Affinage

RYK

Tyrosine-protein kinase RYK · UniProt P34925

Length
607 aa
Mass
67.8 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1993 Medium

    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

    PMID:1334548 PMID:8386829 PMID:8390040

    Open questions at the time
    • Catalytic inactivity inferred from sequence, not yet tested functionally
    • No ligand or signaling partner identified
  2. 1999 High

    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

    PMID:10454588

    Open questions at the time
    • Ligand identity unknown at this stage
    • Mechanism linking inactive kinase domain to MAPK activation not defined
  3. 2002 Medium

    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

    PMID:10932185 PMID:11956217 PMID:15796903

    Open questions at the time
    • Functional consequence of Eph association not fully resolved
    • Human/mouse discrepancy in AF-6 binding unexplained
  4. 2004 High

    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

    PMID:15369677 PMID:15454084

    Open questions at the time
    • How a pseudokinase relays the Dvl signal mechanistically unresolved
    • Relationship between canonical and non-canonical branches unclear
  5. 2009 High

    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

    PMID:16116452 PMID:16280981 PMID:16723543 PMID:19473059

    Open questions at the time
    • Intracellular effectors downstream of repulsion only partly defined (RhoA/ROCK)
    • How a graded Wnt input is converted to directional cytoskeletal response not fully mapped
  6. 2009 High

    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

    PMID:19000841 PMID:19269974

    Open questions at the time
    • Direct transcriptional targets of the ICD not yet identified in these studies
    • Stoichiometry and regulation of cleavage in vivo unclear
  7. 2011 High

    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

    PMID:21205786 PMID:21875946

    Open questions at the time
    • 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
  8. 2012 High

    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

    PMID:22773843 PMID:23144463 PMID:28660073

    Open questions at the time
    • 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
  9. 2012 High

    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

    PMID:18539923 PMID:18809723 PMID:20660632

    Open questions at the time
    • 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
  10. 2017 High

    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

    PMID:28729735 PMID:29180410

    Open questions at the time
    • Full transcriptional target repertoire of the ICD-Smek1/2 complex unknown
    • How the membrane-proximal subdomain restrains dendrites mechanistically undefined
  11. 2022 High

    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

    PMID:31776260 PMID:32994164 PMID:35671428

    Open questions at the time
    • Mechanism by which RYK suppresses NF-κB-driven inflammation not detailed
    • How RYK selectively reads WNT5A over other receptors in each tissue unclear
  12. 2025 High

    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

    PMID:32979370 PMID:40208942 PMID:41708863

    Open questions at the time
    • Whether GPNMB-ERK signaling is independent of or convergent with Wnt/RYK signaling unresolved
    • Whether RYK is therapeutically tractable across these disease contexts untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0001618 virus receptor activity 2
Localization
GO:0005634 nucleus 3 GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-1430728 Metabolism 1
Partners
ARRB2CDC37DVLEPHB3FZD7MIB1SMEK1VANGL2

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 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. cDNA cloning, sequence analysis, structural prediction Proceedings of the National Academy of Sciences of the United States of America Medium 1334548
1993 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. cDNA cloning from ovarian cancer cell line, sequence analysis, chromosomal mapping Oncogene Medium 8386829 8390040
1999 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. Chimeric receptor assay, in vitro kinase assay, site-directed mutagenesis, homology modelling Molecular and cellular biology High 10454588
2000 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. Gene targeting (knockout mice), biochemical co-immunoprecipitation, genetic phenocopy analysis Nature genetics High 10932185
2002 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. Co-immunoprecipitation (in vitro and in vivo), domain deletion analysis The Journal of biological chemistry Medium 11956217
2004 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. Co-immunoprecipitation, reporter assays (TCF/LEF), siRNA transgenic mice, neurite outgrowth assays Cell High 15454084
2004 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. Genetic epistasis, domain deletion analysis, loss-of-function mutants in C. elegans Cell High 15369677
2005 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. Collagen gel repulsion assays, intrathecal antibody injection in neonatal mice, in vivo axon tracing Nature neuroscience High 16116452
2006 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. Ryk knockout mice, in utero electroporation, axon tracing, repulsion assays The Journal of neuroscience : the official journal of the Society for Neuroscience High 16723543
2006 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. In vivo overexpression and dominant-negative approaches, axon tracing, growth cone turning assays Nature High 16280981
2008 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. Biochemical cleavage assay, nuclear fractionation, gain/loss-of-function in neural progenitors, in utero electroporation Developmental cell High 19000841
2008 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. Co-immunoprecipitation, morpholino knockdown in Xenopus, endocytosis assays, live imaging The Journal of cell biology High 18809723
2008 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. Genetic epistasis in Drosophila, co-immunoprecipitation, phosphorylation assays, dominant gain-of-function suppression Development (Cambridge, England) High 18539923
2009 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. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, nuclear fractionation, overexpression and knockdown The Journal of biological chemistry High 19269974
2010 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. Morpholino knockdown in zebrafish, co-culture directional migration assays, Ca2+ imaging, cell protrusion analysis The Journal of cell biology High 20660632
2011 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. Ryk knockout mice, in utero electroporation of Ryk ICD, in vitro neural progenitor cultures, immunostaining Development (Cambridge, England) High 21205786
2011 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. Co-immunoprecipitation, ubiquitination assay, plasma membrane localization assay, knockdown/overexpression, genetic interaction in C. elegans The Journal of cell biology High 21875946
2012 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. Co-immunoprecipitation, genetic epistasis (double heterozygote analysis), knockout mice, immunostaining of inner ear The Journal of biological chemistry High 22773843 23144463
2014 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. C. elegans genetics, mouse striatal cell culture, FOXO reporter assays, gamma-secretase modulation, Co-IP implied by binding claims PLoS biology Medium 24960609
2015 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. siRNA knockdown, trans-endothelial resistance measurement, WIF1 antagonist, live cell imaging of cytoskeletal rearrangements, phosphoprotein analysis Cell adhesion & migration Medium 27159116
2017 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. KO/knockdown and overexpression in dissociated neurons, domain deletion analysis, in vivo morphological analysis of cortical neurons Scientific reports High 28729735
2017 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. Co-immunoprecipitation, nuclear fractionation, chromatin immunoprecipitation, knockout mice, transcriptional reporter assays Proceedings of the National Academy of Sciences of the United States of America High 29180410
2017 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. In vivo CST tracing, in vitro biochemical fractionation, dominant-negative and overexpression approaches Cell discovery Medium 28660073
2019 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. Cell-type-specific conditional knockout (Cre-lox), transcriptomic analysis, morphological analysis Proceedings of the National Academy of Sciences of the United States of America High 31776260
2019 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. In utero electroporation (gain-of-function of Ryk ICD), conditional KO, in vivo interneuron fate analysis Neuron High 31257105
2020 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. Ryk knockout mice, Wnt5a knockout comparison, live imaging of filopodial dynamics, genetic ablation of ROR2 Development (Cambridge, England) High 32994164
2021 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. X-ray crystallography, WNT-binding assays, hydrogen-deuterium exchange analysis Cell reports High 34686333
2022 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. Mesenchyme-specific conditional knockout (Cre-lox), single-cell transcriptomics, in vitro signaling assays Proceedings of the National Academy of Sciences of the United States of America High 35671428
2025 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. Astrocyte-specific conditional knockout (Cre-lox), single-cell transcriptomics, immunostaining, morphological analysis Proceedings of the National Academy of Sciences of the United States of America High 40208942
2026 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. Unbiased cell-surface protein library screen, hepatocyte-specific conditional knockout, ERK1/2 phosphorylation assays, transcriptional target analysis, in vivo MASH models Nature High 41708863
2009 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. In vitro neurite growth assay with RhoA/ROCK inhibitors, intrathecal antibody injection in spinal cord injury model, axon tracing Journal of neurotrauma Medium 19473059
2005 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. Co-immunoprecipitation with domain deletion mutants, cortical slice electroporation, cell migration assay Biochemical and biophysical research communications Medium 15796903
2020 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. In vitro DRG neuron electrophysiology, Western blot of membrane fractions, intrathecal antibody injection, CaMKII inhibitor Experimental neurology Medium 32979370
2020 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. siRNA knockdown and overexpression in MSCs, Wnt reporter assays, hematopoietic progenitor co-culture, domain deletion analysis Experimental & molecular medicine Medium 32724069

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell 360 15454084
2006 Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping. Nature 229 16280981
2005 Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract. Nature neuroscience 219 16116452
2006 The Wnt receptor Ryk is required for Wnt5a-mediated axon guidance on the contralateral side of the corpus callosum. The Journal of neuroscience : the official journal of the Society for Neuroscience 190 16723543
2014 The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction. Cold Spring Harbor perspectives in biology 159 24370848
2004 C. elegans LIN-18 is a Ryk ortholog and functions in parallel to LIN-17/Frizzled in Wnt signaling. Cell 153 15369677
2000 Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nature genetics 142 10932185
1992 RYK, a receptor tyrosine kinase-related molecule with unusual kinase domain motifs. Proceedings of the National Academy of Sciences of the United States of America 121 1334548
2008 Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis. Developmental cell 108 19000841
2012 The Wnt coreceptor Ryk regulates Wnt/planar cell polarity by modulating the degradation of the core planar cell polarity component Vangl2. The Journal of biological chemistry 103 23144463
2008 Ryk cooperates with Frizzled 7 to promote Wnt11-mediated endocytosis and is essential for Xenopus laevis convergent extension movements. The Journal of cell biology 93 18809723
1994 The proto-oncogene of v-eyk (v-ryk) is a novel receptor-type protein tyrosine kinase with extracellular Ig/GN-III domains. The Journal of biological chemistry 93 7507487
2011 Mindbomb 1, an E3 ubiquitin ligase, forms a complex with RYK to activate Wnt/β-catenin signaling. The Journal of cell biology 85 21875946
2016 Ryk controls remapping of motor cortex during functional recovery after spinal cord injury. Nature neuroscience 78 27065364
2015 Wnt/Ryk signaling contributes to neuropathic pain by regulating sensory neuron excitability and spinal synaptic plasticity in rats. Pain 78 26407042
2009 Wnt-Ryk signaling mediates axon growth inhibition and limits functional recovery after spinal cord injury. Journal of neurotrauma 78 19473059
2012 The Wnt receptor Ryk plays a role in mammalian planar cell polarity signaling. The Journal of biological chemistry 70 22773843
2010 Wnt5b-Ryk pathway provides directional signals to regulate gastrulation movement. The Journal of cell biology 69 20660632
2008 Src family kinases are required for WNT5 signaling through the Derailed/RYK receptor in the Drosophila embryonic central nervous system. Development (Cambridge, England) 67 18539923
1999 Functional analysis of H-Ryk, an atypical member of the receptor tyrosine kinase family. Molecular and cellular biology 67 10454588
2011 Antagonism of LIN-17/Frizzled and LIN-18/Ryk in nematode vulva induction reveals evolutionary alterations in core developmental pathways. PLoS biology 64 21814488
1992 A novel oncogene, v-ryk, encoding a truncated receptor tyrosine kinase is transduced into the RPL30 virus without loss of viral sequences. Journal of virology 56 1527848
2014 Wnt5a regulates hematopoietic stem cell proliferation and repopulation through the Ryk receptor. Stem cells (Dayton, Ohio) 55 23939973
1995 The Drosophila learning and memory gene linotte encodes a putative receptor tyrosine kinase homologous to the human RYK gene product. FEBS letters 54 7656987
2019 WNT/RYK signaling restricts goblet cell differentiation during lung development and repair. Proceedings of the National Academy of Sciences of the United States of America 45 31776260
2018 The biochemistry, signalling and disease relevance of RYK and other WNT-binding receptor tyrosine kinases. Growth factors (Chur, Switzerland) 42 29806777
2017 RYK promotes the stemness of glioblastoma cells via the WNT/ β-catenin pathway. Oncotarget 41 28086236
2001 Revelations of the RYK receptor. BioEssays : news and reviews in molecular, cellular and developmental biology 41 11135307
2016 Wnt5A/Ryk signaling critically affects barrier function in human vascular endothelial cells. Cell adhesion & migration 40 27159116
2014 The conserved transmembrane RING finger protein PLR-1 downregulates Wnt signaling by reducing Frizzled, Ror and Ryk cell-surface levels in C. elegans. Development (Cambridge, England) 40 24401370
2007 Different Wnt signals act through the Frizzled and RYK receptors during Drosophila salivary gland migration. Development (Cambridge, England) 40 17507403
2006 Ryk: a novel Wnt receptor regulating axon pathfinding. The international journal of biochemistry & cell biology 39 16971168
2002 RYK, a catalytically inactive receptor tyrosine kinase, associates with EphB2 and EphB3 but does not interact with AF-6. The Journal of biological chemistry 39 11956217
2014 The Wnt receptor Ryk reduces neuronal and cell survival capacity by repressing FOXO activity during the early phases of mutant huntingtin pathogenicity. PLoS biology 38 24960609
1993 Molecular cloning and chromosomal localisation of the human homologue of a receptor related to tyrosine kinases (RYK). Oncogene 38 8386829
2020 Non-Canonical WNT5A Signaling Through RYK Contributes to Aggressive Phenotype of the Rheumatoid Fibroblast-Like Synoviocytes. Frontiers in immunology 37 33178184
2018 Role of WNT5A receptors FZD5 and RYK in prostate cancer cells. Oncotarget 32 29930766
2014 Ryk is essential for Wnt-5a-dependent invasiveness in human glioma. Journal of biochemistry 32 24621529
2011 The Wnt receptor Ryk controls specification of GABAergic neurons versus oligodendrocytes during telencephalon development. Development (Cambridge, England) 32 21205786
1996 H-RYK, an unusual receptor kinase: isolation and analysis of expression in ovarian cancer. Molecular medicine (Cambridge, Mass.) 32 8726462
2006 A mutation in RYK is a genetic factor for nonsyndromic cleft lip and palate. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 31 16681403
2022 Downregulation of exosomal miR-7-5p promotes breast cancer migration and invasion by targeting RYK and participating in the atypical WNT signalling pathway. Cellular & molecular biology letters 28 36210461
1993 The human ryk cDNA sequence predicts a protein containing two putative transmembrane segments and a tyrosine kinase catalytic domain. Oncogene 28 8390040
2019 Non-canonical Wnt Signaling through Ryk Regulates the Generation of Somatostatin- and Parvalbumin-Expressing Cortical Interneurons. Neuron 27 31257105
2014 Altered expression of atypical PKC and Ryk in the spinal cord of a mouse model of amyotrophic lateral sclerosis. Developmental neurobiology 27 24123880
2020 Wnt5b/Ryk-mediated membrane trafficking of P2X3 receptors contributes to bone cancer pain. Experimental neurology 26 32979370
2013 Ryk, a receptor regulating Wnt5a-mediated neurogenesis and axon morphogenesis of ventral midbrain dopaminergic neurons. Stem cells and development 26 23517308
2017 The Wnt receptor Ryk is a negative regulator of mammalian dendrite morphogenesis. Scientific reports 25 28729735
2016 The non-canonical Wnt receptor Ryk regulates hematopoietic stem cell repopulation in part by controlling proliferation and apoptosis. Cell death & disease 24 27882948
1995 The receptor tyrosine kinase-related gene (ryk) demonstrates lineage and stage-specific expression in hematopoietic cells. Journal of immunology (Baltimore, Md. : 1950) 24 7822791
2017 Ryk receptors on unmyelinated nerve fibers mediate excitatory synaptic transmission and CCL2 release during neuropathic pain induced by peripheral nerve injury. Molecular pain 23 28565999
2009 Cdc37 regulates Ryk signaling by stabilizing the cleaved Ryk intracellular domain. The Journal of biological chemistry 23 19269974
2013 Immunoreactivity of Wnt5a, Fzd2, Fzd6, and Ryk in glioblastoma: evaluative methodology for DAB chromogenic immunostaining. Brain tumor pathology 22 23748645
1999 Genomic structure and expression of the mouse growth factor receptor related to tyrosine kinases (Ryk). The Journal of biological chemistry 22 10066802
2014 The Yin and Yang of Wnt/Ryk axon guidance in development and regeneration. Science China. Life sciences 21 24643419
2013 A fully human inhibitory monoclonal antibody to the Wnt receptor RYK. PloS one 21 24058687
2017 Smek1/2 is a nuclear chaperone and cofactor for cleaved Wnt receptor Ryk, regulating cortical neurogenesis. Proceedings of the National Academy of Sciences of the United States of America 20 29180410
2015 Wnt5a, Ryk and Ror2 expression in glioblastoma subgroups. Pathology, research and practice 20 26596412
2007 Disruption of Esrom and Ryk identifies the roof plate boundary as an intermediate target for commissure formation. Molecular and cellular neurosciences 20 18060805
2005 Receptor related to tyrosine kinase RYK regulates cell migration during cortical development. Biochemical and biophysical research communications 20 15796903
2021 A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer's Disease and Type 2 Diabetes. The Biochemical journal 19 34409981
2021 ROR and RYK extracellular region structures suggest that receptor tyrosine kinases have distinct WNT-recognition modes. Cell reports 18 34686333
2019 RYK, a receptor of noncanonical Wnt ligand Wnt5a, is positively correlated with gastric cancer tumorigenesis and potential of liver metastasis. American journal of physiology. Gastrointestinal and liver physiology 18 31869240
2013 The Ryk receptor is expressed in glial and fibronectin-expressing cells after spinal cord injury. Journal of neurotrauma 18 23320533
2012 WNT5 interacts with the Ryk receptors doughnut and derailed to mediate muscle attachment site selection in Drosophila melanogaster. PloS one 18 22403643
2008 Upregulation of Ryk expression in rat dorsal root ganglia after peripheral nerve injury. Brain research bulletin 17 18773946
1998 Embryonic expression and activity of doughnut, a second RYK homolog in Drosophila. Mechanisms of development 17 9858720
2015 Human epicardial cell-conditioned medium contains HGF/IgG complexes that phosphorylate RYK and protect against vascular injury. Cardiovascular research 16 26025956
1999 Overexpression of H-Ryk in mouse fibroblasts confers transforming ability in vitro and in vivo: correlation with up-regulation in epithelial ovarian cancer. Cancer research 16 10344726
2014 Wnt5a induces Ryk-dependent and -independent effects on callosal axon and dendrite growth. Growth factors (Chur, Switzerland) 15 24471468
2004 Ryk: another heretical Wnt receptor defies the canon. Science's STKE : signal transduction knowledge environment 15 15598975
1998 Ryk is expressed in a differentiation-specific manner in epithelial tissues and is strongly induced in decidualizing uterine stroma. Oncogene 13 10030667
2019 Knockdown of long noncoding RNA WNT5A-AS restores the fate of neural stem cells exposed to sevoflurane via inhibiting WNT5A/Ryk-ROS signaling. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 12 31545269
2015 The C. elegans Chp/Wrch Ortholog CHW-1 Contributes to LIN-18/Ryk and LIN-17/Frizzled Signaling in Cell Polarity. PloS one 12 26208319
2009 t(3;21)(q22;q22) leading to truncation of the RYK gene in atypical chronic myeloid leukemia. Cancer letters 12 19168282
2022 WNT/RYK signaling functions as an antiinflammatory modulator in the lung mesenchyme. Proceedings of the National Academy of Sciences of the United States of America 11 35671428
2021 Dose-dependence in acquisition of drug tolerant phenotype and high RYK expression as a mechanism of osimertinib tolerance in lung cancer. Lung cancer (Amsterdam, Netherlands) 11 33631449
2017 Ryk regulates Wnt5a repulsion of mouse corticospinal tract through modulating planar cell polarity signaling. Cell discovery 11 28660073
2014 Wnt5 and drl/ryk gradients pattern the Drosophila olfactory dendritic map. The Journal of neuroscience : the official journal of the Society for Neuroscience 11 25378162
1999 Expression of receptor tyrosine kinase RYK in developing rat central nervous system. Brain research. Developmental brain research 11 10209253
2015 WNT receptors profile expression in mature blood cells and immature leukemic cells: RYK emerges as a hallmark receptor of acute leukemia. European journal of haematology 9 26561210
2004 In vivo evidence for a regulatory role of the kinase activity of the linotte/derailed receptor tyrosine kinase, a Drosophila Ryk ortholog. Development genes and evolution 9 15611849
2021 δ-Protocadherins regulate neural progenitor cell division by antagonizing Ryk and Wnt/β-catenin signaling. iScience 7 34430817
2020 Interplay between axonal Wnt5-Vang and dendritic Wnt5-Drl/Ryk signaling controls glomerular patterning in the Drosophila antennal lobe. PLoS genetics 7 32357156
2020 Ryk modulates the niche activity of mesenchymal stromal cells by fine-tuning canonical Wnt signaling. Experimental & molecular medicine 7 32724069
2020 RYK-mediated filopodial pathfinding facilitates midgut elongation. Development (Cambridge, England) 7 32994164
2021 PAX7, PAX9 and RYK Expression in Cleft Affected Tissue. Medicina (Kaunas, Lithuania) 6 34684112
2021 Receptor Tyrosine Kinases ror1/2 and ryk Are Co-expressed with Multiple Wnt Signaling Components During Early Development of Sea Urchin Embryos. The Biological bulletin 6 34706206
2018 Deficiency of the Wnt receptor Ryk causes multiple cardiac and outflow tract defects. Growth factors (Chur, Switzerland) 6 30035654
2002 Cell-type-specific expression of protein tyrosine kinase-related receptor RYK in the central nervous system of the rat. Brain research. Molecular brain research 6 12225882
1995 Localization of two mouse genes encoding the protein tyrosine kinase receptor-related protein RYK. Mammalian genome : official journal of the International Mammalian Genome Society 6 7613029
2022 Comprehensive analysis reveals COPB2 and RYK associated with tumor stages of larynx squamous cell carcinoma. BMC cancer 3 35715770
2025 Astrocytic Ryk signaling coordinates scarring and wound healing after spinal cord injury. Proceedings of the National Academy of Sciences of the United States of America 2 40208942
2024 Wnt5a/Ryk signaling contributes to bone cancer pain by sensitizing the peripheral nociceptors through JNK-mediated TRPV1 pathway in rats. Pain 2 39382316
2014 Function of the Ryk intracellular domain in C. elegans vulval development. Developmental dynamics : an official publication of the American Association of Anatomists 1 24975394
2026 RYK is a GPNMB receptor that drives MASH. Nature 0 41708863
2026 Dihydrocapsaicin Secreted by RYK Silenced Bone Marrow-Derived Mesenchymal Stem Cells Triggers Apoptosis of Gastric Cancer Cells. Cancer management and research 0 41890221
2026 RYK silencing-modified bone marrow-derived mesenchymal stem cells suppress gastric cancer progression. In vitro cellular & developmental biology. Animal 0 41963704
2025 Analysis of MSX1, RYK, NFκB p65, and CCL4 Proteins and MSX2, RYK, and PTX3 Genes in Human Cleft Lip Tissue. International journal of molecular sciences 0 41226636
2024 Astrocytic Ryk signaling coordinates scarring and wound healing after spinal cord injury. bioRxiv : the preprint server for biology 0 39463959

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