{"gene":"DOK7","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2006,"finding":"Dok-7 is essential for MuSK activation and neuromuscular synaptogenesis; the Dok-7 phosphotyrosine-binding (PTB) domain and its target site on MuSK are indispensable for MuSK activation in cultured myotubes, and mice lacking Dok-7 form neither acetylcholine receptor clusters nor neuromuscular synapses.","method":"Genetic knockout (Dok-7-null mice), in vitro myotube assays, domain mutagenesis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo knockout with defined phenotype plus in vitro mechanistic domain mutagenesis, foundational paper replicated by multiple subsequent studies","pmids":["16794080"],"is_preprint":false},{"year":2010,"finding":"The crystal structure of the Dok7 PH-PTB domains in complex with a phosphopeptide from MuSK's Dok7-binding site revealed a dimeric arrangement of Dok7 PH-PTB that facilitates trans-autophosphorylation of the MuSK kinase activation loop, providing the molecular basis for MuSK activation by Dok7.","method":"X-ray crystallography, biochemical dimerization assays, structure-guided mutagenesis","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with biochemical validation; mechanistic model of dimerization-driven trans-autophosphorylation directly demonstrated","pmids":["20603078"],"is_preprint":false},{"year":2009,"finding":"Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates its kinase activity; neural agrin requires Dok-7 to activate MuSK. In vivo overexpression of Dok-7 increased MuSK activation and promoted NMJ formation. Dok-7 is also required for the correct localization of MuSK to the central region of muscle.","method":"In vitro MuSK kinase activation assays, in vivo overexpression in muscle, immunofluorescence localization","journal":"Science Signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct kinase activation assay plus in vivo overexpression with functional readout, replicated by other labs","pmids":["19244212"],"is_preprint":false},{"year":2010,"finding":"Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which recruits the adaptor proteins Crk and Crk-L. Selective inactivation of Crk and Crk-L in skeletal muscle causes severe defects in neuromuscular synapse formation in vivo, placing Crk/Crk-L downstream of Dok-7 in NMJ signaling.","method":"Mass spectrometry identification of Dok-7 phosphotyrosines, Co-IP/pulldown of Crk/Crk-L, conditional muscle-specific Crk/Crk-L knockout mice with NMJ phenotyping","journal":"Genes & Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction studies plus in vivo genetic epistasis with defined NMJ phenotype","pmids":["21041412"],"is_preprint":false},{"year":2007,"finding":"A chromosome region maintenance 1 (CRM1)-dependent nuclear export signal (NES) in the C-terminal region of Dok-7 is essential for its cytoplasmic localization; disruption of the NES causes nuclear accumulation and impairs Dok-7/MuSK interaction in myotubes. The N-terminal PH domain mediates nuclear import of Dok-7. Src homology 2 (SH2) target motifs in the C-terminal region are also active and crucial for MuSK activation.","method":"Subcellular localization by fluorescence microscopy, CRM1 inhibitor (leptomycin B) treatment, domain mutagenesis in myotube AChR clustering assays","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence in myotubes, multiple domain mutants tested","pmids":["18165682"],"is_preprint":false},{"year":2021,"finding":"The most common disease-causing DOK7 mutation (1124_1127dup) causes neonatal lethality in mice primarily due to severe deficiency in MuSK phosphorylation/activation rather than loss of DOK7 C-terminal tyrosine phosphorylation. Agonist antibodies against MuSK restored neuromuscular synapse formation and prevented lethality in Dok7CM mice.","method":"Mouse knock-in model (Dok7CM and Dok72YF), MuSK phosphorylation assays, agonist antibody rescue experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — knock-in mouse models with phosphorylation assays and antibody rescue, published in high-impact journal with multiple orthogonal approaches","pmids":["34163073"],"is_preprint":false},{"year":2015,"finding":"Protein kinase CK2 physically interacts with Dok-7 at the neuromuscular junction and phosphorylates Dok-7 at several serine residues. Phosphomimetic Dok-7 mutants cluster nicotinic AChRs in C2C12 myotubes at significantly higher frequency than wild-type Dok-7.","method":"Co-immunoprecipitation, in vitro CK2 kinase assay, phosphomimetic mutagenesis with AChR clustering assay in C2C12 myotubes","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus in vitro kinase assay and functional clustering assay, single lab","pmids":["26198629"],"is_preprint":false},{"year":2017,"finding":"The C-terminal region of Dok-7 plays a key but not fully essential role in MuSK activation: purified recombinant Dok-7 lacking the C-terminal region (Dok-7-ΔC) showed marginal but significant MuSK kinase activation in vitro and in myotubes, in contrast to PH- or PTB-domain mutants which showed none. Forced expression of Dok-7-ΔC partially rescued Dok-7-deficient mice, but resulted in only marginal MuSK activation and abnormally small NMJs.","method":"Quantitative in vitro MuSK kinase assays with purified recombinant proteins, myotube transfection assays, rescue of Dok-7 knockout mice by transgenic expression","journal":"Journal of Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins plus in vivo genetic rescue, single lab but multiple orthogonal methods","pmids":["28069867"],"is_preprint":false},{"year":2020,"finding":"APC2 (core subunit of APC/C E3 ligase) is enriched at the post-synapse of NMJs and negatively regulates agrin signaling by promoting ubiquitination of DOK7 at lysine 243 for its proteolytic degradation; this degradation requires MuSK kinase activity and phosphorylation of tyrosine 106 in DOK7.","method":"Subcellular fractionation/immunostaining, ubiquitination assays, site-directed mutagenesis (K243, Y106), AChR clustering assays","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination assay with site mutagenesis and functional AChR clustering readout, single lab","pmids":["32687671"],"is_preprint":false},{"year":2020,"finding":"Quantitative phosphoproteomic analysis (CRISPR/Cas9 Dok-7 mutant myotubes + iTRAQ) identified 13 Dok-7-dependent tyrosine-phosphorylated proteins downstream of agrin/Dok-7 signaling, including Anxa3; knockdown of Anxa3 inhibited agrin-induced AChR clustering in myotubes, and reduction of Anxa3 in mouse muscles caused abnormal postsynaptic development.","method":"CRISPR/Cas9 knockout, quantitative phosphoproteomics (iTRAQ), in vitro AChR clustering assay, in vivo mouse muscle knockdown","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative phosphoproteomics combined with in vitro and in vivo validation, single lab","pmids":["32043676"],"is_preprint":false},{"year":2017,"finding":"The splicing factor SRSF1 binds a cis-element near the 3' end of DOK7 exon 4 and suppresses selection of an intron-distal 5' splice site in intron 4, thereby promoting production of full-length functional Dok-7 mRNA. SRSF1 acts by inhibiting U1 snRNP association with the intron-distal 5' SS and enhancing U1 snRNP association with the intron-proximal 5' SS.","method":"Block-scanning mutagenesis, RNA affinity purification with mass spectrometry, SRSF1 knockdown/artificial tethering (MS2 system), early spliceosome complex isolation","journal":"Scientific Reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (mutagenesis, RNA pulldown-MS, knockdown, MS2 tethering, spliceosome complex analysis) in single lab","pmids":["28874828"],"is_preprint":false},{"year":2023,"finding":"The missense mutation p.G64R in the PH domain of Dok-7 reduces protein expression to ~10% of wild-type and causes formation of insoluble aggresomes at the juxtanuclear region in myoblasts, co-localizing with autophagosome markers. Patient-derived iPS cells show juxtanuclear DOK7 aggregates, reduced endogenous DOK7 expression, and reduced MuSK phosphorylation.","method":"Transfection of C2C12 myotubes/myoblasts and COS7 cells, patient-derived iPS cells with CRISPR/Cas9 isogenic correction, immunofluorescence, Western blot (MuSK phosphorylation), proteasome inhibitor (MG132) treatment","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell-based systems including patient iPSCs with isogenic controls, single lab","pmids":["36579833"],"is_preprint":false},{"year":2016,"finding":"Molecular dynamics simulations indicate that the Dok7 PH domain associates with PIP-containing membranes through positively charged loops (β1/β2, β3/β4, β5/β6) that interact with negatively charged PIP headgroups, and that this membrane association involves both canonical and atypical PIP-binding sites, leading to local clustering of PIP molecules.","method":"Multiscale molecular dynamics simulations (coarse-grained and atomistic), density landscape calculation","journal":"PLoS Computational Biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation","pmids":["27459095"],"is_preprint":false},{"year":2010,"finding":"In zebrafish, Dok-7 is crucial for the earliest step of NMJ development (AChR cluster formation in the middle of the muscle fiber prior to motor neuron contact). At later stages, Dok-7 is not absolutely essential for synapse formation, but its absence results in smaller synaptic contacts. Dok-7 also has a role in slow muscle fiber arrangement that appears independent of MuSK.","method":"Zebrafish morpholino knockdown, immunofluorescence of AChR clusters and NMJ structure, live imaging of muscle fiber arrangement","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function in zebrafish model with defined NMJ and muscle phenotypes, single lab","pmids":["20147321"],"is_preprint":false},{"year":2016,"finding":"Silencing of Dok-7 in adult rat tibialis anterior muscle by shRNA electroporation reduced AChR protein levels at the NMJ by ~25% and significantly impaired neuromuscular transmission when a subclinical dose of anti-AChR antibody was applied, demonstrating that Dok-7 levels influence AChR cluster resistance to antibody-mediated attack.","method":"In vivo shRNA electroporation in rat muscle, passive transfer myasthenia gravis model, electrophysiology (neuromuscular transmission recording), AChR quantification by immunostaining","journal":"American Journal of Pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown with electrophysiological and immunostaining readouts, single lab","pmids":["27658713"],"is_preprint":false},{"year":2010,"finding":"MuSK mutations A727V (catalytic loop) and M605I (kinase domain) in CMS patients severely or moderately impair interaction between MuSK and Dok-7, while not impairing interaction with LRP4 or Tid1, demonstrating that impaired MuSK-Dok-7 interaction is a major determinant of pathogenesis in MuSK-mutation CMS.","method":"Expression studies in MuSK-deficient myotubes, co-immunoprecipitation of MuSK mutants with Dok-7/LRP4/Tid1, AChR clustering assays","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP in disease-relevant cell system with multiple binding partners tested, single lab","pmids":["20371544"],"is_preprint":false},{"year":2024,"finding":"Dok-7 expression in skeletal muscle is regulated by the transcriptional coactivator PGC1α; luciferase reporter assays show that the Dok-7 promoter activity is greatly increased by co-expression of PGC1α and estrogen receptor-related receptor α (ERRα), and skeletal muscle-specific PGC1α knockout mice have reduced Dok-7 expression and impaired NMJ formation.","method":"Skeletal muscle-specific PGC1α knockout and overexpression mice, luciferase promoter assay, RT-qPCR, NMJ morphological analysis","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic models plus promoter reporter assay, single lab","pmids":["38245592"],"is_preprint":false},{"year":2025,"finding":"Phosphoproteomic analysis (phosphorylated iTRAQ) identified JPH2 as a Dok-7-dependent serine/threonine phosphorylated protein downstream of agrin/Dok-7 signaling; knockdown or functional perturbation of JPH2 impaired AChR clustering in muscle cells.","method":"Phosphorylated iTRAQ proteomics, AChR clustering assays in muscle cells","journal":"FEBS Letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — phosphoproteomic screen with single downstream validation, single lab, abstract-level detail only","pmids":["40290048"],"is_preprint":false}],"current_model":"DOK7 encodes a cytoplasmic adaptor protein expressed in skeletal muscle that binds the intracellular domain of the receptor tyrosine kinase MuSK via its PTB domain; upon membrane recruitment through its PH domain, Dok-7 dimerizes to drive trans-autophosphorylation of the MuSK activation loop, thereby activating MuSK and orchestrating acetylcholine receptor clustering and neuromuscular junction formation. Downstream, agrin-stimulated phosphorylation of two C-terminal tyrosines in Dok-7 recruits Crk and Crk-L adaptors, which are essential for full presynaptic and postsynaptic differentiation. Dok-7 protein levels are regulated by CK2-mediated serine phosphorylation (enhancing AChR clustering) and by APC2/C-mediated ubiquitination at K243 (promoting proteolytic degradation, dependent on MuSK activity and DOK7 Y106 phosphorylation). The splicing factor SRSF1 controls production of functional full-length Dok-7 mRNA, and the transcriptional coactivator PGC1α regulates DOK7 gene expression in muscle."},"narrative":{"mechanistic_narrative":"DOK7 encodes a muscle-intrinsic cytoplasmic adaptor that is the obligate activator of the receptor tyrosine kinase MuSK and is essential for acetylcholine receptor (AChR) clustering and neuromuscular junction (NMJ) formation [PMID:16794080, PMID:19244212]. Dok-7 binds the cytoplasmic domain of MuSK through its phosphotyrosine-binding (PTB) domain, and a dimeric arrangement of its PH-PTB module bound to a MuSK phosphopeptide drives trans-autophosphorylation of the MuSK activation loop, providing the structural basis for kinase activation [PMID:16794080, PMID:20603078]; agrin-dependent MuSK activation requires Dok-7, and Dok-7 also directs MuSK to the central region of muscle [PMID:19244212]. Both the PH and PTB domains are strictly required for MuSK activation, whereas the C-terminal region is important but not absolutely essential, contributing to full activation and normal NMJ size [PMID:18165682, PMID:28069867]. Downstream, agrin-induced phosphorylation of two C-terminal tyrosines recruits the Crk and Crk-L adaptors, which are required in muscle for synapse formation [PMID:21041412], and Dok-7-dependent signaling further engages effectors including Anxa3 in postsynaptic development [PMID:32043676]. Dok-7 abundance and activity are tuned by post-translational and gene-regulatory inputs: CK2 binds and phosphorylates Dok-7 on serines to enhance AChR clustering [PMID:26198629], APC2/APC/C-mediated ubiquitination at K243 (dependent on MuSK activity and Dok-7 Y106 phosphorylation) promotes its degradation [PMID:32687671], the splicing factor SRSF1 ensures production of full-length functional Dok-7 mRNA [PMID:28874828], and the coactivator PGC1α with ERRα drives DOK7 transcription in muscle [PMID:38245592]. DOK7 mutations cause congenital myasthenic syndrome: the common 1124_1127dup allele produces neonatal lethality through severe loss of MuSK activation that is rescued by MuSK agonist antibodies [PMID:34163073], and the PH-domain p.G64R mutation destabilizes Dok-7 into juxtanuclear aggresomes with reduced MuSK phosphorylation [PMID:36579833].","teleology":[{"year":2006,"claim":"Established that Dok-7 is the essential muscle-intrinsic activator of MuSK, answering how MuSK is switched on to build the neuromuscular synapse.","evidence":"Dok-7-null mice and PTB-domain/MuSK-site mutagenesis in cultured myotubes","pmids":["16794080"],"confidence":"High","gaps":["Did not resolve the structural mechanism of activation","C-terminal tyrosine signaling not yet defined"]},{"year":2009,"claim":"Showed Dok-7 directly binds and activates the MuSK cytoplasmic kinase and is required for agrin-driven activation and central MuSK localization, placing Dok-7 mechanistically within the agrin pathway.","evidence":"In vitro MuSK kinase activation assays, in vivo muscle overexpression, immunofluorescence localization","pmids":["19244212"],"confidence":"High","gaps":["Mechanism of dimerization-driven activation not shown","Downstream effectors of activated MuSK not mapped"]},{"year":2010,"claim":"Defined the molecular basis of MuSK activation: a dimeric Dok-7 PH-PTB arrangement positions two MuSK molecules for trans-autophosphorylation of the activation loop.","evidence":"X-ray crystallography of PH-PTB bound to MuSK phosphopeptide with biochemical dimerization and structure-guided mutagenesis","pmids":["20603078"],"confidence":"High","gaps":["Membrane recruitment step not structurally resolved","Role of C-terminal region in activation not addressed"]},{"year":2010,"claim":"Identified the C-terminal signaling output of Dok-7, showing agrin-induced tyrosine phosphorylation recruits Crk/Crk-L adaptors essential for synapse formation.","evidence":"Mass spectrometry of Dok-7 phosphotyrosines, Crk/Crk-L Co-IP, muscle-specific Crk/Crk-L conditional knockout mice","pmids":["21041412"],"confidence":"High","gaps":["Effectors downstream of Crk/Crk-L not defined","Relative contribution of activation vs. C-terminal signaling unresolved"]},{"year":2007,"claim":"Established Dok-7 subcellular trafficking, showing a CRM1-dependent NES maintains cytoplasmic localization required for productive MuSK interaction while the PH domain mediates nuclear import.","evidence":"Fluorescence localization, leptomycin B treatment, domain mutagenesis in myotube AChR clustering assays","pmids":["18165682"],"confidence":"High","gaps":["Functional significance of nuclear Dok-7 unknown","Regulation of shuttling not defined"]},{"year":2010,"claim":"Established conservation of Dok-7 function in vivo, showing it drives the earliest aneural AChR clustering and influences muscle fiber arrangement in a partly MuSK-independent manner.","evidence":"Zebrafish morpholino knockdown with AChR/NMJ imaging and muscle fiber live imaging","pmids":["20147321"],"confidence":"Medium","gaps":["Mechanism of MuSK-independent muscle fiber role unknown","Morpholino specificity not genetically confirmed"]},{"year":2010,"claim":"Connected MuSK CMS pathogenesis to the Dok-7 interface by showing specific MuSK mutations selectively disrupt MuSK-Dok-7 binding.","evidence":"Co-IP of MuSK mutants with Dok-7/LRP4/Tid1 in MuSK-deficient myotubes with AChR clustering assays","pmids":["20371544"],"confidence":"Medium","gaps":["Quantitative binding affinities not measured","Single-lab Co-IP without structural confirmation"]},{"year":2015,"claim":"Revealed kinase regulation of Dok-7, showing CK2 binds and phosphorylates Dok-7 serines to enhance its AChR-clustering activity.","evidence":"Co-IP, in vitro CK2 kinase assay, phosphomimetic mutagenesis with C2C12 AChR clustering","pmids":["26198629"],"confidence":"Medium","gaps":["In vivo relevance of CK2 phosphorylation not established","Specific serine sites and their individual contributions unclear"]},{"year":2016,"claim":"Provided a structural model of membrane engagement, predicting the Dok-7 PH domain binds PIP-containing membranes via charged loops and clusters PIP lipids.","evidence":"Multiscale molecular dynamics simulations and density landscape calculation","pmids":["27459095"],"confidence":"Low","gaps":["Computational prediction only, no experimental validation","Physiological PIP species and binding affinity not tested"]},{"year":2016,"claim":"Demonstrated that Dok-7 dosage determines NMJ robustness, showing reduced Dok-7 lowers synaptic AChR and sensitizes to antibody-mediated attack.","evidence":"In vivo shRNA electroporation in rat muscle, passive-transfer MG model, electrophysiology and AChR immunostaining","pmids":["27658713"],"confidence":"Medium","gaps":["Single-lab study","Mechanism linking Dok-7 level to AChR stability not defined"]},{"year":2017,"claim":"Dissected domain requirements, showing PH and PTB are obligatory for MuSK activation while the C-terminal region contributes a significant but non-essential boost to activation and NMJ size.","evidence":"Quantitative in vitro MuSK kinase assays with recombinant Dok-7-ΔC, myotube transfection, transgenic rescue of Dok-7 knockout mice","pmids":["28069867"],"confidence":"High","gaps":["Molecular reason for residual ΔC activity unclear","Single lab"]},{"year":2017,"claim":"Identified a splicing checkpoint, showing SRSF1 promotes intron-proximal 5' splice site use to generate full-length functional Dok-7 mRNA.","evidence":"Block-scanning mutagenesis, RNA affinity purification-MS, SRSF1 knockdown and MS2 tethering, early spliceosome complex analysis","pmids":["28874828"],"confidence":"High","gaps":["In vivo muscle relevance of this splicing control not shown","Other splicing regulators of DOK7 not surveyed"]},{"year":2020,"claim":"Revealed negative feedback on Dok-7 abundance, showing APC2/APC/C ubiquitinates Dok-7 at K243 for degradation in a MuSK-activity and Y106-phosphorylation dependent manner.","evidence":"Fractionation/immunostaining, ubiquitination assays, K243/Y106 mutagenesis, AChR clustering assays","pmids":["32687671"],"confidence":"Medium","gaps":["In vivo physiological role of this degradation not tested","Single lab"]},{"year":2020,"claim":"Expanded the agrin/Dok-7 phosphosignaling network, identifying Anxa3 as a Dok-7-dependent effector required for postsynaptic development.","evidence":"CRISPR Dok-7 mutant myotubes with iTRAQ phosphoproteomics, AChR clustering assays, in vivo muscle knockdown","pmids":["32043676"],"confidence":"Medium","gaps":["Direct kinase acting on Anxa3 not identified","Mechanism of Anxa3 action on clustering unknown"]},{"year":2021,"claim":"Defined the pathogenic mechanism of the most common DOK7 CMS mutation and a therapeutic route, showing 1124_1127dup causes lethality via loss of MuSK activation rescuable by MuSK agonist antibodies.","evidence":"Dok7CM and Dok72YF knock-in mice, MuSK phosphorylation assays, agonist antibody rescue","pmids":["34163073"],"confidence":"High","gaps":["Long-term efficacy of antibody therapy not assessed","Mechanism by which the duplication impairs activation not structurally resolved"]},{"year":2023,"claim":"Defined a destabilizing CMS mechanism, showing the PH-domain p.G64R mutation reduces Dok-7 to ~10% and forms juxtanuclear aggresomes with impaired MuSK phosphorylation.","evidence":"Cell-line transfection, patient iPS cells with isogenic CRISPR correction, immunofluorescence, Western blot, MG132 treatment","pmids":["36579833"],"confidence":"Medium","gaps":["In vivo confirmation lacking","Pathway clearing the aggregates not fully defined"]},{"year":2024,"claim":"Identified transcriptional control of DOK7, showing PGC1α with ERRα drives Dok-7 expression required for NMJ formation.","evidence":"Muscle-specific PGC1α knockout/overexpression mice, luciferase promoter assay, RT-qPCR, NMJ morphology","pmids":["38245592"],"confidence":"Medium","gaps":["Direct ERRα binding sites on DOK7 promoter not mapped","Single lab"]},{"year":2025,"claim":"Extended the Dok-7-dependent phosphosignaling network to serine/threonine targets, implicating JPH2 in AChR clustering.","evidence":"Phosphorylated iTRAQ proteomics with AChR clustering assays in muscle cells","pmids":["40290048"],"confidence":"Low","gaps":["Single downstream validation, abstract-level detail only","Kinase acting on JPH2 not identified","In vivo role not established"]},{"year":null,"claim":"How the upstream regulatory layers (CK2 phosphorylation, APC2 degradation, SRSF1 splicing, PGC1α transcription) are coordinated in vivo to set Dok-7 levels and tune NMJ maintenance remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated in vivo model linking the regulatory inputs","Temporal dynamics of Dok-7 turnover during synapse maturation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,13,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,11,15]}],"complexes":[],"partners":["MUSK","CRK","CRKL","CSNK2A1","ANC2","SRSF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q18PE1","full_name":"Protein Dok-7","aliases":["Downstream of tyrosine kinase 7"],"length_aa":504,"mass_kda":53.1,"function":"Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis. Acts in aneural activation of MUSK and subsequent acetylcholine receptor (AchR) clustering in myotubes. 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Japanese journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18540360","citation_count":1,"is_preprint":false},{"pmid":"39944742","id":"PMC_39944742","title":"Dose escalation pre-clinical trial of novel DOK7-AAV in mouse model of DOK7 congenital myasthenia.","date":"2025","source":"Brain communications","url":"https://pubmed.ncbi.nlm.nih.gov/39944742","citation_count":1,"is_preprint":false},{"pmid":"33714798","id":"PMC_33714798","title":"Diagnosis of DOK7 congenital myasthenic syndrome during pregnancy: A case report and literature review.","date":"2021","source":"Clinical neurology and neurosurgery","url":"https://pubmed.ncbi.nlm.nih.gov/33714798","citation_count":1,"is_preprint":false},{"pmid":"37303354","id":"PMC_37303354","title":"When Breathing Becomes a Challenge: A Case of Congenital Myasthenia Gravis in an Indian Neonate With a DOK-7 Gene Mutation.","date":"2023","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/37303354","citation_count":1,"is_preprint":false},{"pmid":"37611271","id":"PMC_37611271","title":"Congenital Myasthenic Syndrome Caused by DOK7 Mutation in a Quinquagenarian Male with Calf Hypertrophy.","date":"2023","source":"Journal of clinical neuromuscular disease","url":"https://pubmed.ncbi.nlm.nih.gov/37611271","citation_count":1,"is_preprint":false},{"pmid":"31453852","id":"PMC_31453852","title":"Phenotypic Differences in 2 Unrelated Cases Carrying Identical DOK7 Mutations.","date":"2019","source":"Journal of clinical neuromuscular disease","url":"https://pubmed.ncbi.nlm.nih.gov/31453852","citation_count":1,"is_preprint":false},{"pmid":"38756045","id":"PMC_38756045","title":"Effective treatment with oral Salbutamol on late onset respiratory impairment in a DOK7 Congenital Myasthenia Syndrome: a case report.","date":"2024","source":"Multidisciplinary respiratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38756045","citation_count":1,"is_preprint":false},{"pmid":"40290048","id":"PMC_40290048","title":"Agrin/Dok-7-induced JPH2 phosphorylation in muscle cells is involved in AChR clustering.","date":"2025","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/40290048","citation_count":0,"is_preprint":false},{"pmid":"40330390","id":"PMC_40330390","title":"Congenital Myasthenic Syndrome With Adult Onset Due to the Novel Heterozygous c.1399_1404del Variant in the Downstream of Tyrosine Kinase-7 (DOK7): A Case Report.","date":"2025","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/40330390","citation_count":0,"is_preprint":false},{"pmid":"36337064","id":"PMC_36337064","title":"Epigenteic Alteration of DOK7 Gene CpG Island in Blood Leukocyte of Patients with Gastric Cancer and Intestinal Methaplasia.","date":"2022","source":"Iranian journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/36337064","citation_count":0,"is_preprint":false},{"pmid":"40390963","id":"PMC_40390963","title":"DOK7 Gene Novel Homozygous Mutation is Related to Fetal Akinesia Deformation Sequence 3.","date":"2023","source":"Journal of obstetrics and gynaecology of India","url":"https://pubmed.ncbi.nlm.nih.gov/40390963","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36634,"output_tokens":4754,"usd":0.090606,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12863,"output_tokens":5283,"usd":0.098195,"stage2_stop_reason":"end_turn"},"total_usd":0.188801,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Dok-7 is essential for MuSK activation and neuromuscular synaptogenesis; the Dok-7 phosphotyrosine-binding (PTB) domain and its target site on MuSK are indispensable for MuSK activation in cultured myotubes, and mice lacking Dok-7 form neither acetylcholine receptor clusters nor neuromuscular synapses.\",\n      \"method\": \"Genetic knockout (Dok-7-null mice), in vitro myotube assays, domain mutagenesis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo knockout with defined phenotype plus in vitro mechanistic domain mutagenesis, foundational paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"16794080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The crystal structure of the Dok7 PH-PTB domains in complex with a phosphopeptide from MuSK's Dok7-binding site revealed a dimeric arrangement of Dok7 PH-PTB that facilitates trans-autophosphorylation of the MuSK kinase activation loop, providing the molecular basis for MuSK activation by Dok7.\",\n      \"method\": \"X-ray crystallography, biochemical dimerization assays, structure-guided mutagenesis\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with biochemical validation; mechanistic model of dimerization-driven trans-autophosphorylation directly demonstrated\",\n      \"pmids\": [\"20603078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates its kinase activity; neural agrin requires Dok-7 to activate MuSK. In vivo overexpression of Dok-7 increased MuSK activation and promoted NMJ formation. Dok-7 is also required for the correct localization of MuSK to the central region of muscle.\",\n      \"method\": \"In vitro MuSK kinase activation assays, in vivo overexpression in muscle, immunofluorescence localization\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct kinase activation assay plus in vivo overexpression with functional readout, replicated by other labs\",\n      \"pmids\": [\"19244212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which recruits the adaptor proteins Crk and Crk-L. Selective inactivation of Crk and Crk-L in skeletal muscle causes severe defects in neuromuscular synapse formation in vivo, placing Crk/Crk-L downstream of Dok-7 in NMJ signaling.\",\n      \"method\": \"Mass spectrometry identification of Dok-7 phosphotyrosines, Co-IP/pulldown of Crk/Crk-L, conditional muscle-specific Crk/Crk-L knockout mice with NMJ phenotyping\",\n      \"journal\": \"Genes & Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction studies plus in vivo genetic epistasis with defined NMJ phenotype\",\n      \"pmids\": [\"21041412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A chromosome region maintenance 1 (CRM1)-dependent nuclear export signal (NES) in the C-terminal region of Dok-7 is essential for its cytoplasmic localization; disruption of the NES causes nuclear accumulation and impairs Dok-7/MuSK interaction in myotubes. The N-terminal PH domain mediates nuclear import of Dok-7. Src homology 2 (SH2) target motifs in the C-terminal region are also active and crucial for MuSK activation.\",\n      \"method\": \"Subcellular localization by fluorescence microscopy, CRM1 inhibitor (leptomycin B) treatment, domain mutagenesis in myotube AChR clustering assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence in myotubes, multiple domain mutants tested\",\n      \"pmids\": [\"18165682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The most common disease-causing DOK7 mutation (1124_1127dup) causes neonatal lethality in mice primarily due to severe deficiency in MuSK phosphorylation/activation rather than loss of DOK7 C-terminal tyrosine phosphorylation. Agonist antibodies against MuSK restored neuromuscular synapse formation and prevented lethality in Dok7CM mice.\",\n      \"method\": \"Mouse knock-in model (Dok7CM and Dok72YF), MuSK phosphorylation assays, agonist antibody rescue experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — knock-in mouse models with phosphorylation assays and antibody rescue, published in high-impact journal with multiple orthogonal approaches\",\n      \"pmids\": [\"34163073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Protein kinase CK2 physically interacts with Dok-7 at the neuromuscular junction and phosphorylates Dok-7 at several serine residues. Phosphomimetic Dok-7 mutants cluster nicotinic AChRs in C2C12 myotubes at significantly higher frequency than wild-type Dok-7.\",\n      \"method\": \"Co-immunoprecipitation, in vitro CK2 kinase assay, phosphomimetic mutagenesis with AChR clustering assay in C2C12 myotubes\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus in vitro kinase assay and functional clustering assay, single lab\",\n      \"pmids\": [\"26198629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The C-terminal region of Dok-7 plays a key but not fully essential role in MuSK activation: purified recombinant Dok-7 lacking the C-terminal region (Dok-7-ΔC) showed marginal but significant MuSK kinase activation in vitro and in myotubes, in contrast to PH- or PTB-domain mutants which showed none. Forced expression of Dok-7-ΔC partially rescued Dok-7-deficient mice, but resulted in only marginal MuSK activation and abnormally small NMJs.\",\n      \"method\": \"Quantitative in vitro MuSK kinase assays with purified recombinant proteins, myotube transfection assays, rescue of Dok-7 knockout mice by transgenic expression\",\n      \"journal\": \"Journal of Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins plus in vivo genetic rescue, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28069867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"APC2 (core subunit of APC/C E3 ligase) is enriched at the post-synapse of NMJs and negatively regulates agrin signaling by promoting ubiquitination of DOK7 at lysine 243 for its proteolytic degradation; this degradation requires MuSK kinase activity and phosphorylation of tyrosine 106 in DOK7.\",\n      \"method\": \"Subcellular fractionation/immunostaining, ubiquitination assays, site-directed mutagenesis (K243, Y106), AChR clustering assays\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination assay with site mutagenesis and functional AChR clustering readout, single lab\",\n      \"pmids\": [\"32687671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Quantitative phosphoproteomic analysis (CRISPR/Cas9 Dok-7 mutant myotubes + iTRAQ) identified 13 Dok-7-dependent tyrosine-phosphorylated proteins downstream of agrin/Dok-7 signaling, including Anxa3; knockdown of Anxa3 inhibited agrin-induced AChR clustering in myotubes, and reduction of Anxa3 in mouse muscles caused abnormal postsynaptic development.\",\n      \"method\": \"CRISPR/Cas9 knockout, quantitative phosphoproteomics (iTRAQ), in vitro AChR clustering assay, in vivo mouse muscle knockdown\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative phosphoproteomics combined with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"32043676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The splicing factor SRSF1 binds a cis-element near the 3' end of DOK7 exon 4 and suppresses selection of an intron-distal 5' splice site in intron 4, thereby promoting production of full-length functional Dok-7 mRNA. SRSF1 acts by inhibiting U1 snRNP association with the intron-distal 5' SS and enhancing U1 snRNP association with the intron-proximal 5' SS.\",\n      \"method\": \"Block-scanning mutagenesis, RNA affinity purification with mass spectrometry, SRSF1 knockdown/artificial tethering (MS2 system), early spliceosome complex isolation\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (mutagenesis, RNA pulldown-MS, knockdown, MS2 tethering, spliceosome complex analysis) in single lab\",\n      \"pmids\": [\"28874828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The missense mutation p.G64R in the PH domain of Dok-7 reduces protein expression to ~10% of wild-type and causes formation of insoluble aggresomes at the juxtanuclear region in myoblasts, co-localizing with autophagosome markers. Patient-derived iPS cells show juxtanuclear DOK7 aggregates, reduced endogenous DOK7 expression, and reduced MuSK phosphorylation.\",\n      \"method\": \"Transfection of C2C12 myotubes/myoblasts and COS7 cells, patient-derived iPS cells with CRISPR/Cas9 isogenic correction, immunofluorescence, Western blot (MuSK phosphorylation), proteasome inhibitor (MG132) treatment\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell-based systems including patient iPSCs with isogenic controls, single lab\",\n      \"pmids\": [\"36579833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Molecular dynamics simulations indicate that the Dok7 PH domain associates with PIP-containing membranes through positively charged loops (β1/β2, β3/β4, β5/β6) that interact with negatively charged PIP headgroups, and that this membrane association involves both canonical and atypical PIP-binding sites, leading to local clustering of PIP molecules.\",\n      \"method\": \"Multiscale molecular dynamics simulations (coarse-grained and atomistic), density landscape calculation\",\n      \"journal\": \"PLoS Computational Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation\",\n      \"pmids\": [\"27459095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In zebrafish, Dok-7 is crucial for the earliest step of NMJ development (AChR cluster formation in the middle of the muscle fiber prior to motor neuron contact). At later stages, Dok-7 is not absolutely essential for synapse formation, but its absence results in smaller synaptic contacts. Dok-7 also has a role in slow muscle fiber arrangement that appears independent of MuSK.\",\n      \"method\": \"Zebrafish morpholino knockdown, immunofluorescence of AChR clusters and NMJ structure, live imaging of muscle fiber arrangement\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function in zebrafish model with defined NMJ and muscle phenotypes, single lab\",\n      \"pmids\": [\"20147321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Silencing of Dok-7 in adult rat tibialis anterior muscle by shRNA electroporation reduced AChR protein levels at the NMJ by ~25% and significantly impaired neuromuscular transmission when a subclinical dose of anti-AChR antibody was applied, demonstrating that Dok-7 levels influence AChR cluster resistance to antibody-mediated attack.\",\n      \"method\": \"In vivo shRNA electroporation in rat muscle, passive transfer myasthenia gravis model, electrophysiology (neuromuscular transmission recording), AChR quantification by immunostaining\",\n      \"journal\": \"American Journal of Pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown with electrophysiological and immunostaining readouts, single lab\",\n      \"pmids\": [\"27658713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MuSK mutations A727V (catalytic loop) and M605I (kinase domain) in CMS patients severely or moderately impair interaction between MuSK and Dok-7, while not impairing interaction with LRP4 or Tid1, demonstrating that impaired MuSK-Dok-7 interaction is a major determinant of pathogenesis in MuSK-mutation CMS.\",\n      \"method\": \"Expression studies in MuSK-deficient myotubes, co-immunoprecipitation of MuSK mutants with Dok-7/LRP4/Tid1, AChR clustering assays\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP in disease-relevant cell system with multiple binding partners tested, single lab\",\n      \"pmids\": [\"20371544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Dok-7 expression in skeletal muscle is regulated by the transcriptional coactivator PGC1α; luciferase reporter assays show that the Dok-7 promoter activity is greatly increased by co-expression of PGC1α and estrogen receptor-related receptor α (ERRα), and skeletal muscle-specific PGC1α knockout mice have reduced Dok-7 expression and impaired NMJ formation.\",\n      \"method\": \"Skeletal muscle-specific PGC1α knockout and overexpression mice, luciferase promoter assay, RT-qPCR, NMJ morphological analysis\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic models plus promoter reporter assay, single lab\",\n      \"pmids\": [\"38245592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Phosphoproteomic analysis (phosphorylated iTRAQ) identified JPH2 as a Dok-7-dependent serine/threonine phosphorylated protein downstream of agrin/Dok-7 signaling; knockdown or functional perturbation of JPH2 impaired AChR clustering in muscle cells.\",\n      \"method\": \"Phosphorylated iTRAQ proteomics, AChR clustering assays in muscle cells\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — phosphoproteomic screen with single downstream validation, single lab, abstract-level detail only\",\n      \"pmids\": [\"40290048\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DOK7 encodes a cytoplasmic adaptor protein expressed in skeletal muscle that binds the intracellular domain of the receptor tyrosine kinase MuSK via its PTB domain; upon membrane recruitment through its PH domain, Dok-7 dimerizes to drive trans-autophosphorylation of the MuSK activation loop, thereby activating MuSK and orchestrating acetylcholine receptor clustering and neuromuscular junction formation. Downstream, agrin-stimulated phosphorylation of two C-terminal tyrosines in Dok-7 recruits Crk and Crk-L adaptors, which are essential for full presynaptic and postsynaptic differentiation. Dok-7 protein levels are regulated by CK2-mediated serine phosphorylation (enhancing AChR clustering) and by APC2/C-mediated ubiquitination at K243 (promoting proteolytic degradation, dependent on MuSK activity and DOK7 Y106 phosphorylation). The splicing factor SRSF1 controls production of functional full-length Dok-7 mRNA, and the transcriptional coactivator PGC1α regulates DOK7 gene expression in muscle.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DOK7 encodes a muscle-intrinsic cytoplasmic adaptor that is the obligate activator of the receptor tyrosine kinase MuSK and is essential for acetylcholine receptor (AChR) clustering and neuromuscular junction (NMJ) formation [#0, #2]. Dok-7 binds the cytoplasmic domain of MuSK through its phosphotyrosine-binding (PTB) domain, and a dimeric arrangement of its PH-PTB module bound to a MuSK phosphopeptide drives trans-autophosphorylation of the MuSK activation loop, providing the structural basis for kinase activation [#0, #1]; agrin-dependent MuSK activation requires Dok-7, and Dok-7 also directs MuSK to the central region of muscle [#2]. Both the PH and PTB domains are strictly required for MuSK activation, whereas the C-terminal region is important but not absolutely essential, contributing to full activation and normal NMJ size [#4, #7]. Downstream, agrin-induced phosphorylation of two C-terminal tyrosines recruits the Crk and Crk-L adaptors, which are required in muscle for synapse formation [#3], and Dok-7-dependent signaling further engages effectors including Anxa3 in postsynaptic development [#9]. Dok-7 abundance and activity are tuned by post-translational and gene-regulatory inputs: CK2 binds and phosphorylates Dok-7 on serines to enhance AChR clustering [#6], APC2/APC/C-mediated ubiquitination at K243 (dependent on MuSK activity and Dok-7 Y106 phosphorylation) promotes its degradation [#8], the splicing factor SRSF1 ensures production of full-length functional Dok-7 mRNA [#10], and the coactivator PGC1\\u03b1 with ERR\\u03b1 drives DOK7 transcription in muscle [#16]. DOK7 mutations cause congenital myasthenic syndrome: the common 1124_1127dup allele produces neonatal lethality through severe loss of MuSK activation that is rescued by MuSK agonist antibodies [#5], and the PH-domain p.G64R mutation destabilizes Dok-7 into juxtanuclear aggresomes with reduced MuSK phosphorylation [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that Dok-7 is the essential muscle-intrinsic activator of MuSK, answering how MuSK is switched on to build the neuromuscular synapse.\",\n      \"evidence\": \"Dok-7-null mice and PTB-domain/MuSK-site mutagenesis in cultured myotubes\",\n      \"pmids\": [\"16794080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural mechanism of activation\", \"C-terminal tyrosine signaling not yet defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed Dok-7 directly binds and activates the MuSK cytoplasmic kinase and is required for agrin-driven activation and central MuSK localization, placing Dok-7 mechanistically within the agrin pathway.\",\n      \"evidence\": \"In vitro MuSK kinase activation assays, in vivo muscle overexpression, immunofluorescence localization\",\n      \"pmids\": [\"19244212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of dimerization-driven activation not shown\", \"Downstream effectors of activated MuSK not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the molecular basis of MuSK activation: a dimeric Dok-7 PH-PTB arrangement positions two MuSK molecules for trans-autophosphorylation of the activation loop.\",\n      \"evidence\": \"X-ray crystallography of PH-PTB bound to MuSK phosphopeptide with biochemical dimerization and structure-guided mutagenesis\",\n      \"pmids\": [\"20603078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane recruitment step not structurally resolved\", \"Role of C-terminal region in activation not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the C-terminal signaling output of Dok-7, showing agrin-induced tyrosine phosphorylation recruits Crk/Crk-L adaptors essential for synapse formation.\",\n      \"evidence\": \"Mass spectrometry of Dok-7 phosphotyrosines, Crk/Crk-L Co-IP, muscle-specific Crk/Crk-L conditional knockout mice\",\n      \"pmids\": [\"21041412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effectors downstream of Crk/Crk-L not defined\", \"Relative contribution of activation vs. C-terminal signaling unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established Dok-7 subcellular trafficking, showing a CRM1-dependent NES maintains cytoplasmic localization required for productive MuSK interaction while the PH domain mediates nuclear import.\",\n      \"evidence\": \"Fluorescence localization, leptomycin B treatment, domain mutagenesis in myotube AChR clustering assays\",\n      \"pmids\": [\"18165682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of nuclear Dok-7 unknown\", \"Regulation of shuttling not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established conservation of Dok-7 function in vivo, showing it drives the earliest aneural AChR clustering and influences muscle fiber arrangement in a partly MuSK-independent manner.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with AChR/NMJ imaging and muscle fiber live imaging\",\n      \"pmids\": [\"20147321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MuSK-independent muscle fiber role unknown\", \"Morpholino specificity not genetically confirmed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected MuSK CMS pathogenesis to the Dok-7 interface by showing specific MuSK mutations selectively disrupt MuSK-Dok-7 binding.\",\n      \"evidence\": \"Co-IP of MuSK mutants with Dok-7/LRP4/Tid1 in MuSK-deficient myotubes with AChR clustering assays\",\n      \"pmids\": [\"20371544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative binding affinities not measured\", \"Single-lab Co-IP without structural confirmation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed kinase regulation of Dok-7, showing CK2 binds and phosphorylates Dok-7 serines to enhance its AChR-clustering activity.\",\n      \"evidence\": \"Co-IP, in vitro CK2 kinase assay, phosphomimetic mutagenesis with C2C12 AChR clustering\",\n      \"pmids\": [\"26198629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of CK2 phosphorylation not established\", \"Specific serine sites and their individual contributions unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided a structural model of membrane engagement, predicting the Dok-7 PH domain binds PIP-containing membranes via charged loops and clusters PIP lipids.\",\n      \"evidence\": \"Multiscale molecular dynamics simulations and density landscape calculation\",\n      \"pmids\": [\"27459095\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only, no experimental validation\", \"Physiological PIP species and binding affinity not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that Dok-7 dosage determines NMJ robustness, showing reduced Dok-7 lowers synaptic AChR and sensitizes to antibody-mediated attack.\",\n      \"evidence\": \"In vivo shRNA electroporation in rat muscle, passive-transfer MG model, electrophysiology and AChR immunostaining\",\n      \"pmids\": [\"27658713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Mechanism linking Dok-7 level to AChR stability not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dissected domain requirements, showing PH and PTB are obligatory for MuSK activation while the C-terminal region contributes a significant but non-essential boost to activation and NMJ size.\",\n      \"evidence\": \"Quantitative in vitro MuSK kinase assays with recombinant Dok-7-\\u0394C, myotube transfection, transgenic rescue of Dok-7 knockout mice\",\n      \"pmids\": [\"28069867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular reason for residual \\u0394C activity unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a splicing checkpoint, showing SRSF1 promotes intron-proximal 5' splice site use to generate full-length functional Dok-7 mRNA.\",\n      \"evidence\": \"Block-scanning mutagenesis, RNA affinity purification-MS, SRSF1 knockdown and MS2 tethering, early spliceosome complex analysis\",\n      \"pmids\": [\"28874828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo muscle relevance of this splicing control not shown\", \"Other splicing regulators of DOK7 not surveyed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed negative feedback on Dok-7 abundance, showing APC2/APC/C ubiquitinates Dok-7 at K243 for degradation in a MuSK-activity and Y106-phosphorylation dependent manner.\",\n      \"evidence\": \"Fractionation/immunostaining, ubiquitination assays, K243/Y106 mutagenesis, AChR clustering assays\",\n      \"pmids\": [\"32687671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo physiological role of this degradation not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the agrin/Dok-7 phosphosignaling network, identifying Anxa3 as a Dok-7-dependent effector required for postsynaptic development.\",\n      \"evidence\": \"CRISPR Dok-7 mutant myotubes with iTRAQ phosphoproteomics, AChR clustering assays, in vivo muscle knockdown\",\n      \"pmids\": [\"32043676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase acting on Anxa3 not identified\", \"Mechanism of Anxa3 action on clustering unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the pathogenic mechanism of the most common DOK7 CMS mutation and a therapeutic route, showing 1124_1127dup causes lethality via loss of MuSK activation rescuable by MuSK agonist antibodies.\",\n      \"evidence\": \"Dok7CM and Dok72YF knock-in mice, MuSK phosphorylation assays, agonist antibody rescue\",\n      \"pmids\": [\"34163073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term efficacy of antibody therapy not assessed\", \"Mechanism by which the duplication impairs activation not structurally resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a destabilizing CMS mechanism, showing the PH-domain p.G64R mutation reduces Dok-7 to ~10% and forms juxtanuclear aggresomes with impaired MuSK phosphorylation.\",\n      \"evidence\": \"Cell-line transfection, patient iPS cells with isogenic CRISPR correction, immunofluorescence, Western blot, MG132 treatment\",\n      \"pmids\": [\"36579833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo confirmation lacking\", \"Pathway clearing the aggregates not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified transcriptional control of DOK7, showing PGC1\\u03b1 with ERR\\u03b1 drives Dok-7 expression required for NMJ formation.\",\n      \"evidence\": \"Muscle-specific PGC1\\u03b1 knockout/overexpression mice, luciferase promoter assay, RT-qPCR, NMJ morphology\",\n      \"pmids\": [\"38245592\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ERR\\u03b1 binding sites on DOK7 promoter not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the Dok-7-dependent phosphosignaling network to serine/threonine targets, implicating JPH2 in AChR clustering.\",\n      \"evidence\": \"Phosphorylated iTRAQ proteomics with AChR clustering assays in muscle cells\",\n      \"pmids\": [\"40290048\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single downstream validation, abstract-level detail only\", \"Kinase acting on JPH2 not identified\", \"In vivo role not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the upstream regulatory layers (CK2 phosphorylation, APC2 degradation, SRSF1 splicing, PGC1\\u03b1 transcription) are coordinated in vivo to set Dok-7 levels and tune NMJ maintenance remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated in vivo model linking the regulatory inputs\", \"Temporal dynamics of Dok-7 turnover during synapse maturation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 13, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 11, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MUSK\", \"CRK\", \"CRKL\", \"CSNK2A1\", \"ANC2\", \"SRSF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}