DOK7 is an intracellular signaling protein that organizes neuromuscular junction formation through the muscle receptor tyrosine kinase MUSK. Its N-terminal pleckstrin-homology and phosphotyrosine-binding regions promote receptor pairing and activation, while phosphorylation of the C-terminal tail enables recruitment of CRK-family adaptors for downstream synaptic differentiation. DOK7 is associated with the muscle postsynaptic compartment; additional nucleoplasmic and mitochondrial pools have been observed in human cell lines. Biallelic pathogenic variants cause congenital myasthenic syndromes, and severe disruption can cause fetal akinesia. Alternative transcripts encode products that differ in their receptor-binding regions or signaling tails.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Verified binary association with EFEMP2 without an established signaling role. Reason: The literal human DOK7–EFEMP2 pair is present in three IntAct records for the HuRI study: validated two-hybrid, array and prey-pooling records. Both sequence ROGIDs match the current canonical reference sequences. The paper describes pairwise retesting and sequence confirmation; population-level orthogonal validation is not claimed for this individual pair. Retain the positive interaction under the project binding policy. EFEMP2 extracellular-matrix biology does not establish a specific signaling or cytoskeletal binding function for DOK7, and different usual compartments do not invalidate the measured binary interaction. Supporting Evidence: PMID:32296183 pairwise verification by quadruplicate retesting and sequence confirmation |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Positive nucleoplasmic localization in human cell lines. Reason: The HPA ICC/IF record has enhanced reliability and reports nucleoplasmic staining with antibodies HPA059449 and HPA062780 in MCF-7 and Rh30; HPA059449 also reports U2OS. Retain this experimentally observed, nonexclusive pool. These transformed-cell observations do not assign the neuromuscular MUSK-activation mechanism to the nucleoplasm or identify a natural splice product. Supporting Evidence: GO_REF:0000052 https://www.proteinatlas.org/ENSG00000175920-DOK7/subcellular |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Positive mitochondrial localization in Rh30 cells. Reason: The HPA ICC/IF record independently reports mitochondria as an additional location in Rh30 with both HPA059449 and HPA062780, at enhanced validation; the second antibody records single-cell intensity variation. This is positive cell-context evidence, not a presumed targeting-sequence prediction. Retain the nonexclusive mitochondrial pool without inventing a mitochondrial biochemical function or transferring the pattern to all tissues and products. Supporting Evidence: GO_REF:0000052 https://www.proteinatlas.org/ENSG00000175920-DOK7/subcellular |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | MODIFY | Summary: Resolve the membrane pool to postsynaptic membrane. Reason: The official human record carries a by-similarity membrane/synapse assignment. The exact mouse Q18PE0 donor record has postsynaptic-membrane IDA evidence from PMID:16794080, consistent with muscle-intrinsic MUSK signaling and receptor clustering. The refinement specifies the established postsynaptic functional pool without claiming that the electronic mapping itself measured a narrower human compartment. It does not exclude the HPA nuclear or mitochondrial pools. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER The plasma-membrane mapping is valid. The narrower postsynaptic location is supported by the ortholog and target mechanism, not by an assay in the source mapping. Proposed replacements: postsynaptic membrane |
| GO:0007167 enzyme-linked receptor protein signaling pathway | IEA GO_REF:0000107 | MODIFY | Summary: Specify cell-surface receptor tyrosine-kinase signaling. Reason: DOK7 participates in the agrin–LRP4–MUSK signaling system by receptor activation and phosphotail-mediated downstream recruitment. The current replacement definition includes ligand-initiated surface receptor tyrosine-kinase signaling and is a typed descendant of the broader enzyme-linked receptor pathway. Mouse Dok7 experiments support this pathway; human fragment biophysics and disease evidence independently support the conserved mechanism. This refinement does not claim that DOK7 is the receptor or kinase catalyst. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q18PE0 SUPPORTS TRANSFER Exact donor identity and experimental signaling annotations verified; source-level organism and construct limits are retained. Proposed replacements: cell surface receptor protein tyrosine kinase signaling pathway |
| GO:0007528 neuromuscular junction development | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved participation in neuromuscular junction development. Reason: Human DOK7 leaf PTN002502548 descends from the stated PTN001092033 node in PTHR21636. The saved IBD source assigns neuromuscular junction development at that node, grounded in mouse evidence. Its dated donor list differs from the original GOA list that also names zebrafish; the original source fields are preserved. DOK7 performs receptor activation and adaptor recruitment during synaptic assembly, rather than merely being a passive substrate. Human synaptopathy and the mechanistic ortholog experiments support this inherited developmental function. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN001092033 SUPPORTS TRANSFER Actual root-to-target descent and GO:0007528 IBD verified. No donor-count objection; dated source differences are explicit. |
| GO:0019901 protein kinase binding | IBA GO_REF:0000033 | MODIFY | Summary: Specify receptor tyrosine kinase binding. Reason: The relevant partner is MUSK, a receptor with protein tyrosine kinase activity. Human DOK7 PH–PTB residues 1–220 were used for solution binding/oligomerization with the rat MUSK cytoplasmic region in PMID:20603078. Mouse PH–PTB supplied the ligand-bound crystal and direct kinase-stimulation experiments. The receptor-specific binding subclass captures the demonstrated partner class without transferring mouse activation assays to human protein or equating an engineered fragment with every natural product. Kinase activation is represented separately from binding. The PAINT node is valid, and target human evidence among the IBD sources is legitimate grounding rather than circular propagation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN001092033 SUPPORTS TRANSFER GO:0019901 IBD, human/mouse experimental grounding and target descent verified. Specificity is strengthened by the independently examined target partner. Proposed replacements: receptor tyrosine kinase binding |
| GO:0019901 protein kinase binding | IDA PMID:20603078 The cytoplasmic adaptor protein Dok7 activates the receptor ... | MODIFY | Summary: Specify the directly assayed receptor-kinase partner. Reason: The relevant partner is MUSK, a receptor with protein tyrosine kinase activity. Human DOK7 PH–PTB residues 1–220 were used for solution binding/oligomerization with the rat MUSK cytoplasmic region in PMID:20603078. Mouse PH–PTB supplied the ligand-bound crystal and direct kinase-stimulation experiments. The receptor-specific binding subclass captures the demonstrated partner class without transferring mouse activation assays to human protein or equating an engineered fragment with every natural product. Kinase activation is represented separately from binding. Proposed replacements: receptor tyrosine kinase binding Supporting Evidence: |
| GO:0019901 protein kinase binding | IEA GO_REF:0000120 | MODIFY | Summary: Refine convergent electronic kinase binding to receptor tyrosine kinase binding. Reason: The relevant partner is MUSK, a receptor with protein tyrosine kinase activity. Human DOK7 PH–PTB residues 1–220 were used for solution binding/oligomerization with the rat MUSK cytoplasmic region in PMID:20603078. Mouse PH–PTB supplied the ligand-bound crystal and direct kinase-stimulation experiments. The receptor-specific binding subclass captures the demonstrated partner class without transferring mouse activation assays to human protein or equating an engineered fragment with every natural product. Kinase activation is represented separately from binding. The combined GO_REF source includes a verified Dok-7 InterPro family match and mouse ortholog evidence; the exact current ARBA triggering condition remains unresolved and is not used as an independent mechanistic experiment. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR037746 SUPPORTS TRANSFER The actual Protein Dok-7 family maps to kinase binding and matches target residues 1–495. This is supported target-family evidence. UniProtKB:Q18PE0 SUPPORTS TRANSFER The mouse ortholog has experimental MUSK binding; target human fragment evidence is independently available. ARBA:ARBA00028598 UNRESOLVED The current rule still emits GO:0019901 but has 32 disjunctive condition sets. The exact historical target condition was not reconstructed from the summarized Gene3D record; other listed sources and direct target evidence support the claim. Proposed replacements: receptor tyrosine kinase binding |
| GO:0031594 neuromuscular junction | IEA GO_REF:0000107 | ACCEPT | Summary: DOK7 acts at the neuromuscular junction. Reason: The exact mouse donor record and official localization annotation support neuromuscular-junction enrichment, with the muscle-side functional pool further resolved to postsynaptic membrane. Human congenital myasthenic synaptopathy is consistent with the conserved synaptic role but is not substituted for a direct human localization assay. Preserve the junction-level assertion without implying a presynaptic DOK7 pool. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q18PE0 SUPPORTS TRANSFER The donor has experimental neuromuscular-junction localization and a consistent postsynaptic functional context. |
| GO:0035022 positive regulation of Rac protein signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain inherited positive Rac-pathway regulation with mechanistic limits. Reason: The exact mouse donor has curated positive Rac-regulation annotations, including IDA/IMP from PMID:16794080. This is a positive inherited regulatory assertion, not a proposed intrinsic Rac exchange activity. The separately recovered PMID:21041412 establishes CRK/CRKL recruitment but discusses recruitment of Rac/Rho exchange factors as a hypothesis rather than measuring it directly. Retain the curated downstream regulation contextually; do not infer a demonstrated human DOK7–Rac catalytic interaction or reconstruct unseen experiments in the unavailable 2006 full text. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q18PE0 SUPPORTS TRANSFER The donor has experimental GO:0035022 assertions. The downstream linkage remains mechanistically less resolved than receptor activation and adaptor recruitment. |
| GO:0035091 phosphatidylinositol binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Conserved phosphoinositide-binding activity supports membrane recruitment. Reason: The exact mouse donor has IDA phosphatidylinositol-binding evidence from PMID:20603078. Its lipid-binding experiment used mouse PH–PTB protein; the human PH-containing product and conserved architecture support transfer. The term explicitly includes phosphorylated phosphatidylinositol derivatives. Retain this accessory membrane-binding activity without asserting an exclusive lipid species, a direct assay of every human isoform, or identical activity for products that alter the PH domain. The official DOMAIN annotation ranks PI(3,4,5)P3 above PI(3,4)P2 and PI(4,5)P2; this records a preference rather than exclusive recognition of one lipid. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q18PE0 SUPPORTS TRANSFER Mouse lipid binding is directly assayed; human transfer remains product- and species-scoped. |
| GO:0035591 signaling adaptor activity | IEA GO_REF:0000107 | MODIFY | Summary: Resolve the adaptor role to receptor tyrosine kinase signaling. Reason: MUSK-associated DOK7 recruits CRK and CRKL through its phosphorylated tail. PMID:21041412 uses murine Dok7 cloned from C2 cells, phosphopeptide affinity purification and agrin-dependent cellular co-immunoprecipitation; phosphosite mutations impair receptor clustering despite largely retained kinase activation. This supports the narrower adaptor definition: bringing a transmembrane receptor tyrosine kinase and downstream molecules together for coordinated signaling. The human role is an ortholog inference; human host cells in that paper do not make the Dok7 construct human. The direct kinase-activator mechanism and downstream adaptor mechanism are distinct. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q18PE0 SUPPORTS TRANSFER Actual mouse adaptor experiments establish the coordinated recruitment function, supporting transfer and receptor-specific refinement. Proposed replacements: transmembrane receptor protein tyrosine kinase adaptor activity |
| GO:0045202 synapse | IEA GO_REF:0000044 | MODIFY | Summary: Resolve the synaptic pool to postsynaptic membrane and neuromuscular junction. Reason: The official human record carries a by-similarity membrane/synapse assignment. The exact mouse Q18PE0 donor record has postsynaptic-membrane IDA evidence from PMID:16794080, consistent with muscle-intrinsic MUSK signaling and receptor clustering. The refinement specifies the established postsynaptic functional pool without claiming that the electronic mapping itself measured a narrower human compartment. It does not exclude the HPA nuclear or mitochondrial pools. The independently supported neuromuscular-junction descendant also retains the anatomical specificity of this synapse assignment. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB-SubCell:SL-0258 SUPPORTS TRANSFER The synapse mapping is sound. The conserved muscle postsynaptic compartment supplies the narrower location; other cellular pools remain retained. Proposed replacements: postsynaptic membrane neuromuscular junction |
| GO:0045211 postsynaptic membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Conserved postsynaptic-membrane role in muscle signaling. Reason: The imported ortholog assertion is supported by exact mouse Q18PE0 postsynaptic-membrane IDA evidence and the muscle-intrinsic MUSK/DOK7 mechanism. Preserve the specific functional location while making the mouse-to-human inference explicit. The kinase study uses human solution fragments but mouse direct activation experiments; neither establishes exclusive localization of all human splice products. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q18PE0 SUPPORTS TRANSFER The donor has experimental GO:0045211 support from PMID:16794080. This is not a localization inferred from HPA fractionation. |
| GO:0061098 positive regulation of protein tyrosine kinase activity | IDA PMID:20603078 The cytoplasmic adaptor protein Dok7 activates the receptor ... | ACCEPT | Summary: DOK7 positively regulates MUSK tyrosine kinase activity. Reason: The primary study measures increased MUSK autophosphorylation and separates receptor binding from efficient activation using DOK7 dimer-interface mutants. Human PH–PTB supplies solution binding/oligomerization evidence, while mouse PH–PTB and mouse full-length Dok7 supply the direct kinase and cellular activation assays. This supports conserved positive regulation of protein tyrosine kinase activity and the activator mechanism, without assigning kinase catalysis to DOK7. Supporting Evidence: |
| GO:0030296 protein tyrosine kinase activator activity | ISS PMID:20603078 The cytoplasmic adaptor protein Dok7 activates the receptor ... | NEW | Summary: Propose the MUSK-activating molecular activity represented in the first core function. Reason: Mouse Dok7 PH–PTB directly increases MUSK autophosphorylation in the purified-component assay, and dimer-interface mutants separate receptor binding from efficient activation. The human PH–PTB construct binds phosphorylated rat MUSK and supports the conserved receptor-organizing mechanism, but was not the species used in the direct kinase-rate assay. Therefore this human proposal uses sequence-similarity evidence from the verified mouse Dok7 ortholog Q18PE0, rather than claiming human IDA. DOK7 performs the activation step; MUSK performs phosphotransfer. The activator term is distinct from the receptor-binding terms and is not their ancestor or descendant. This gene-level inference does not establish equivalent activity for all natural isoforms. |
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Download this section (compressed HTML)Q: How do the four natural DOK7 products differ in stability, receptor activation, adaptor recruitment and cellular distribution?
Q: What is the molecular role of the nucleoplasmic and mitochondrial DOK7 pools observed in human cell lines, and are these pools present in differentiated skeletal muscle?
Q: Which exchange factors directly connect DOK7–CRK/CRKL signaling to Rac regulation in muscle?
Q: Can the phosphotyrosine-recognition mechanism seen with mouse PH–PTB and the MUSK pTyr553 peptide be directly verified for the human products, to support a separate GO:0001784 phosphotyrosine residue binding assertion alongside the receptor-binding annotation?
Experiment: Compare accession-resolved natural DOK7 products at matched expression in muscle cells, measuring MUSK binding and activation, CRK/CRKL recruitment, AChR clustering and localization. Include sequence-confirmed controls that distinguish changes in abundance from altered signaling.
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