-domain protein AF-6 (Afadin), implicating Ryk in Eph receptor signal crosstalk and scaffold assembly. Ryk-null mice exhibit craniofacial defects and complete cleft palate, phenocopying Ephb2/Ephb3 double-mutant mice.","method":"Gene targeting (knockout mice), biochemical co-immunoprecipitation, genetic phenocopy analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO phenotype combined with biochemical Co-IP, genetic interaction with Eph receptors, multiple orthogonal methods","pmids":["10932185"],"is_preprint":false},{"year":2002,"finding":"Human RYK associates with EphB2 and EphB3 (requiring both extracellular and cytoplasmic domains of RYK, independent of Eph receptor activation) but is not phosphorylated by them. Human RYK does NOT bind AF-6 in vitro or in vivo, contrasting with murine Ryk.","method":"Co-immunoprecipitation (in vitro and in vivo), domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab Co-IP, single method; negative result on AF-6 binding is mechanistically informative","pmids":["11956217"],"is_preprint":false},{"year":2004,"finding":"Mammalian Ryk functions as a Wnt coreceptor together with Frizzled for Wnt ligands. Ryk binds directly to Dishevelled and through this interaction activates the canonical Wnt/TCF pathway. Ryk is required for Wnt-3a-induced neurite outgrowth and for Wnt-1-induced TCF activation. Transgenic mice expressing Ryk siRNA show axon guidance defects.","method":"Co-immunoprecipitation, reporter assays (TCF/LEF), siRNA transgenic mice, neurite outgrowth assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function in vivo and in vitro, multiple orthogonal methods, replicated across contexts","pmids":["15454084"],"is_preprint":false},{"year":2004,"finding":"C. elegans LIN-18 is a Ryk ortholog whose WIF (Wnt inhibitory factor) extracellular domain is required for function, while the kinase domain is dispensable. LIN-18/Ryk functions in a parallel pathway to LIN-17/Frizzled in Wnt-mediated cell fate patterning during vulva development. Wnt ligands LIN-44, MOM-2, and CWN-2 redundantly regulate P7.p patterning.","method":"Genetic epistasis, domain deletion analysis, loss-of-function mutants in C. elegans","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with domain requirements, parallel pathway established by double-mutant analysis","pmids":["15369677"],"is_preprint":false},{"year":2005,"finding":"Ryk acts as a high-affinity receptor for Wnt ligands that mediates chemorepulsion of corticospinal tract (CST) axons. Wnts expressed in an anterior-to-posterior decreasing gradient in the spinal cord repel CST axons through Ryk expressed on these axons. Intrathecal anti-Ryk antibody blocked posterior growth of CST axons.","method":"Collagen gel repulsion assays, intrathecal antibody injection in neonatal mice, in vivo axon tracing","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro repulsion assay, in vivo antibody blockade with axon tracing, multiple orthogonal methods","pmids":["16116452"],"is_preprint":false},{"year":2006,"finding":"Wnt5a acts as a chemorepulsive ligand for Ryk to drive callosal axons toward the contralateral hemisphere after crossing the midline. Loss of Ryk in mice impedes callosal axon escape from the midline and impairs fasciculation of axons before midline crossing, revealing Ryk as a guidance receptor for corpus callosum formation.","method":"Ryk knockout mice, in utero electroporation, axon tracing, repulsion assays","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mutant phenotype, direct assays of axon behavior, defined ligand-receptor pair","pmids":["16723543"],"is_preprint":false},{"year":2006,"finding":"Wnt3 acts through Ryk (expressed in a ventral-to-dorsal decreasing gradient on retinal ganglion cell axons) to mediate repulsive responses during retinotectal topographic mapping along the medial-lateral axis. Dominant-negative Ryk in dorsal RGC axons caused medial shift of termination zones, while overexpression of Wnt3 in the lateral tectum repelled termination zones.","method":"In vivo overexpression and dominant-negative approaches, axon tracing, growth cone turning assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gain- and loss-of-function, direct topographic mapping analysis, multiple orthogonal methods","pmids":["16280981"],"is_preprint":false},{"year":2008,"finding":"Ryk is cleaved (by gamma-secretase) and its intracellular C-terminal fragment (ICD) translocates to the nucleus in response to Wnt3 stimulation. The cleaved Ryk ICD is required for Wnt3-induced neuronal differentiation both in vitro and in vivo during cortical neurogenesis.","method":"Biochemical cleavage assay, nuclear fractionation, gain/loss-of-function in neural progenitors, in utero electroporation","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — demonstrated proteolytic cleavage biochemically, nuclear translocation by fractionation, in vivo rescue experiments","pmids":["19000841"],"is_preprint":false},{"year":2008,"finding":"Ryk cooperates with Frizzled7 to mediate Wnt11-stimulated endocytosis of Dishevelled via beta-arrestin 2. Ryk interacts with both Wnt11 and beta-arrestin 2. Depletion of Ryk prevents Dvl endocytosis and impairs non-canonical Wnt11/Fz7-mediated CE movements in Xenopus gastrulation.","method":"Co-immunoprecipitation, morpholino knockdown in Xenopus, endocytosis assays, live imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, loss-of-function phenotype, endocytosis assay, multiple methods in single study","pmids":["18809723"],"is_preprint":false},{"year":2008,"finding":"Drosophila Src family kinases SRC64B and SRC42A are required for WNT5-mediated signaling through Derailed (RYK ortholog). Derailed and SRC64B form a complex; this complex contains catalytically active SRC64B and requires SRC64B kinase activity for complex formation/stability. Derailed is phosphorylated in a SRC64B-dependent manner, and coexpression activates SRC64B. Mammalian RYK and the SRC64B ortholog also form complexes. WNT5/Derailed signaling does not regulate TCF/LEF-dependent transcription.","method":"Genetic epistasis in Drosophila, co-immunoprecipitation, phosphorylation assays, dominant gain-of-function suppression","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical complex formation, phosphorylation assay, genetic epistasis, conservation confirmed in mammalian cells","pmids":["18539923"],"is_preprint":false},{"year":2009,"finding":"Ryk ICD undergoes ubiquitination and proteasomal degradation. Cdc37 (a subunit of the Hsp90 chaperone complex) interacts with Ryk ICD, inhibits its proteasomal degradation, and promotes its nuclear localization. Overexpression of Cdc37 increases Ryk ICD levels and nuclear localization; knockdown reduces Ryk ICD stability. The Cdc37-Ryk ICD complex is disrupted during neural differentiation of embryonic stem cells.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, nuclear fractionation, overexpression and knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical Co-IP, ubiquitination assay, nuclear fractionation, multiple orthogonal methods in single study","pmids":["19269974"],"is_preprint":false},{"year":2010,"finding":"Wnt5b signals through Ryk (not through Frizzled2) to provide directional cues for cell migration during zebrafish gastrulation. Ryk deficiency impairs Wnt5b-induced Ca2+ activity and directional cell protrusions. Fz2 recruits Dvl to the membrane upon Wnt5b stimulation, while Ryk mediates a separate pathway leading to directed cell migration away from the Wnt5b source.","method":"Morpholino knockdown in zebrafish, co-culture directional migration assays, Ca2+ imaging, cell protrusion analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo morpholino KD, directional co-culture assay, Ca2+ signaling readout, multiple orthogonal methods","pmids":["20660632"],"is_preprint":false},{"year":2011,"finding":"Ryk promotes GABAergic neuron production while repressing oligodendrocyte formation in the ventral telencephalon by negatively regulating Olig2 expression and inducing Dlx2. The cleaved intracellular domain of Ryk is sufficient to regulate this cell-fate switch. Ryk is required for GABAergic neuron induction by Wnt3a.","method":"Ryk knockout mice, in utero electroporation of Ryk ICD, in vitro neural progenitor cultures, immunostaining","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO phenotype, ICD gain-of-function rescue, defined transcriptional targets, multiple methods","pmids":["21205786"],"is_preprint":false},{"year":2011,"finding":"MIB1 (Mindbomb 1), an E3 ubiquitin ligase, physically and functionally interacts with RYK. MIB1 promotes ubiquitination of RYK and reduces its steady-state levels at the plasma membrane. MIB1 is sufficient to activate Wnt/β-catenin signaling in an endogenous RYK-dependent manner. Both RYK and MIB1 are required for Wnt-3A-mediated β-catenin activation. In C. elegans, ceMIB genetically interacts with lin-18/RYK in vulva development.","method":"Co-immunoprecipitation, ubiquitination assay, plasma membrane localization assay, knockdown/overexpression, genetic interaction in C. elegans","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical ubiquitination assay, Co-IP, functional epistasis in mammals and C. elegans, multiple orthogonal methods","pmids":["21875946"],"is_preprint":false},{"year":2012,"finding":"Ryk interacts with Vangl2 both genetically and biochemically; this interaction is potentiated by Wnt5a. Ryk regulates PCP signaling by promoting Vangl2 stability. Loss of Ryk in a Vangl2+/- background causes PCP defects including open neural tube, inner ear hair cell misalignment, and shortened limbs. Ryk transduces Wnt5a signaling by forming a complex with Vangl2. Ryk also activates RhoA, a downstream PCP effector.","method":"Co-immunoprecipitation, genetic epistasis (double heterozygote analysis), knockout mice, immunostaining of inner ear","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical Co-IP, double-mutant genetic epistasis, multiple PCP phenotypic readouts, multiple labs and papers","pmids":["23144463","22773843"],"is_preprint":false},{"year":2014,"finding":"Ryk ICD (generated by gamma-secretase cleavage) represses neuroprotective FOXO activity by binding to the FOXO co-factor beta-catenin. Ryk-ICD fragment suppresses neuroprotection in expanded-polyQ nematodes and represses FOXO transcriptional activity. Reducing gamma-secretase PS1 levels compensated for Ryk cytotoxicity in mutant HTT cells.","method":"C. elegans genetics, mouse striatal cell culture, FOXO reporter assays, gamma-secretase modulation, Co-IP implied by binding claims","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional assays in two organisms, FOXO reporter, loss-of-function rescue, but binding claims not fully detailed in abstract","pmids":["24960609"],"is_preprint":false},{"year":2015,"finding":"Wnt5a signals through Ryk to disrupt endothelial barrier function via downstream ROCK/LIMK2/CFL1 signaling, leading to stress fiber formation (actin polymerization), disruption of β-catenin and VE-cadherin adherens junctions, and enhanced endothelial permeability. Ryk silencing completely prevented Wnt5a-induced endothelial hyperpermeability. WIF1 (which interferes with the WIF domain of Ryk) prevented actin polymerization.","method":"siRNA knockdown, trans-endothelial resistance measurement, WIF1 antagonist, live cell imaging of cytoskeletal rearrangements, phosphoprotein analysis","journal":"Cell adhesion & migration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with specific pathway readouts, WIF domain antagonist controls, multiple assays","pmids":["27159116"],"is_preprint":false},{"year":2017,"finding":"Ryk acts as a negative regulator of dendrite morphogenesis. Loss of Ryk in hippocampal and cortical neurons promotes excessive dendrite growth and branching in vitro; overexpression restricts these processes. A membrane-proximal subdomain is crucial for Ryk-mediated suppression of dendrite morphogenesis. Ryk haploinsufficient mice exhibit excessive dendrite growth and branching in layer 2/3 pyramidal neurons in vivo.","method":"KO/knockdown and overexpression in dissociated neurons, domain deletion analysis, in vivo morphological analysis of cortical neurons","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — bidirectional (KO + OE) functional analysis, domain requirement identified, in vivo confirmation","pmids":["28729735"],"is_preprint":false},{"year":2017,"finding":"Smek1/2 are nuclear chaperones and cofactors for the cleaved Ryk ICD. Smek1/2 interact with Ryk-ICD, regulate its nuclear localization, and cooperate with it to bind the Dlx1/2 intergenic regulatory element and regulate transcription. Smek1/2 double-KO mice show defects in cortical neuron production and increased neural stem cells.","method":"Co-immunoprecipitation, nuclear fractionation, chromatin immunoprecipitation, knockout mice, transcriptional reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — biochemical Co-IP, ChIP at target gene, KO phenotype, nuclear localization experiments, multiple orthogonal methods","pmids":["29180410"],"is_preprint":false},{"year":2017,"finding":"Ryk modulates PCP signaling in CST axon guidance through asymmetric regulation of Vangl2 distribution. Under high Wnt5a concentrations, cytoplasmic Ryk increases and promotes cytoplasmic redistribution of Vangl2, inhibiting Frizzled3 cytoplasmic translocation. Under low Wnt5a, Ryk stabilizes Vangl2 at the plasma membrane, promoting Frizzled3 cytoplasmic translocation.","method":"In vivo CST tracing, in vitro biochemical fractionation, dominant-negative and overexpression approaches","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vivo and in vitro analyses, biochemical fractionation, single lab but multiple readouts","pmids":["28660073"],"is_preprint":false},{"year":2019,"finding":"RYK functions as a WNT coreceptor in airway epithelial cells to restrict goblet cell differentiation and maintain airway epithelial cell balance. Epithelial-specific Ryk deletion causes goblet cell hyperplasia and mucus hypersecretion. Club cell-specific Ryk deletion leads to goblet cell hyperplasia during airway regeneration. Ryk promotes WNT/β-catenin signaling in the lung epithelium.","method":"Cell-type-specific conditional knockout (Cre-lox), transcriptomic analysis, morphological analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO, defined phenotypic readouts, transcriptomic follow-up","pmids":["31776260"],"is_preprint":false},{"year":2019,"finding":"Non-canonical Wnt-Ryk signaling (via Ryk ICD) regulates specification of somatostatin (SST)- versus parvalbumin (PV)-expressing cortical interneurons in a dose-dependent manner. Ryk gain-of-function ICD signaling regulates SST and PV fate. This acts through non-canonical signaling, not canonical β-catenin.","method":"In utero electroporation (gain-of-function of Ryk ICD), conditional KO, in vivo interneuron fate analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo gain- and loss-of-function, direct cell fate readout, ICD-specific experiments distinguish canonical vs. non-canonical","pmids":["31257105"],"is_preprint":false},{"year":2020,"finding":"WNT5A-RYK signaling acts as a navigation system for post-mitotic daughter cells to extend basally oriented filopodial protrusions during midgut elongation. Loss of Ryk phenocopies the Wnt5a-/- phenotype, perturbing filopodial pathfinding and leading to apoptosis. Epithelial ROR2 is dispensable for this process, establishing RYK as the specific WNT5A receptor in this context.","method":"Ryk knockout mice, Wnt5a knockout comparison, live imaging of filopodial dynamics, genetic ablation of ROR2","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO phenocopy of ligand mutant, parallel receptor KO as negative control, direct imaging readout","pmids":["32994164"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of the extracellular regions of Drosophila RYK ortholog Derailed-2 (Drl-2) reveal that the WIF domain lacks the lipid-binding site seen in WIF-1, and cannot accommodate the acyl chain typically attached to WNTs. Despite lacking an acyl chain, recombinant DWnt-5 can bind the Drosophila RYK ortholog. These structures provide insight into how WNTs recruit RYK into signaling complexes.","method":"X-ray crystallography, WNT-binding assays, hydrogen-deuterium exchange analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination plus binding assays; Drosophila ortholog but directly informative for RYK WIF domain mechanism","pmids":["34686333"],"is_preprint":false},{"year":2022,"finding":"WNT/RYK signaling in lung mesenchymal cells acts as an anti-inflammatory modulator and cell survival factor. Mesenchymal-specific Ryk deletion leads to lung hypoplasia, inflammation, alveolar simplification, and upregulation of pro-apoptotic and inflammatory genes. RYK signaling acts through β-catenin and NF-κB to suppress mesenchymal cell death and excessive inflammatory cytokine production.","method":"Mesenchyme-specific conditional knockout (Cre-lox), single-cell transcriptomics, in vitro signaling assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO, scRNA-seq, in vitro pathway validation, multiple readouts","pmids":["35671428"],"is_preprint":false},{"year":2025,"finding":"Ryk expression is induced in astrocytes after spinal cord injury. Astrocyte-specific knockout of Ryk elongates reactive astrocytes, accelerates glial border formation, reduces scar size, and accelerates multi-cell-type injury responses. Elongation of astrocyte processes after Ryk KO is mediated by NrCAM (a cell adhesion molecule induced by Ryk KO). Ryk thus negatively regulates astrocyte morphological remodeling after injury.","method":"Astrocyte-specific conditional knockout (Cre-lox), single-cell transcriptomics, immunostaining, morphological analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO, scRNA-seq, identification of downstream mediator NrCAM, multiple orthogonal readouts","pmids":["40208942"],"is_preprint":false},{"year":2026,"finding":"RYK is identified as a functional receptor for the GPNMB ectodomain (G-ECD). G-ECD binding to RYK activates ERK1/2 signaling, which transcriptionally activates PPARγ-CD36 and SREBP1C pathways, promoting hepatic lipid uptake and lipogenesis leading to MASH. Hepatocyte-specific Ryk ablation protects mice against MASH and abolishes pathogenic effects of G-ECD. RYK was identified via unbiased screen of cell-surface-displayed transmembrane protein library.","method":"Unbiased cell-surface protein library screen, hepatocyte-specific conditional knockout, ERK1/2 phosphorylation assays, transcriptional target analysis, in vivo MASH models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — unbiased receptor identification screen, conditional KO confirmation, defined signaling pathway (ERK→PPARγ/SREBP1C), multiple therapeutic interventions tested","pmids":["41708863"],"is_preprint":false},{"year":2009,"finding":"Wnt5a expression is induced in reactive astrocytes around spinal cord injury sites. In vitro, Wnt5a inhibits neurite growth of postnatal cerebellar neurons by activating RhoA/Rho-kinase through Ryk. Intrathecal anti-Ryk antibody in rats with thoracic contusion resulted in significant CST axonal growth and enhanced functional recovery.","method":"In vitro neurite growth assay with RhoA/ROCK inhibitors, intrathecal antibody injection in spinal cord injury model, axon tracing","journal":"Journal of neurotrauma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro mechanistic pathway (RhoA/ROCK), in vivo antibody blockade with functional readout, single lab","pmids":["19473059"],"is_preprint":false},{"year":2005,"finding":"RYK binds EphB3 through its extracellular leucine-rich motif region; deletion of the LRM-containing extracellular region abolishes EphB3 binding. Overexpression of RYK suppresses cell migration from the ventricular zone in cortical slice cultures, while the LRM deletion mutant (which cannot bind EphB3) has no effect on migration.","method":"Co-immunoprecipitation with domain deletion mutants, cortical slice electroporation, cell migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — domain-deletion Co-IP, in vitro functional slice culture, single lab two methods","pmids":["15796903"],"is_preprint":false},{"year":2020,"finding":"Wnt5b/Ryk signaling promotes trafficking of P2X3 receptors to the membrane of DRG neurons via CaMKII activation, resulting in enhanced α,β-meATP-induced currents and peripheral sensitization contributing to bone cancer pain. Anti-Ryk antibody prevented Wnt5b-induced mechanical allodynia and thermal hyperalgesia and blocked the upregulation of membrane P2X3.","method":"In vitro DRG neuron electrophysiology, Western blot of membrane fractions, intrathecal antibody injection, CaMKII inhibitor","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology, membrane fractionation, in vivo antibody blockade, CaMKII pathway defined","pmids":["32979370"],"is_preprint":false},{"year":2020,"finding":"Ryk modulates the hematopoiesis-supporting niche activity of bone marrow mesenchymal stromal cells (MSCs) by fine-tuning canonical Wnt signaling intensity: Ryk promotes Wnt target gene transactivation at low Wnt concentrations but suppresses it at high concentrations. This Wnt-modulating effect requires both the extracellular and intracellular (pseudokinase-containing) domains of Ryk.","method":"siRNA knockdown and overexpression in MSCs, Wnt reporter assays, hematopoietic progenitor co-culture, domain deletion analysis","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional reporter assays, domain deletion, co-culture readout, single lab","pmids":["32724069"],"is_preprint":false}],"current_model":"RYK is a catalytically inactive (pseudokinase) single-pass transmembrane receptor that binds Wnt ligands (including Wnt1, Wnt3a, Wnt5a, Wnt5b, Wnt11, GPNMB ectodomain) through its extracellular WIF domain, and signals through multiple mechanisms: (1) as a Wnt coreceptor with Frizzled, coupling to Dishevelled to activate canonical Wnt/β-catenin and TCF signaling; (2) through gamma-secretase-mediated cleavage releasing the intracellular domain (ICD) for nuclear translocation, where it acts with Smek1/2 as a transcriptional co-regulator of cell fate genes; (3) through recruitment of Src family kinases (e.g., SRC64B) that phosphorylate Ryk and transduce non-canonical signals; (4) through complex formation with Vangl2 to regulate PCP signaling; (5) by interacting with beta-arrestin 2 and Frizzled to mediate endocytosis-dependent non-canonical Wnt signaling; and (6) through ERK1/2 activation downstream of novel ligands such as the GPNMB ectodomain. The Ryk ICD is stabilized by Cdc37/Hsp90 and degraded via ubiquitin-proteasome pathway; its ubiquitination is also promoted by the E3 ligase MIB1, which reduces plasma membrane Ryk levels and couples receptor internalization to Wnt/β-catenin activation. Physiologically, Ryk functions as a chemorepulsive axon guidance receptor in the CNS, regulates neural progenitor cell fate and interneuron subtype specification, restricts dendrite arborization, controls epithelial cell behavior in the lung and gut, and acts as an anti-inflammatory modulator in lung mesenchyme; while pathologically, Ryk inhibits axonal regeneration after spinal cord injury, promotes MASH via GPNMB-ERK-PPARγ/SREBP1C signaling, and modulates neuropathic and cancer pain through Wnt5a/Wnt5b-mediated sensitization of sensory neurons."},"narrative":{"mechanistic_narrative":"RYK is a catalytically inactive (pseudokinase) single-pass transmembrane receptor that transduces Wnt-family signals to control axon guidance, neural cell-fate decisions, epithelial behavior, and planar cell polarity [PMID:10454588, PMID:15454084, PMID:16116452]. Cloning and sequence analysis established that its kinase-related cytoplasmic domain carries idiosyncratic substitutions in the conserved ATP-binding and DFG/activation motifs, and chimeric-receptor and in vitro kinase assays confirmed it cannot autophosphorylate or phosphorylate substrates, yet still activates the MAPK pathway in a manner dependent on the invariant subdomain-II lysine [PMID:1334548, PMID:8386829, PMID:8390040, PMID:10454588]. RYK binds Wnt ligands through its extracellular WIF domain and functions as a Wnt coreceptor with Frizzled, binding Dishevelled to drive canonical Wnt/TCF signaling [PMID:15454084, PMID:34686333]. A central regulatory event is gamma-secretase cleavage that releases the intracellular domain (ICD), which translocates to the nucleus and, together with the cofactors Smek1/2, occupies the Dlx1/2 regulatory element to govern cortical neurogenesis, GABAergic-versus-oligodendrocyte fate, and interneuron subtype specification by modulating Olig2 and Dlx2 [PMID:19000841, PMID:21205786, PMID:29180410, PMID:31257105]; ICD stability is set by Cdc37/Hsp90-mediated protection from ubiquitin-proteasome degradation [PMID:19269974]. The E3 ligase MIB1 ubiquitinates RYK, reduces its plasma-membrane levels, and couples this to Wnt/β-catenin activation [PMID:21875946]. As a chemorepulsive axon guidance receptor, RYK reads anterior-to-posterior and dorsoventral Wnt gradients (Wnt5a, Wnt3) to repel corticospinal, callosal, and retinal ganglion cell axons, acting through RhoA/Rho-kinase and through asymmetric regulation of the PCP component Vangl2, whose stability and localization RYK controls in complex with it [PMID:16116452, PMID:16723543, PMID:16280981, PMID:23144463, PMID:22773843, PMID:28660073, PMID:19473059]. RYK also engages non-canonical branches: it recruits Src-family kinases that phosphorylate it (Drosophila SRC64B/Derailed), cooperates with Frizzled and beta-arrestin 2 to drive Dishevelled endocytosis in convergent-extension movements, and signals via Wnt5b independently of Frizzled to direct cell migration [PMID:18809723, PMID:18539923, PMID:20660632]. Physiologically RYK restricts goblet-cell differentiation in airway epithelium and acts as an anti-inflammatory survival factor in lung mesenchyme via β-catenin and NF-κB, while in disease it limits axon regeneration and astrocyte remodeling after spinal cord injury, mediates Wnt5b-driven sensory-neuron sensitization in cancer pain, and serves as the receptor for the GPNMB ectodomain that activates ERK1/2–PPARγ/SREBP1C signaling to promote hepatic lipogenesis and MASH [PMID:31776260, PMID:35671428, PMID:40208942, PMID:41708863, PMID:32979370].","teleology":[{"year":1993,"claim":"Establishing whether RYK is a conventional active kinase was the first question, since its receptor-tyrosine-kinase-like architecture implied catalytic signaling; sequence analysis revealed degenerate catalytic motifs predicting it is a pseudokinase.","evidence":"cDNA cloning and sequence/structural analysis, with chromosomal mapping to 3q22","pmids":["1334548","8386829","8390040"],"confidence":"Medium","gaps":["Catalytic inactivity inferred from sequence, not yet tested functionally","No ligand or signaling partner identified"]},{"year":1999,"claim":"Whether a kinase-dead receptor could still signal was unresolved; chimeric-receptor and in vitro kinase assays confirmed RYK cannot autophosphorylate but still activates MAPK in a manner requiring the invariant subdomain-II lysine, defining it as a signaling-competent pseudokinase.","evidence":"Chimeric receptor assay, in vitro kinase assay, site-directed mutagenesis, homology modelling","pmids":["10454588"],"confidence":"High","gaps":["Ligand identity unknown at this stage","Mechanism linking inactive kinase domain to MAPK activation not defined"]},{"year":2002,"claim":"Early interactome work asked how RYK couples to other receptors; Co-IP placed RYK in complexes with EphB2/EphB3 (via both extra- and intracellular domains) and revealed species divergence in AF-6 binding, hinting at scaffolding roles distinct from catalysis.","evidence":"Co-immunoprecipitation and domain deletion in murine and human cells, plus Ryk-null mouse craniofacial phenocopy of Eph mutants","pmids":["10932185","11956217","15796903"],"confidence":"Medium","gaps":["Functional consequence of Eph association not fully resolved","Human/mouse discrepancy in AF-6 binding unexplained"]},{"year":2004,"claim":"The defining advance identified RYK's ligand and pathway: it acts as a Wnt coreceptor with Frizzled, binds Dishevelled, and is required for canonical Wnt/TCF activation and Wnt-3a-induced neurite outgrowth, with the WIF domain (not the kinase domain) being essential as shown in the C. elegans ortholog LIN-18.","evidence":"Reciprocal Co-IP, TCF/LEF reporters, siRNA transgenic mice, neurite assays, and genetic epistasis with domain deletion in C. elegans","pmids":["15454084","15369677"],"confidence":"High","gaps":["How a pseudokinase relays the Dvl signal mechanistically unresolved","Relationship between canonical and non-canonical branches unclear"]},{"year":2009,"claim":"How RYK directs axons was addressed by showing it is a high-affinity Wnt receptor mediating chemorepulsion along anteroposterior and dorsoventral gradients in corticospinal, callosal, and retinal axons, with antibody blockade and gradient manipulations confirming directional guidance.","evidence":"Collagen-gel repulsion, intrathecal anti-Ryk antibody, in vivo axon tracing, in utero electroporation, growth-cone turning, RhoA/ROCK inhibitor analysis","pmids":["16116452","16723543","16280981","19473059"],"confidence":"High","gaps":["Intracellular effectors downstream of repulsion only partly defined (RhoA/ROCK)","How a graded Wnt input is converted to directional cytoskeletal response not fully mapped"]},{"year":2009,"claim":"The route from membrane receptor to nuclear effector was established: gamma-secretase cleaves RYK to release an ICD that translocates to the nucleus to drive Wnt3-induced neuronal differentiation, and Cdc37/Hsp90 was shown to stabilize the ICD against proteasomal degradation.","evidence":"Biochemical cleavage assays, nuclear fractionation, in utero electroporation, ubiquitination assays, proteasome inhibition, Co-IP","pmids":["19000841","19269974"],"confidence":"High","gaps":["Direct transcriptional targets of the ICD not yet identified in these studies","Stoichiometry and regulation of cleavage in vivo unclear"]},{"year":2011,"claim":"The nuclear function and turnover of RYK were mechanistically expanded: the ICD controls a GABAergic-versus-oligodendrocyte cell-fate switch via Olig2/Dlx2, and the E3 ligase MIB1 ubiquitinates RYK, lowers its surface levels, and couples this to Wnt/β-catenin activation.","evidence":"Ryk-KO mice, ICD in utero electroporation, neural progenitor cultures, ubiquitination assays, Co-IP, and C. elegans genetic interaction","pmids":["21205786","21875946"],"confidence":"High","gaps":["How membrane RYK levels quantitatively tune β-catenin output not fully resolved","Direct DNA-binding partners of the ICD at fate genes not yet defined"]},{"year":2012,"claim":"RYK's role in non-canonical planar cell polarity was defined through its physical and genetic interaction with Vangl2, which it stabilizes in a Wnt5a-potentiated manner, with double-heterozygote phenotypes (open neural tube, hair-cell misalignment) and RhoA activation establishing PCP function.","evidence":"Co-IP, double-heterozygote genetic epistasis, knockout mice, inner-ear immunostaining, in vivo CST tracing with fractionation","pmids":["23144463","22773843","28660073"],"confidence":"High","gaps":["Mechanism by which RYK switches Vangl2 between membrane and cytoplasm at different Wnt5a doses incompletely defined","Link between Vangl2 regulation and RhoA activation not fully mapped"]},{"year":2012,"claim":"Non-canonical signaling modules were extended by showing RYK recruits Src-family kinases that phosphorylate it (SRC64B/Derailed), cooperates with Frizzled and beta-arrestin 2 to drive Dishevelled endocytosis during convergent extension, and signals via Wnt5b for directed migration independently of Frizzled2.","evidence":"Drosophila genetic epistasis, Co-IP and phosphorylation assays, Xenopus and zebrafish morpholino knockdown, endocytosis and Ca2+ imaging assays","pmids":["18539923","18809723","20660632"],"confidence":"High","gaps":["How a kinase-dead receptor is phosphorylated and what the phosphosites signal to in mammals unclear","Integration of the multiple non-canonical branches into one model unresolved"]},{"year":2017,"claim":"The nuclear cofactor machinery and additional neuronal roles were defined: Smek1/2 chaperone the ICD to the Dlx1/2 element to regulate transcription and cortical neuron production, and RYK was shown to restrict dendrite arborization via a membrane-proximal subdomain.","evidence":"Co-IP, nuclear fractionation, ChIP at Dlx1/2, Smek1/2 KO mice, plus bidirectional KO/overexpression and domain-deletion in neurons with in vivo confirmation","pmids":["29180410","28729735"],"confidence":"High","gaps":["Full transcriptional target repertoire of the ICD-Smek1/2 complex unknown","How the membrane-proximal subdomain restrains dendrites mechanistically undefined"]},{"year":2022,"claim":"RYK's physiological roles in epithelia and mesenchyme were established through cell-type-specific deletion: it restricts goblet-cell differentiation in airway epithelium via Wnt/β-catenin and acts as an anti-inflammatory survival factor in lung mesenchyme via β-catenin and NF-κB, while also guiding filopodial pathfinding in midgut elongation as the specific WNT5A receptor.","evidence":"Conditional Cre-lox knockouts, single-cell and bulk transcriptomics, live imaging, ROR2-ablation control, in vitro signaling assays","pmids":["31776260","35671428","32994164"],"confidence":"High","gaps":["Mechanism by which RYK suppresses NF-κB-driven inflammation not detailed","How RYK selectively reads WNT5A over other receptors in each tissue unclear"]},{"year":2025,"claim":"Pathological roles in injury and metabolic disease were defined: RYK limits astrocyte remodeling after spinal cord injury via NrCAM, contributes to Wnt5b-driven sensory-neuron sensitization in cancer pain via P2X3/CaMKII, and was identified by unbiased screen as the GPNMB-ectodomain receptor that activates ERK1/2–PPARγ/SREBP1C to drive hepatic lipogenesis and MASH.","evidence":"Astrocyte- and hepatocyte-specific conditional knockouts, single-cell transcriptomics, DRG electrophysiology, membrane fractionation, cell-surface protein library screen, ERK phosphorylation and transcriptional target analysis","pmids":["40208942","32979370","41708863"],"confidence":"High","gaps":["Whether GPNMB-ERK signaling is independent of or convergent with Wnt/RYK signaling unresolved","Whether RYK is therapeutically tractable across these disease contexts untested"]},{"year":null,"claim":"How a single pseudokinase receptor integrates canonical Wnt/β-catenin, non-canonical PCP/Src/beta-arrestin, gamma-secretase/ICD-nuclear, and ERK1/2 (GPNMB) outputs into context-specific cellular responses remains the central open question.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified structural model of how ligand binding selects among downstream branches","Quantitative rules linking Wnt/ligand dose to canonical-versus-non-canonical output undefined","Lack of a mechanism explaining how the catalytically dead intracellular domain transduces phosphorylation-dependent signals"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,7,29]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[5,29]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,21,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[10,21,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,7,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,13,21]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[22,33]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,16,29]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,8,9,15,24]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,8,20,24]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[29]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13,16]}],"complexes":[],"partners":["FZD7","DVL","VANGL2","SMEK1","CDC37","MIB1","ARRB2","EPHB3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P34925","full_name":"Tyrosine-protein kinase RYK","aliases":[],"length_aa":607,"mass_kda":67.8,"function":"May be a coreceptor along with FZD8 of Wnt proteins, such as WNT1, WNT3, WNT3A and WNT5A. Involved in neuron differentiation, axon guidance, corpus callosum establishment and neurite outgrowth. In response to WNT3 stimulation, receptor C-terminal cleavage occurs in its transmembrane region and allows the C-terminal intracellular product to translocate from the cytoplasm to the nucleus where it plays a crucial role in neuronal development","subcellular_location":"Membrane; Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P34925/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RYK","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RYK","total_profiled":1310},"omim":[{"mim_id":"610412","title":"SERINE PALMITOYLTRANSFERASE, SMALL SUBUNIT, B; SPTSSB","url":"https://www.omim.org/entry/610412"},{"mim_id":"609423","title":"HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/609423"},{"mim_id":"605261","title":"NADPH OXIDASE 4; NOX4","url":"https://www.omim.org/entry/605261"},{"mim_id":"604705","title":"MER TYROSINE KINASE PROTOONCOGENE; MERTK","url":"https://www.omim.org/entry/604705"},{"mim_id":"601929","title":"ATPase, Ca(2+)-TRANSPORTING, UBIQUITOUS; ATP2A3","url":"https://www.omim.org/entry/601929"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RYK"},"hgnc":{"alias_symbol":["D3S3195","RYK1","JTK5"],"prev_symbol":["JTK5A"]},"alphafold":{"accession":"P34925","domains":[{"cath_id":"2.60.40.2170","chopping":"65-195","consensus_level":"high","plddt":90.5559,"start":65,"end":195},{"cath_id":"3.30.200.20","chopping":"310-414","consensus_level":"medium","plddt":95.5488,"start":310,"end":414},{"cath_id":"1.10.510.10","chopping":"417-607","consensus_level":"medium","plddt":94.0943,"start":417,"end":607}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P34925","model_url":"https://alphafold.ebi.ac.uk/files/AF-P34925-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P34925-F1-predicted_aligned_error_v6.png","plddt_mean":79.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RYK","jax_strain_url":"https://www.jax.org/strain/search?query=RYK"},"sequence":{"accession":"P34925","fasta_url":"https://rest.uniprot.org/uniprotkb/P34925.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P34925/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P34925"}},"corpus_meta":[{"pmid":"15454084","id":"PMC_15454084","title":"Mammalian 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endocytosis and is essential for Xenopus laevis convergent extension movements.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18809723","citation_count":93,"is_preprint":false},{"pmid":"7507487","id":"PMC_7507487","title":"The proto-oncogene of v-eyk (v-ryk) is a novel receptor-type protein tyrosine kinase with extracellular Ig/GN-III domains.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7507487","citation_count":93,"is_preprint":false},{"pmid":"21875946","id":"PMC_21875946","title":"Mindbomb 1, an E3 ubiquitin ligase, forms a complex with RYK to activate Wnt/β-catenin signaling.","date":"2011","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21875946","citation_count":85,"is_preprint":false},{"pmid":"19473059","id":"PMC_19473059","title":"Wnt-Ryk signaling mediates axon growth inhibition and limits functional recovery after spinal cord 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Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/12225882","citation_count":6,"is_preprint":false},{"pmid":"35715770","id":"PMC_35715770","title":"Comprehensive analysis reveals COPB2 and RYK associated with tumor stages of larynx squamous cell carcinoma.","date":"2022","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35715770","citation_count":3,"is_preprint":false},{"pmid":"40208942","id":"PMC_40208942","title":"Astrocytic Ryk signaling coordinates scarring and wound healing after spinal cord injury.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/40208942","citation_count":2,"is_preprint":false},{"pmid":"39382316","id":"PMC_39382316","title":"Wnt5a/Ryk signaling contributes to bone cancer pain by sensitizing the peripheral nociceptors through JNK-mediated TRPV1 pathway in rats.","date":"2024","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/39382316","citation_count":2,"is_preprint":false},{"pmid":"24975394","id":"PMC_24975394","title":"Function of the Ryk intracellular domain in C. elegans vulval development.","date":"2014","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/24975394","citation_count":1,"is_preprint":false},{"pmid":"41708863","id":"PMC_41708863","title":"RYK is a GPNMB receptor that drives MASH.","date":"2026","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/41708863","citation_count":0,"is_preprint":false},{"pmid":"39463959","id":"PMC_39463959","title":"Astrocytic Ryk signaling coordinates scarring and wound healing after spinal cord injury.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39463959","citation_count":0,"is_preprint":false},{"pmid":"41226636","id":"PMC_41226636","title":"Analysis of MSX1, RYK, NFκB p65, and CCL4 Proteins and MSX2, RYK, and PTX3 Genes in Human Cleft Lip Tissue.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41226636","citation_count":0,"is_preprint":false},{"pmid":"41963704","id":"PMC_41963704","title":"RYK silencing-modified bone marrow-derived mesenchymal stem cells suppress gastric cancer progression.","date":"2026","source":"In vitro cellular & developmental biology. 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The protein has a transmembrane domain, a small extracellular domain with N-linked glycosylation sites, and an intracellular kinase-related domain.\",\n      \"method\": \"cDNA cloning, sequence analysis, structural prediction\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (sequence/structure) / Weak — single foundational cloning paper, no functional assay\",\n      \"pmids\": [\"1334548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Human RYK protein contains a catalytic domain in which the conserved DFG motif is altered to DNA, and conserved residues in ATP-binding (subdomains I and II) and subdomain VI are changed, predicting catalytic inactivity. The gene maps to chromosome 3q22.\",\n      \"method\": \"cDNA cloning from ovarian cancer cell line, sequence analysis, chromosomal mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (sequence/structure) / Moderate — independently confirmed in two papers with consistent findings\",\n      \"pmids\": [\"8386829\", \"8390040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"H-RYK has impaired catalytic activity: using a chimeric receptor approach, H-RYK fails to undergo autophosphorylation or phosphorylate substrates in vitro. Amino acid substitutions in the activation domain account for the loss of catalytic activity. Despite this, ligand stimulation activates the MAPK pathway, and this signaling is abolished by mutation of the invariant lysine K334A in subdomain II.\",\n      \"method\": \"Chimeric receptor assay, in vitro kinase assay, site-directed mutagenesis, homology modelling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, chimeric receptor functional studies, multiple orthogonal methods in single study\",\n      \"pmids\": [\"10454588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Murine Ryk physically associates with EphB2 and EphB3 receptors and with the PDZ-domain protein AF-6 (Afadin), implicating Ryk in Eph receptor signal crosstalk and scaffold assembly. Ryk-null mice exhibit craniofacial defects and complete cleft palate, phenocopying Ephb2/Ephb3 double-mutant mice.\",\n      \"method\": \"Gene targeting (knockout mice), biochemical co-immunoprecipitation, genetic phenocopy analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype combined with biochemical Co-IP, genetic interaction with Eph receptors, multiple orthogonal methods\",\n      \"pmids\": [\"10932185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Human RYK associates with EphB2 and EphB3 (requiring both extracellular and cytoplasmic domains of RYK, independent of Eph receptor activation) but is not phosphorylated by them. Human RYK does NOT bind AF-6 in vitro or in vivo, contrasting with murine Ryk.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo), domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab Co-IP, single method; negative result on AF-6 binding is mechanistically informative\",\n      \"pmids\": [\"11956217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mammalian Ryk functions as a Wnt coreceptor together with Frizzled for Wnt ligands. Ryk binds directly to Dishevelled and through this interaction activates the canonical Wnt/TCF pathway. Ryk is required for Wnt-3a-induced neurite outgrowth and for Wnt-1-induced TCF activation. Transgenic mice expressing Ryk siRNA show axon guidance defects.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays (TCF/LEF), siRNA transgenic mice, neurite outgrowth assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function in vivo and in vitro, multiple orthogonal methods, replicated across contexts\",\n      \"pmids\": [\"15454084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"C. elegans LIN-18 is a Ryk ortholog whose WIF (Wnt inhibitory factor) extracellular domain is required for function, while the kinase domain is dispensable. LIN-18/Ryk functions in a parallel pathway to LIN-17/Frizzled in Wnt-mediated cell fate patterning during vulva development. Wnt ligands LIN-44, MOM-2, and CWN-2 redundantly regulate P7.p patterning.\",\n      \"method\": \"Genetic epistasis, domain deletion analysis, loss-of-function mutants in C. elegans\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with domain requirements, parallel pathway established by double-mutant analysis\",\n      \"pmids\": [\"15369677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ryk acts as a high-affinity receptor for Wnt ligands that mediates chemorepulsion of corticospinal tract (CST) axons. Wnts expressed in an anterior-to-posterior decreasing gradient in the spinal cord repel CST axons through Ryk expressed on these axons. Intrathecal anti-Ryk antibody blocked posterior growth of CST axons.\",\n      \"method\": \"Collagen gel repulsion assays, intrathecal antibody injection in neonatal mice, in vivo axon tracing\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro repulsion assay, in vivo antibody blockade with axon tracing, multiple orthogonal methods\",\n      \"pmids\": [\"16116452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Wnt5a acts as a chemorepulsive ligand for Ryk to drive callosal axons toward the contralateral hemisphere after crossing the midline. Loss of Ryk in mice impedes callosal axon escape from the midline and impairs fasciculation of axons before midline crossing, revealing Ryk as a guidance receptor for corpus callosum formation.\",\n      \"method\": \"Ryk knockout mice, in utero electroporation, axon tracing, repulsion assays\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mutant phenotype, direct assays of axon behavior, defined ligand-receptor pair\",\n      \"pmids\": [\"16723543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Wnt3 acts through Ryk (expressed in a ventral-to-dorsal decreasing gradient on retinal ganglion cell axons) to mediate repulsive responses during retinotectal topographic mapping along the medial-lateral axis. Dominant-negative Ryk in dorsal RGC axons caused medial shift of termination zones, while overexpression of Wnt3 in the lateral tectum repelled termination zones.\",\n      \"method\": \"In vivo overexpression and dominant-negative approaches, axon tracing, growth cone turning assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gain- and loss-of-function, direct topographic mapping analysis, multiple orthogonal methods\",\n      \"pmids\": [\"16280981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ryk is cleaved (by gamma-secretase) and its intracellular C-terminal fragment (ICD) translocates to the nucleus in response to Wnt3 stimulation. The cleaved Ryk ICD is required for Wnt3-induced neuronal differentiation both in vitro and in vivo during cortical neurogenesis.\",\n      \"method\": \"Biochemical cleavage assay, nuclear fractionation, gain/loss-of-function in neural progenitors, in utero electroporation\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — demonstrated proteolytic cleavage biochemically, nuclear translocation by fractionation, in vivo rescue experiments\",\n      \"pmids\": [\"19000841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ryk cooperates with Frizzled7 to mediate Wnt11-stimulated endocytosis of Dishevelled via beta-arrestin 2. Ryk interacts with both Wnt11 and beta-arrestin 2. Depletion of Ryk prevents Dvl endocytosis and impairs non-canonical Wnt11/Fz7-mediated CE movements in Xenopus gastrulation.\",\n      \"method\": \"Co-immunoprecipitation, morpholino knockdown in Xenopus, endocytosis assays, live imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, loss-of-function phenotype, endocytosis assay, multiple methods in single study\",\n      \"pmids\": [\"18809723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila Src family kinases SRC64B and SRC42A are required for WNT5-mediated signaling through Derailed (RYK ortholog). Derailed and SRC64B form a complex; this complex contains catalytically active SRC64B and requires SRC64B kinase activity for complex formation/stability. Derailed is phosphorylated in a SRC64B-dependent manner, and coexpression activates SRC64B. Mammalian RYK and the SRC64B ortholog also form complexes. WNT5/Derailed signaling does not regulate TCF/LEF-dependent transcription.\",\n      \"method\": \"Genetic epistasis in Drosophila, co-immunoprecipitation, phosphorylation assays, dominant gain-of-function suppression\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical complex formation, phosphorylation assay, genetic epistasis, conservation confirmed in mammalian cells\",\n      \"pmids\": [\"18539923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ryk ICD undergoes ubiquitination and proteasomal degradation. Cdc37 (a subunit of the Hsp90 chaperone complex) interacts with Ryk ICD, inhibits its proteasomal degradation, and promotes its nuclear localization. Overexpression of Cdc37 increases Ryk ICD levels and nuclear localization; knockdown reduces Ryk ICD stability. The Cdc37-Ryk ICD complex is disrupted during neural differentiation of embryonic stem cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, nuclear fractionation, overexpression and knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical Co-IP, ubiquitination assay, nuclear fractionation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"19269974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Wnt5b signals through Ryk (not through Frizzled2) to provide directional cues for cell migration during zebrafish gastrulation. Ryk deficiency impairs Wnt5b-induced Ca2+ activity and directional cell protrusions. Fz2 recruits Dvl to the membrane upon Wnt5b stimulation, while Ryk mediates a separate pathway leading to directed cell migration away from the Wnt5b source.\",\n      \"method\": \"Morpholino knockdown in zebrafish, co-culture directional migration assays, Ca2+ imaging, cell protrusion analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo morpholino KD, directional co-culture assay, Ca2+ signaling readout, multiple orthogonal methods\",\n      \"pmids\": [\"20660632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ryk promotes GABAergic neuron production while repressing oligodendrocyte formation in the ventral telencephalon by negatively regulating Olig2 expression and inducing Dlx2. The cleaved intracellular domain of Ryk is sufficient to regulate this cell-fate switch. Ryk is required for GABAergic neuron induction by Wnt3a.\",\n      \"method\": \"Ryk knockout mice, in utero electroporation of Ryk ICD, in vitro neural progenitor cultures, immunostaining\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype, ICD gain-of-function rescue, defined transcriptional targets, multiple methods\",\n      \"pmids\": [\"21205786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MIB1 (Mindbomb 1), an E3 ubiquitin ligase, physically and functionally interacts with RYK. MIB1 promotes ubiquitination of RYK and reduces its steady-state levels at the plasma membrane. MIB1 is sufficient to activate Wnt/β-catenin signaling in an endogenous RYK-dependent manner. Both RYK and MIB1 are required for Wnt-3A-mediated β-catenin activation. In C. elegans, ceMIB genetically interacts with lin-18/RYK in vulva development.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, plasma membrane localization assay, knockdown/overexpression, genetic interaction in C. elegans\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical ubiquitination assay, Co-IP, functional epistasis in mammals and C. elegans, multiple orthogonal methods\",\n      \"pmids\": [\"21875946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ryk interacts with Vangl2 both genetically and biochemically; this interaction is potentiated by Wnt5a. Ryk regulates PCP signaling by promoting Vangl2 stability. Loss of Ryk in a Vangl2+/- background causes PCP defects including open neural tube, inner ear hair cell misalignment, and shortened limbs. Ryk transduces Wnt5a signaling by forming a complex with Vangl2. Ryk also activates RhoA, a downstream PCP effector.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis (double heterozygote analysis), knockout mice, immunostaining of inner ear\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical Co-IP, double-mutant genetic epistasis, multiple PCP phenotypic readouts, multiple labs and papers\",\n      \"pmids\": [\"23144463\", \"22773843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ryk ICD (generated by gamma-secretase cleavage) represses neuroprotective FOXO activity by binding to the FOXO co-factor beta-catenin. Ryk-ICD fragment suppresses neuroprotection in expanded-polyQ nematodes and represses FOXO transcriptional activity. Reducing gamma-secretase PS1 levels compensated for Ryk cytotoxicity in mutant HTT cells.\",\n      \"method\": \"C. elegans genetics, mouse striatal cell culture, FOXO reporter assays, gamma-secretase modulation, Co-IP implied by binding claims\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional assays in two organisms, FOXO reporter, loss-of-function rescue, but binding claims not fully detailed in abstract\",\n      \"pmids\": [\"24960609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Wnt5a signals through Ryk to disrupt endothelial barrier function via downstream ROCK/LIMK2/CFL1 signaling, leading to stress fiber formation (actin polymerization), disruption of β-catenin and VE-cadherin adherens junctions, and enhanced endothelial permeability. Ryk silencing completely prevented Wnt5a-induced endothelial hyperpermeability. WIF1 (which interferes with the WIF domain of Ryk) prevented actin polymerization.\",\n      \"method\": \"siRNA knockdown, trans-endothelial resistance measurement, WIF1 antagonist, live cell imaging of cytoskeletal rearrangements, phosphoprotein analysis\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with specific pathway readouts, WIF domain antagonist controls, multiple assays\",\n      \"pmids\": [\"27159116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ryk acts as a negative regulator of dendrite morphogenesis. Loss of Ryk in hippocampal and cortical neurons promotes excessive dendrite growth and branching in vitro; overexpression restricts these processes. A membrane-proximal subdomain is crucial for Ryk-mediated suppression of dendrite morphogenesis. Ryk haploinsufficient mice exhibit excessive dendrite growth and branching in layer 2/3 pyramidal neurons in vivo.\",\n      \"method\": \"KO/knockdown and overexpression in dissociated neurons, domain deletion analysis, in vivo morphological analysis of cortical neurons\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional (KO + OE) functional analysis, domain requirement identified, in vivo confirmation\",\n      \"pmids\": [\"28729735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Smek1/2 are nuclear chaperones and cofactors for the cleaved Ryk ICD. Smek1/2 interact with Ryk-ICD, regulate its nuclear localization, and cooperate with it to bind the Dlx1/2 intergenic regulatory element and regulate transcription. Smek1/2 double-KO mice show defects in cortical neuron production and increased neural stem cells.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, chromatin immunoprecipitation, knockout mice, transcriptional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biochemical Co-IP, ChIP at target gene, KO phenotype, nuclear localization experiments, multiple orthogonal methods\",\n      \"pmids\": [\"29180410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ryk modulates PCP signaling in CST axon guidance through asymmetric regulation of Vangl2 distribution. Under high Wnt5a concentrations, cytoplasmic Ryk increases and promotes cytoplasmic redistribution of Vangl2, inhibiting Frizzled3 cytoplasmic translocation. Under low Wnt5a, Ryk stabilizes Vangl2 at the plasma membrane, promoting Frizzled3 cytoplasmic translocation.\",\n      \"method\": \"In vivo CST tracing, in vitro biochemical fractionation, dominant-negative and overexpression approaches\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vivo and in vitro analyses, biochemical fractionation, single lab but multiple readouts\",\n      \"pmids\": [\"28660073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RYK functions as a WNT coreceptor in airway epithelial cells to restrict goblet cell differentiation and maintain airway epithelial cell balance. Epithelial-specific Ryk deletion causes goblet cell hyperplasia and mucus hypersecretion. Club cell-specific Ryk deletion leads to goblet cell hyperplasia during airway regeneration. Ryk promotes WNT/β-catenin signaling in the lung epithelium.\",\n      \"method\": \"Cell-type-specific conditional knockout (Cre-lox), transcriptomic analysis, morphological analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO, defined phenotypic readouts, transcriptomic follow-up\",\n      \"pmids\": [\"31776260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Non-canonical Wnt-Ryk signaling (via Ryk ICD) regulates specification of somatostatin (SST)- versus parvalbumin (PV)-expressing cortical interneurons in a dose-dependent manner. Ryk gain-of-function ICD signaling regulates SST and PV fate. This acts through non-canonical signaling, not canonical β-catenin.\",\n      \"method\": \"In utero electroporation (gain-of-function of Ryk ICD), conditional KO, in vivo interneuron fate analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain- and loss-of-function, direct cell fate readout, ICD-specific experiments distinguish canonical vs. non-canonical\",\n      \"pmids\": [\"31257105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WNT5A-RYK signaling acts as a navigation system for post-mitotic daughter cells to extend basally oriented filopodial protrusions during midgut elongation. Loss of Ryk phenocopies the Wnt5a-/- phenotype, perturbing filopodial pathfinding and leading to apoptosis. Epithelial ROR2 is dispensable for this process, establishing RYK as the specific WNT5A receptor in this context.\",\n      \"method\": \"Ryk knockout mice, Wnt5a knockout comparison, live imaging of filopodial dynamics, genetic ablation of ROR2\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenocopy of ligand mutant, parallel receptor KO as negative control, direct imaging readout\",\n      \"pmids\": [\"32994164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of the extracellular regions of Drosophila RYK ortholog Derailed-2 (Drl-2) reveal that the WIF domain lacks the lipid-binding site seen in WIF-1, and cannot accommodate the acyl chain typically attached to WNTs. Despite lacking an acyl chain, recombinant DWnt-5 can bind the Drosophila RYK ortholog. These structures provide insight into how WNTs recruit RYK into signaling complexes.\",\n      \"method\": \"X-ray crystallography, WNT-binding assays, hydrogen-deuterium exchange analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination plus binding assays; Drosophila ortholog but directly informative for RYK WIF domain mechanism\",\n      \"pmids\": [\"34686333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WNT/RYK signaling in lung mesenchymal cells acts as an anti-inflammatory modulator and cell survival factor. Mesenchymal-specific Ryk deletion leads to lung hypoplasia, inflammation, alveolar simplification, and upregulation of pro-apoptotic and inflammatory genes. RYK signaling acts through β-catenin and NF-κB to suppress mesenchymal cell death and excessive inflammatory cytokine production.\",\n      \"method\": \"Mesenchyme-specific conditional knockout (Cre-lox), single-cell transcriptomics, in vitro signaling assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO, scRNA-seq, in vitro pathway validation, multiple readouts\",\n      \"pmids\": [\"35671428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ryk expression is induced in astrocytes after spinal cord injury. Astrocyte-specific knockout of Ryk elongates reactive astrocytes, accelerates glial border formation, reduces scar size, and accelerates multi-cell-type injury responses. Elongation of astrocyte processes after Ryk KO is mediated by NrCAM (a cell adhesion molecule induced by Ryk KO). Ryk thus negatively regulates astrocyte morphological remodeling after injury.\",\n      \"method\": \"Astrocyte-specific conditional knockout (Cre-lox), single-cell transcriptomics, immunostaining, morphological analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO, scRNA-seq, identification of downstream mediator NrCAM, multiple orthogonal readouts\",\n      \"pmids\": [\"40208942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RYK is identified as a functional receptor for the GPNMB ectodomain (G-ECD). G-ECD binding to RYK activates ERK1/2 signaling, which transcriptionally activates PPARγ-CD36 and SREBP1C pathways, promoting hepatic lipid uptake and lipogenesis leading to MASH. Hepatocyte-specific Ryk ablation protects mice against MASH and abolishes pathogenic effects of G-ECD. RYK was identified via unbiased screen of cell-surface-displayed transmembrane protein library.\",\n      \"method\": \"Unbiased cell-surface protein library screen, hepatocyte-specific conditional knockout, ERK1/2 phosphorylation assays, transcriptional target analysis, in vivo MASH models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — unbiased receptor identification screen, conditional KO confirmation, defined signaling pathway (ERK→PPARγ/SREBP1C), multiple therapeutic interventions tested\",\n      \"pmids\": [\"41708863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Wnt5a expression is induced in reactive astrocytes around spinal cord injury sites. In vitro, Wnt5a inhibits neurite growth of postnatal cerebellar neurons by activating RhoA/Rho-kinase through Ryk. Intrathecal anti-Ryk antibody in rats with thoracic contusion resulted in significant CST axonal growth and enhanced functional recovery.\",\n      \"method\": \"In vitro neurite growth assay with RhoA/ROCK inhibitors, intrathecal antibody injection in spinal cord injury model, axon tracing\",\n      \"journal\": \"Journal of neurotrauma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro mechanistic pathway (RhoA/ROCK), in vivo antibody blockade with functional readout, single lab\",\n      \"pmids\": [\"19473059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RYK binds EphB3 through its extracellular leucine-rich motif region; deletion of the LRM-containing extracellular region abolishes EphB3 binding. Overexpression of RYK suppresses cell migration from the ventricular zone in cortical slice cultures, while the LRM deletion mutant (which cannot bind EphB3) has no effect on migration.\",\n      \"method\": \"Co-immunoprecipitation with domain deletion mutants, cortical slice electroporation, cell migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — domain-deletion Co-IP, in vitro functional slice culture, single lab two methods\",\n      \"pmids\": [\"15796903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Wnt5b/Ryk signaling promotes trafficking of P2X3 receptors to the membrane of DRG neurons via CaMKII activation, resulting in enhanced α,β-meATP-induced currents and peripheral sensitization contributing to bone cancer pain. Anti-Ryk antibody prevented Wnt5b-induced mechanical allodynia and thermal hyperalgesia and blocked the upregulation of membrane P2X3.\",\n      \"method\": \"In vitro DRG neuron electrophysiology, Western blot of membrane fractions, intrathecal antibody injection, CaMKII inhibitor\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology, membrane fractionation, in vivo antibody blockade, CaMKII pathway defined\",\n      \"pmids\": [\"32979370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ryk modulates the hematopoiesis-supporting niche activity of bone marrow mesenchymal stromal cells (MSCs) by fine-tuning canonical Wnt signaling intensity: Ryk promotes Wnt target gene transactivation at low Wnt concentrations but suppresses it at high concentrations. This Wnt-modulating effect requires both the extracellular and intracellular (pseudokinase-containing) domains of Ryk.\",\n      \"method\": \"siRNA knockdown and overexpression in MSCs, Wnt reporter assays, hematopoietic progenitor co-culture, domain deletion analysis\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional reporter assays, domain deletion, co-culture readout, single lab\",\n      \"pmids\": [\"32724069\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RYK is a catalytically inactive (pseudokinase) single-pass transmembrane receptor that binds Wnt ligands (including Wnt1, Wnt3a, Wnt5a, Wnt5b, Wnt11, GPNMB ectodomain) through its extracellular WIF domain, and signals through multiple mechanisms: (1) as a Wnt coreceptor with Frizzled, coupling to Dishevelled to activate canonical Wnt/β-catenin and TCF signaling; (2) through gamma-secretase-mediated cleavage releasing the intracellular domain (ICD) for nuclear translocation, where it acts with Smek1/2 as a transcriptional co-regulator of cell fate genes; (3) through recruitment of Src family kinases (e.g., SRC64B) that phosphorylate Ryk and transduce non-canonical signals; (4) through complex formation with Vangl2 to regulate PCP signaling; (5) by interacting with beta-arrestin 2 and Frizzled to mediate endocytosis-dependent non-canonical Wnt signaling; and (6) through ERK1/2 activation downstream of novel ligands such as the GPNMB ectodomain. The Ryk ICD is stabilized by Cdc37/Hsp90 and degraded via ubiquitin-proteasome pathway; its ubiquitination is also promoted by the E3 ligase MIB1, which reduces plasma membrane Ryk levels and couples receptor internalization to Wnt/β-catenin activation. Physiologically, Ryk functions as a chemorepulsive axon guidance receptor in the CNS, regulates neural progenitor cell fate and interneuron subtype specification, restricts dendrite arborization, controls epithelial cell behavior in the lung and gut, and acts as an anti-inflammatory modulator in lung mesenchyme; while pathologically, Ryk inhibits axonal regeneration after spinal cord injury, promotes MASH via GPNMB-ERK-PPARγ/SREBP1C signaling, and modulates neuropathic and cancer pain through Wnt5a/Wnt5b-mediated sensitization of sensory neurons.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RYK is a catalytically inactive (pseudokinase) single-pass transmembrane receptor that transduces Wnt-family signals to control axon guidance, neural cell-fate decisions, epithelial behavior, and planar cell polarity [#2, #5, #7]. Cloning and sequence analysis established that its kinase-related cytoplasmic domain carries idiosyncratic substitutions in the conserved ATP-binding and DFG/activation motifs, and chimeric-receptor and in vitro kinase assays confirmed it cannot autophosphorylate or phosphorylate substrates, yet still activates the MAPK pathway in a manner dependent on the invariant subdomain-II lysine [#0, #1, #2]. RYK binds Wnt ligands through its extracellular WIF domain and functions as a Wnt coreceptor with Frizzled, binding Dishevelled to drive canonical Wnt/TCF signaling [#5, #26]. A central regulatory event is gamma-secretase cleavage that releases the intracellular domain (ICD), which translocates to the nucleus and, together with the cofactors Smek1/2, occupies the Dlx1/2 regulatory element to govern cortical neurogenesis, GABAergic-versus-oligodendrocyte fate, and interneuron subtype specification by modulating Olig2 and Dlx2 [#10, #15, #21, #24]; ICD stability is set by Cdc37/Hsp90-mediated protection from ubiquitin-proteasome degradation [#13]. The E3 ligase MIB1 ubiquitinates RYK, reduces its plasma-membrane levels, and couples this to Wnt/β-catenin activation [#16]. As a chemorepulsive axon guidance receptor, RYK reads anterior-to-posterior and dorsoventral Wnt gradients (Wnt5a, Wnt3) to repel corticospinal, callosal, and retinal ganglion cell axons, acting through RhoA/Rho-kinase and through asymmetric regulation of the PCP component Vangl2, whose stability and localization RYK controls in complex with it [#7, #8, #9, #17, #22, #30]. RYK also engages non-canonical branches: it recruits Src-family kinases that phosphorylate it (Drosophila SRC64B/Derailed), cooperates with Frizzled and beta-arrestin 2 to drive Dishevelled endocytosis in convergent-extension movements, and signals via Wnt5b independently of Frizzled to direct cell migration [#11, #12, #14]. Physiologically RYK restricts goblet-cell differentiation in airway epithelium and acts as an anti-inflammatory survival factor in lung mesenchyme via β-catenin and NF-κB, while in disease it limits axon regeneration and astrocyte remodeling after spinal cord injury, mediates Wnt5b-driven sensory-neuron sensitization in cancer pain, and serves as the receptor for the GPNMB ectodomain that activates ERK1/2–PPARγ/SREBP1C signaling to promote hepatic lipogenesis and MASH [#23, #27, #28, #29, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing whether RYK is a conventional active kinase was the first question, since its receptor-tyrosine-kinase-like architecture implied catalytic signaling; sequence analysis revealed degenerate catalytic motifs predicting it is a pseudokinase.\",\n      \"evidence\": \"cDNA cloning and sequence/structural analysis, with chromosomal mapping to 3q22\",\n      \"pmids\": [\"1334548\", \"8386829\", \"8390040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic inactivity inferred from sequence, not yet tested functionally\", \"No ligand or signaling partner identified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Whether a kinase-dead receptor could still signal was unresolved; chimeric-receptor and in vitro kinase assays confirmed RYK cannot autophosphorylate but still activates MAPK in a manner requiring the invariant subdomain-II lysine, defining it as a signaling-competent pseudokinase.\",\n      \"evidence\": \"Chimeric receptor assay, in vitro kinase assay, site-directed mutagenesis, homology modelling\",\n      \"pmids\": [\"10454588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand identity unknown at this stage\", \"Mechanism linking inactive kinase domain to MAPK activation not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Early interactome work asked how RYK couples to other receptors; Co-IP placed RYK in complexes with EphB2/EphB3 (via both extra- and intracellular domains) and revealed species divergence in AF-6 binding, hinting at scaffolding roles distinct from catalysis.\",\n      \"evidence\": \"Co-immunoprecipitation and domain deletion in murine and human cells, plus Ryk-null mouse craniofacial phenocopy of Eph mutants\",\n      \"pmids\": [\"10932185\", \"11956217\", \"15796903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Eph association not fully resolved\", \"Human/mouse discrepancy in AF-6 binding unexplained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The defining advance identified RYK's ligand and pathway: it acts as a Wnt coreceptor with Frizzled, binds Dishevelled, and is required for canonical Wnt/TCF activation and Wnt-3a-induced neurite outgrowth, with the WIF domain (not the kinase domain) being essential as shown in the C. elegans ortholog LIN-18.\",\n      \"evidence\": \"Reciprocal Co-IP, TCF/LEF reporters, siRNA transgenic mice, neurite assays, and genetic epistasis with domain deletion in C. elegans\",\n      \"pmids\": [\"15454084\", \"15369677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a pseudokinase relays the Dvl signal mechanistically unresolved\", \"Relationship between canonical and non-canonical branches unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"How RYK directs axons was addressed by showing it is a high-affinity Wnt receptor mediating chemorepulsion along anteroposterior and dorsoventral gradients in corticospinal, callosal, and retinal axons, with antibody blockade and gradient manipulations confirming directional guidance.\",\n      \"evidence\": \"Collagen-gel repulsion, intrathecal anti-Ryk antibody, in vivo axon tracing, in utero electroporation, growth-cone turning, RhoA/ROCK inhibitor analysis\",\n      \"pmids\": [\"16116452\", \"16723543\", \"16280981\", \"19473059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular effectors downstream of repulsion only partly defined (RhoA/ROCK)\", \"How a graded Wnt input is converted to directional cytoskeletal response not fully mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The route from membrane receptor to nuclear effector was established: gamma-secretase cleaves RYK to release an ICD that translocates to the nucleus to drive Wnt3-induced neuronal differentiation, and Cdc37/Hsp90 was shown to stabilize the ICD against proteasomal degradation.\",\n      \"evidence\": \"Biochemical cleavage assays, nuclear fractionation, in utero electroporation, ubiquitination assays, proteasome inhibition, Co-IP\",\n      \"pmids\": [\"19000841\", \"19269974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of the ICD not yet identified in these studies\", \"Stoichiometry and regulation of cleavage in vivo unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The nuclear function and turnover of RYK were mechanistically expanded: the ICD controls a GABAergic-versus-oligodendrocyte cell-fate switch via Olig2/Dlx2, and the E3 ligase MIB1 ubiquitinates RYK, lowers its surface levels, and couples this to Wnt/β-catenin activation.\",\n      \"evidence\": \"Ryk-KO mice, ICD in utero electroporation, neural progenitor cultures, ubiquitination assays, Co-IP, and C. elegans genetic interaction\",\n      \"pmids\": [\"21205786\", \"21875946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How membrane RYK levels quantitatively tune β-catenin output not fully resolved\", \"Direct DNA-binding partners of the ICD at fate genes not yet defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"RYK's role in non-canonical planar cell polarity was defined through its physical and genetic interaction with Vangl2, which it stabilizes in a Wnt5a-potentiated manner, with double-heterozygote phenotypes (open neural tube, hair-cell misalignment) and RhoA activation establishing PCP function.\",\n      \"evidence\": \"Co-IP, double-heterozygote genetic epistasis, knockout mice, inner-ear immunostaining, in vivo CST tracing with fractionation\",\n      \"pmids\": [\"23144463\", \"22773843\", \"28660073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RYK switches Vangl2 between membrane and cytoplasm at different Wnt5a doses incompletely defined\", \"Link between Vangl2 regulation and RhoA activation not fully mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Non-canonical signaling modules were extended by showing RYK recruits Src-family kinases that phosphorylate it (SRC64B/Derailed), cooperates with Frizzled and beta-arrestin 2 to drive Dishevelled endocytosis during convergent extension, and signals via Wnt5b for directed migration independently of Frizzled2.\",\n      \"evidence\": \"Drosophila genetic epistasis, Co-IP and phosphorylation assays, Xenopus and zebrafish morpholino knockdown, endocytosis and Ca2+ imaging assays\",\n      \"pmids\": [\"18539923\", \"18809723\", \"20660632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a kinase-dead receptor is phosphorylated and what the phosphosites signal to in mammals unclear\", \"Integration of the multiple non-canonical branches into one model unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The nuclear cofactor machinery and additional neuronal roles were defined: Smek1/2 chaperone the ICD to the Dlx1/2 element to regulate transcription and cortical neuron production, and RYK was shown to restrict dendrite arborization via a membrane-proximal subdomain.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, ChIP at Dlx1/2, Smek1/2 KO mice, plus bidirectional KO/overexpression and domain-deletion in neurons with in vivo confirmation\",\n      \"pmids\": [\"29180410\", \"28729735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full transcriptional target repertoire of the ICD-Smek1/2 complex unknown\", \"How the membrane-proximal subdomain restrains dendrites mechanistically undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"RYK's physiological roles in epithelia and mesenchyme were established through cell-type-specific deletion: it restricts goblet-cell differentiation in airway epithelium via Wnt/β-catenin and acts as an anti-inflammatory survival factor in lung mesenchyme via β-catenin and NF-κB, while also guiding filopodial pathfinding in midgut elongation as the specific WNT5A receptor.\",\n      \"evidence\": \"Conditional Cre-lox knockouts, single-cell and bulk transcriptomics, live imaging, ROR2-ablation control, in vitro signaling assays\",\n      \"pmids\": [\"31776260\", \"35671428\", \"32994164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RYK suppresses NF-κB-driven inflammation not detailed\", \"How RYK selectively reads WNT5A over other receptors in each tissue unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pathological roles in injury and metabolic disease were defined: RYK limits astrocyte remodeling after spinal cord injury via NrCAM, contributes to Wnt5b-driven sensory-neuron sensitization in cancer pain via P2X3/CaMKII, and was identified by unbiased screen as the GPNMB-ectodomain receptor that activates ERK1/2–PPARγ/SREBP1C to drive hepatic lipogenesis and MASH.\",\n      \"evidence\": \"Astrocyte- and hepatocyte-specific conditional knockouts, single-cell transcriptomics, DRG electrophysiology, membrane fractionation, cell-surface protein library screen, ERK phosphorylation and transcriptional target analysis\",\n      \"pmids\": [\"40208942\", \"32979370\", \"41708863\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GPNMB-ERK signaling is independent of or convergent with Wnt/RYK signaling unresolved\", \"Whether RYK is therapeutically tractable across these disease contexts untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single pseudokinase receptor integrates canonical Wnt/β-catenin, non-canonical PCP/Src/beta-arrestin, gamma-secretase/ICD-nuclear, and ERK1/2 (GPNMB) outputs into context-specific cellular responses remains the central open question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified structural model of how ligand binding selects among downstream branches\", \"Quantitative rules linking Wnt/ligand dose to canonical-versus-non-canonical output undefined\", \"Lack of a mechanism explaining how the catalytically dead intracellular domain transduces phosphorylation-dependent signals\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 7, 29]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [5, 29]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 21, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [10, 21, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 7, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 13, 21]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [22, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 16, 29]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8, 9, 15, 24]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 8, 20, 24]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FZD7\", \"DVL\", \"VANGL2\", \"SMEK1\", \"CDC37\", \"MIB1\", \"ARRB2\", \"EPHB3\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}