LMTK1 (formerly AATK) is an alternatively spliced serine/threonine protein kinase of the lemur-tail kinase family. The 1,374-amino-acid reference product contains a predicted N-terminal transmembrane helix and an N-proximal kinase domain, whereas shorter isoforms alter or remove these regions. LMTK1 is membrane-associated and occurs in cytoplasmic and perinuclear compartments. LMTK1 phosphorylates TP53 at Ser366, and its kinase activity can restrain cell proliferation. In rodent neurons, a transmembrane-domain-free LMTK1A form acts at Rab11-positive recycling endosomes, where a CDK5/p35-LMTK1-Rab11 pathway regulates endosomal traffic and limits axon, dendrite, and dendritic-spine growth. LMTK1 also associates with protein phosphatase 1 catalytic subunits, although the physiological role of this interaction remains unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0051402 neuron apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: A mouse cerebellar-granule-cell study found that wild-type AATK enhanced apoptosis relative to a kinase-deficient construct under low-KCl conditions. This supports the PAINT transfer as a conserved neuronal context, but neuronal apoptosis is not the best-supported core role of human LMTK1. Reason: Retain the annotation as a non-core, orthology-supported process. The source study is explicitly about mouse Aatk and the cached record is abstract-only, so it does not establish a direct human neuronal-apoptosis annotation. Direct human evidence instead establishes serine/threonine kinase activity; neuronal differentiation was observed in a human cell line with unresolved construct species, and the endosomal-trafficking evidence is rodent or heterologous. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1197518 · mouse Aatk SUPPORTS TRANSFER The mouse source has direct experimental support for a role in apoptosis of mature cerebellar granule neurons (PMID:11314040), although the full text is unavailable in the cache and the role is contextual rather than core. PANTHER:PTN002815112 · PANTHER ancestral node SUPPORTS TRANSFER The PAINT node links the orthologous mammalian LMTK1 proteins; no evidence of loss in human was identified, but the transfer remains indirect. Supporting Evidence: PMID:11314040 The number of apoptotic granule cells overexpressing wild-type AATYK protein was significantly greater than the number of apoptotic granule cells overexpressing a mutant AATYK that lacked tyrosine kinase activity in low concentrations of KCl. |
| GO:0004713 protein tyrosine kinase activity | IBA GO_REF:0000033 | UNDECIDED | Summary: The mouse donor paper reports tyrosine kinase activity, whereas direct human evidence establishes serine/threonine kinase activity and TP53 Ser366 phosphorylation. The heterogeneous human phosphotyrosine profiles do not resolve whether LMTK1 also has weak or dual tyrosine activity. Reason: Leave the tyrosine-specific IBA undecided. The cached mouse abstract explicitly reports tyrosine activity, its full assay details are unavailable, and the later positive human serine/threonine evidence does not logically exclude dual specificity. Nevertheless, the current PANTHER family is named for serine/threonine-protein kinases, PMID:20422042 likewise classifies AATYK1 as a serine/threonine kinase, and the matched human PTK/STK profiling in PMID:35902728 produced heterogeneous PTK profiles but a clearly divergent STK profile. GO:0004674 and GO:0106310 are independently supported human annotations rather than replacements that disprove this phylogenetic row. Propagation Review Root cause: UNRESOLVED Sources checked: MGI:MGI:1197518 · mouse Aatk UNRESOLVED PMID:11314040 reports tyrosine kinase activity for mouse Aatk, but the full assay details are unavailable and the target-specific human evidence does not exclude weak or dual tyrosine activity. PANTHER:PTN002815112 · PANTHER ancestral node UNRESOLVED The node supports orthology, and the current PANTHER family is named for serine/threonine-protein kinases, but the older mouse tyrosine-activity report prevents confident rejection of possible dual specificity. Supporting Evidence: PMID:11314040 AATYK possessed tyrosine kinase activity and was autophosphorylated when expressed in 293 cells. PMID:35902728 The individual basal activity profiles of all three replicates for AATK wt and AATK KD in the PTK assay was very heterogeneous (Fig. S11A). In contrast, the activity profiles from the STK assay comparing the AATK wt and AATK KD expressing clone pools depicted a clearly diverging activity profile (Fig. S11B). PMID:20422042 Apoptosis-associated tyrosine kinase 1 (AATYK1), a novel serine/threonine kinase that is highly expressed in the brain, is involved in neurite extension and apoptosis of cerebellar granule neurons; however, its precise function remains unknown. file:interpro/panther/PTHR24417/PTHR24417-metadata.yaml Serine/threonine-protein kinase LMTK |
| GO:0007420 brain development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: A broad developmental consequence is plausible from mouse-neuron studies in which LMTK1 regulates axon extension and dendritic-spine formation through Rab11-positive endosome trafficking. It is downstream context rather than the core molecular activity. Reason: Retain the PAINT annotation as a non-core developmental role. The available mechanistic experiments were performed in mouse cortical neurons and mouse brain, so they support orthology transfer but not direct human brain-development evidence. The better-bounded conserved role is orthology-supported control of neuronal recycling-endosome trafficking; its conservation and catalytic mechanism in human neurons remain untested. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:1197518 · mouse Aatk SUPPORTS TRANSFER Direct mouse-neuron and mouse-brain studies support neuronal morphogenesis and synapse-development phenotypes, while the broad brain-development term remains a downstream summary. PANTHER:PTN002815112 · PANTHER ancestral node SUPPORTS TRANSFER The PAINT node transfers the conserved neuronal developmental context across LMTK1 orthologs; human evidence remains indirect for this process. Supporting Evidence: PMID:22573681 Thus, LMTK1 can negatively control axonal outgrowth by regulating Rab11A activity in a Cdk5-dependent manner, and Cdk5-LMTK1-Rab11 is a novel signaling pathway involved in axonal outgrowth. PMID:31628178 Depletion of LMTK1 increases spine formation, maturation, and density in primary cultured neurons and in mouse brain of either sex. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro-mapped protein kinase activity is correct but unnecessarily broad. Direct human assays establish serine/threonine rather than generic kinase activity. Reason: Replace the parent protein kinase term with the experimentally supported protein serine/threonine kinase activity term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR001245 · serine/threonine/tyrosine protein kinase catalytic domain SUPPORTS TRANSFER The domain supports kinase activity but maps at a broader level than direct human substrate-specificity evidence. InterPro:IPR008266 · tyrosine kinase active-site signature SUPPORTS SOURCE BUT NOT TARGET A sequence signature supports a kinase fold but does not establish tyrosine substrate specificity for human LMTK1. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:35902728 Via large-scale kinomic profiling and kinase assays, we demonstrate that AATK acts a Ser/Thr kinase that phosphorylates TP53 at Ser366. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: Correct core molecular function. Direct comparison of human AATK/LMTK1 wild-type and kinase-dead proteins establishes serine/threonine kinase activity, including direct phosphorylation of TP53 at Ser366. Reason: The EC mapping agrees with direct target-specific human biochemical evidence and is the appropriate specificity level for the demonstrated activity. This gene-level annotation describes kinase-competent LMTK1 products; human isoform 2 lacks residues 1-433, including the annotated kinase domain. Propagation Review Root cause: NO FAILURE CORE Sources checked: EC:2.7.11.1 · non-specific serine/threonine protein kinase SUPPORTS TRANSFER The EC assignment matches the activity demonstrated directly for human LMTK1 in PMID:35902728. Supporting Evidence: PMID:35902728 Via large-scale kinomic profiling and kinase assays, we demonstrate that AATK acts a Ser/Thr kinase that phosphorylates TP53 at Ser366. |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro entry is named for the LMTK1 serine/threonine kinase domain but is mapped to tyrosine-specific activity. Direct human evidence establishes serine/threonine activity, and current PANTHER metadata independently classifies the LMTK family as serine/threonine protein kinases. Reason: Replace the tyrosine-specific electronic mapping with GO:0004674. The source entry itself is a serine/threonine-protein kinase LMTK1 catalytic domain, the PTHR24417 family is named serine/threonine-protein kinase LMTK, PMID:20422042 classifies AATYK1 as a serine/threonine kinase, and matched human profiling in PMID:35902728 yielded heterogeneous PTK profiles but a clearly divergent STK profile. Possible weak dual tyrosine activity is not formally excluded, but it does not justify this demonstrably mis-scoped InterPro-to-GO mapping. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR042817 · serine/threonine-protein kinase LMTK1 catalytic domain SOURCE BAD The domain classification supports kinase activity, but its tyrosine-specific GO mapping is inconsistent with the entry name, current PANTHER family classification, and target-level serine/threonine evidence. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:35902728 The individual basal activity profiles of all three replicates for AATK wt and AATK KD in the PTK assay was very heterogeneous (Fig. S11A). In contrast, the activity profiles from the STK assay comparing the AATK wt and AATK KD expressing clone pools depicted a clearly diverging activity profile (Fig. S11B). PMID:20422042 Apoptosis-associated tyrosine kinase 1 (AATYK1), a novel serine/threonine kinase that is highly expressed in the brain, is involved in neurite extension and apoptosis of cerebellar granule neurons; however, its precise function remains unknown. file:interpro/panther/PTHR24417/PTHR24417-metadata.yaml Serine/threonine-protein kinase LMTK |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ATP binding is chemically compatible with the conserved kinase domain and with ATP-dependent phosphotransfer, but it is a generic, mechanistically uninformative annotation beside the catalytic kinase terms. Reason: Retain ATP binding as a real, non-core molecular feature. The ATP-binding-site signature and active kinase domain support the annotation, but catalytic protein serine/threonine kinase activity is the more informative core function; the separate binding term is not being treated as ontologically entailed by catalysis. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR000719 · protein kinase domain SUPPORTS TRANSFER The kinase domain supports ATP use, but the generic binding annotation adds little beyond the catalytic function. InterPro:IPR017441 · protein kinase ATP-binding-site signature SUPPORTS TRANSFER The signature supports ATP binding while remaining less informative than the experimentally established phosphotransferase activity. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Correct broad location. AATYK expressed in human SH-SY5Y cells showed cytoplasmic localization by indirect immunofluorescence, although the cached abstract does not identify the transfected cDNA species. Reason: Accept the UniProt vocabulary mapping with curator deference and human-cell localization support. This should not be described as unambiguous direct assay of human Q6ZMQ8 because the abstract-only source leaves the construct species unresolved. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0086 · UniProtKB cytoplasm vocabulary term SUPPORTS TRANSFER The mapped UniProt location is backed by human-cell immunofluorescence in PMID:10837911. Supporting Evidence: PMID:10837911 Indirect immunofluorescent staining of the clones revealed AATYK to be localized in the cytoplasm. |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Broad membrane localization is supported for canonical human Q6ZMQ8-1 by a predicted transmembrane helix at residues 32-52. Rodent LMTK1A is instead a transmembrane-domain-lacking isoform whose recycling-endosome attachment depends on N-terminal palmitoylation, so that literature is compartmental orthology evidence rather than proof of human canonical topology. Reason: Accept the broad gene-level membrane term from the canonical human sequence prediction. This is not direct experimental proof of human topology: Q6ZMQ8-2 lacks residues 1-433, including the transmembrane segment and kinase domain, and rodent LMTK1A reaches recycling endosomes by a different attachment mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0162 · UniProtKB membrane vocabulary term SUPPORTS TRANSFER The mapping agrees with the predicted transmembrane helix of canonical human Q6ZMQ8-1. Rodent neuronal endosome evidence is consistent only at the broad compartment level and uses a distinct palmitoylation-based mechanism. Supporting Evidence: file:human/LMTK1/LMTK1-uniprot.txt CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250}; Single-pass type I CC membrane protein {ECO:0000250}. PMID:18691334 AATYK1A, an isoform without a transmembrane domain, is highly expressed in neurons. We identified palmitoylation of AATYK1A at three N-terminal cysteine residues in cortical cultured neurons and COS-7 cells and found that palmitoylation determined localization of AATYK1A to the transferrin receptor-positive recycling endosomes. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Correct subcellular location. UniProt records predominantly perinuclear cytoplasmic localization from the human-cell study, and mouse-neuron experiments place LMTK1 with Rab11A at the perinuclear region. Reason: The mapping is consistent with LMTK1's association with the pericentrosomal recycling-endosome compartment. The cached human paper is abstract-only and does not expose the perinuclear assay details, so the curated UniProt statement is retained rather than second-guessed. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0198 · UniProtKB perinuclear-region vocabulary term SUPPORTS TRANSFER The UniProt location is curator-linked to PMID:10837911 and agrees with independent mouse-neuron recycling-endosome localization. Supporting Evidence: file:human/LMTK1/LMTK1-uniprot.txt CC {ECO:0000269|PubMed:10837911}. Cytoplasm, perinuclear region CC {ECO:0000269|PubMed:10837911}. Note=Predominantly perinuclear. PMID:22573681 LMTK1 was expressed and was phosphorylated at Ser34, the Cdk5 phosphorylation site, at the time of axonal outgrowth in culture and colocalized with Rab11A, the small GTPase that regulates recycling endosome traffic, at the perinuclear region and in the axon. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Correct core molecular function. A direct human in vitro kinase assay identifies phosphorylation of TP53 at Ser366, supporting protein serine kinase activity. Reason: The Rhea-derived serine-specific term is directly corroborated by a defined human protein substrate and site, rather than only by family classification. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:17989 · L-seryl-protein phosphorylation reaction SUPPORTS TRANSFER The mapped reaction matches direct phosphorylation of TP53 Ser366 by human AATK/LMTK1. Supporting Evidence: PMID:35902728 In vitro kinase assay supported that AATK is a Ser/Thr kinase phosphorylating TP53 at Ser366 (Fig. 5D). |
| GO:0005515 protein binding | IPI PMID:22321011 Protein phosphatase 1α interacting proteins in the human bra... | MODIFY | Summary: The IPI row records an interaction with PPP1CA from a human-brain PP1alpha interaction screen. Independent functional work identified a PP1 docking motif in AATYK1 and a PP1-dependent scaffolding role, so a specific PP1-binding term is justified. Reason: Replace generic protein binding with protein phosphatase 1 binding. The source row identifies the PP1alpha catalytic subunit, and PMID:17267545 supplies the missing mechanistic evidence that the PP1 interaction depends on an AATYK1 docking motif and contributes to a scaffold function. The gene-level human IPI supports the replacement independently; the heterologous motif mechanism should not be generalized across human splice products without isoform-resolved validation. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:22321011 Sixty-six proteins were recognized to bind PP1α, 39 being novel PIPs. PMID:17267545 We identified a PP1 docking motif in AATYK1 and demonstrated interaction using yeast-2-hybrid analysis. |
| GO:0005515 protein binding | IPI PMID:25852190 Integrative analysis of kinase networks in TRAIL-induced apo... | MODIFY | Summary: The normalized IPI row records PPP1CC and PPP1CA from a large kinase-network study. Dedicated AATYK1 work independently demonstrates PP1 docking and a PP1-dependent scaffolding function, supporting a more specific binding term. Reason: Replace generic protein binding with protein phosphatase 1 binding. The proteomics row alone does not establish an enzyme-substrate relationship, but its two PP1 catalytic-subunit partners agree with motif-dependent PP1 binding and functional scaffolding in PMID:17267545. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:25852190 We assembled protein interaction maps using mass spectrometry-based protein interaction analysis and quantitative phosphoproteomics. PMID:17267545 Furthermore, the physical interaction between PP1 and AATYK was required for inhibition of NKCC1 activity in Xenopus laevis oocytes. |
| GO:0005515 protein binding | IPI PMID:28065597 A Global Analysis of the Receptor Tyrosine Kinase-Protein Ph... | MODIFY | Summary: The normalized IPI row records PPP1CC and PPP1CA from a systematic kinase-phosphatase interactome. Independent motif and functional evidence for AATYK1-PP1 binding supports replacement by the specific PP1-binding term. Reason: The source explicitly cautions that detected interactions are not equivalent to enzyme-substrate relationships. This review therefore makes no phosphorylation or dephosphorylation claim, but the replicated PP1 catalytic-subunit partners plus PMID:17267545 justify protein phosphatase 1 binding. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:28065597 However, it should be noted that these interactions are not equivalent to enzyme-substrate interactions, and therefore do not necessarily suggest that the involved phosphatase directly dephosphorylates a given RTK or, conversely, that the RTK can phosphorylate the phosphatase. PMID:17267545 We identified a PP1 docking motif in AATYK1 and demonstrated interaction using yeast-2-hybrid analysis. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: The IPI row records a binary interaction with TEPSIN in the HuRI reference map. The pair may be reproducible, but generic protein binding is not an informative molecular function and no LMTK1-specific role follows from the screen alone. Reason: Retain the partner provenance while flagging the generic GO term. A mechanistic endocytic-adaptor relationship would need targeted validation in a relevant cell context. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:35384245 Physical and functional interactome atlas of human receptor ... | MODIFY | Summary: The IPI row records PPP1CC from a systematic AP-MS/BioID interaction atlas. The observed association agrees with independent evidence for motif-dependent PP1 binding and can be represented by a specific PP1-binding term. Reason: Replace generic protein binding with protein phosphatase 1 binding. The study included the LMR family for completeness and its PPP1CC observation is consistent with the AATYK1 PP1-docking motif and PP1-dependent scaffolding mechanism reported in PMID:17267545. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:35384245 We use affinity purification coupled to mass spectrometry (AP-MS) to characterize stable binding partners and RTK-protein complexes, proximity-dependent biotin identification (BioID) to identify transient and proximal interactions, and an in vitro kinase assay to identify RTK substrates. PMID:17267545 Taken together, our data are consistent with AATYK1 indirectly inhibiting the SPAK/WNK4 activation of the cotransporter by scaffolding an inhibitory phosphatase in proximity to a stimulatory kinase. |
| GO:0018105 peptidyl-serine phosphorylation | IDA PMID:35902728 Epigenetically silenced apoptosis-associated tyrosine kinase... | NEW | Summary: Direct human kinase assays show that LMTK1 phosphorylates TP53 at Ser366. Reason: This missing process annotation captures the experimentally demonstrated phosphotransfer reaction and its defined human protein substrate. Supporting Evidence: PMID:35902728 In vitro kinase assay supported that AATK is a Ser/Thr kinase phosphorylating TP53 at Ser366 (Fig. 5D). |
| GO:0008285 negative regulation of cell population proliferation | IMP PMID:35902728 Epigenetically silenced apoptosis-associated tyrosine kinase... | NEW | Summary: Wild-type human LMTK1 suppresses growth relative to controls and a kinase-dead mutant in the tested human cell models. Reason: Direct perturbation supports this missing annotation, but the result comes from engineered cancer and transformed-cell contexts and is retained as a context-specific, non-core phenotype rather than a general physiological role. It is therefore deliberately omitted from core_functions. Supporting Evidence: PMID:35902728 Moreover, growth suppression through AATK relies on its kinase activity. |
| GO:0030517 negative regulation of axon extension | ISO PMID:22573681 LMTK1/AATYK1 is a novel regulator of axonal outgrowth that a... | NEW | Summary: Mouse Lmtk1 knockdown, knockout, and rescue experiments show that it restrains axon extension through Rab11A-positive endosome trafficking. Reason: Strong mouse ortholog evidence supports conservative transfer of this missing process annotation to human LMTK1. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q80YE4 · mouse Lmtk1 SUPPORTS TRANSFER The experiments directly test mouse Lmtk1, whereas the target is human LMTK1. Historical neuronal LMTK1A nomenclature does not map one-to-one onto current human Q6ZMQ8 isoforms, so this is a gene-level orthology transfer and no human isoform is assigned. Supporting Evidence: PMID:22573681 Thus, LMTK1 can negatively control axonal outgrowth by regulating Rab11A activity in a Cdk5-dependent manner, and Cdk5-LMTK1-Rab11 is a novel signaling pathway involved in axonal outgrowth. |
| GO:0050774 negative regulation of dendrite morphogenesis | ISO PMID:24672056 LMTK1 regulates dendritic formation by regulating movement o... | NEW | Summary: Mouse neuronal and in-vivo loss-of-function experiments show that Lmtk1 restrains dendrite growth and branching through Rab11A-positive endosomes. Reason: Strong mouse ortholog evidence supports conservative transfer of this missing process annotation to human LMTK1. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q80YE4 · mouse Lmtk1 SUPPORTS TRANSFER The experiments directly test mouse Lmtk1, whereas the target is human LMTK1. Historical neuronal LMTK1A nomenclature does not map one-to-one onto current human Q6ZMQ8 isoforms, so this is a gene-level orthology transfer and no human isoform is assigned. Supporting Evidence: PMID:24672056 Thus LMTK1 negatively controls dendritic formation by regulating Rab11A-positive endosomal trafficking in a Cdk5-dependent manner, indicating the Cdk5-LMTK1-Rab11A pathway as a regulatory mechanism of dendrite development as well as axon outgrowth. |
| GO:0061002 negative regulation of dendritic spine morphogenesis | ISO PMID:31628178 The LMTK1-TBC1D9B-Rab11A Cascade Regulates Dendritic Spine F... | NEW | Summary: Depletion or kinase inactivation of mouse Lmtk1 increases dendritic-spine formation, maturation, and density in cultured neurons and mouse brain. Reason: Strong mouse ortholog evidence supports conservative transfer of this missing process annotation to human LMTK1. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q80YE4 · mouse Lmtk1 SUPPORTS TRANSFER The experiments directly test mouse Lmtk1, whereas the target is human LMTK1. Historical neuronal LMTK1A nomenclature does not map one-to-one onto current human Q6ZMQ8 isoforms, so this is a gene-level orthology transfer and no human isoform is assigned. Supporting Evidence: PMID:31628178 Depletion of LMTK1 increases spine formation, maturation, and density in primary cultured neurons and in mouse brain of either sex. |
| GO:2001135 regulation of endocytic recycling | ISO PMID:24672056 LMTK1 regulates dendritic formation by regulating movement o... | NEW | Summary: Mouse Lmtk1 regulates Rab11A-positive endosomal trafficking in neurons. Reason: The direction-neutral term conservatively represents the orthology-supported recycling-endosome role without asserting that every transport parameter or cargo is regulated in the same direction in human cells. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q80YE4 · mouse Lmtk1 SUPPORTS TRANSFER The experiments directly test mouse Lmtk1, whereas the target is human LMTK1. Historical neuronal LMTK1A nomenclature does not map one-to-one onto current human Q6ZMQ8 isoforms, so this is a gene-level orthology transfer and no human isoform is assigned. Supporting Evidence: PMID:24672056 Thus LMTK1 negatively controls dendritic formation by regulating Rab11A-positive endosomal trafficking in a Cdk5-dependent manner, indicating the Cdk5-LMTK1-Rab11A pathway as a regulatory mechanism of dendrite development as well as axon outgrowth. |
| GO:0055037 recycling endosome | ISO PMID:18691334 Palmitoylation-dependent endosomal localization of AATYK1A a... | NEW | Summary: Mouse Lmtk1A localizes to transferrin-receptor-positive recycling endosomes in neuronal and heterologous cells through N-terminal palmitoylation. Reason: Add the missing recycling-endosome location by orthology. The evidence directly tests the mouse ortholog and a historical transmembrane-domain-free LMTK1A form, so this is a gene-level ISO transfer rather than human IDA and is not assigned to a current numbered human isoform. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q80YE4 · mouse Lmtk1 SUPPORTS TRANSFER The localization is directly established for mouse Lmtk1A. Historical LMTK1A nomenclature and its palmitoylation-based membrane attachment do not map one-to-one onto current human Q6ZMQ8 isoforms, so the transfer is kept at gene and compartment level. Supporting Evidence: PMID:18691334 AATYK1A, an isoform without a transmembrane domain, is highly expressed in neurons. We identified palmitoylation of AATYK1A at three N-terminal cysteine residues in cortical cultured neurons and COS-7 cells and found that palmitoylation determined localization of AATYK1A to the transferrin receptor-positive recycling endosomes. |
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Download this section (compressed HTML)Q: Which current human Q6ZMQ8 isoform was used in PMID:35902728?
Q: Is the LMTK1-TBC1D9B-Rab11A pathway conserved in human neurons, and which human isoform executes it?
Q: Is TBC1D9B a direct LMTK1 substrate or an indirect pathway component?
Q: Does human LMTK1 possess reproducible intrinsic tyrosine kinase activity in addition to protein serine kinase activity?
Q: Do the recurrent human PPP1CA and PPP1CC interactions support a physiological PP1-STK39 scaffold?
Experiment: Sequence-map the PMID:35902728 construct and compare purified Q6ZMQ8-1, Q6ZMQ8-2, and Q6ZMQ8-3 for TP53 Ser366 phosphorylation and unbiased serine/threonine substrate specificity.
Experiment: Use CRISPR knockout and sequence-defined isoform rescue in human iPSC-derived neurons with live Rab11A imaging and quantitative axon, dendrite, and spine measurements.
Experiment: Perform LMTK1-dependent neuronal phosphoproteomics followed by purified-protein assays and phosphosite-mutant rescue to test TBC1D9B as a direct substrate.
Experiment: Measure purified human LMTK1 activity on matched serine, threonine, and tyrosine substrates with kinase-dead controls and phospho-amino-acid analysis.
Experiment: Identify the PMID:17267545 construct sequence, validate endogenous PPP1CA and PPP1CC binding by reciprocal immunoprecipitation, mutate the candidate PP1-docking motif, and test PP1-STK39 pathway output independently of LMTK1 catalysis.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The human construct used for the direct kinase work in PMID:35902728 has not been mapped unambiguously to a current Q6ZMQ8 isoform.
OPEN BIOLOGYCURATION RESIDUAL_SUBGAP
What is known: Q6ZMQ8-2 lacks residues 1-433, including the kinase domain, whereas Q6ZMQ8-1 and Q6ZMQ8-3 retain the kinase domain.
Significance: Isoform mapping is required before catalytic activity or TP53 phosphorylation can be assigned to a specific human isoform.
What would resolve it: Sequence the experimental construct and assay purified, sequence-defined Q6ZMQ8 isoforms.
Gap: Conservation of the LMTK1-TBC1D9B-Rab11A pathway in endogenous human neurons is untested.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Knockout, knockdown, rescue, trafficking, and neuronal-morphogenesis evidence is strong for the mouse ortholog, but historical LMTK1A does not map cleanly to a current human isoform.
Significance: This determines whether the orthology-supported neuronal role can become direct human evidence.
What would resolve it: Perform endogenous perturbation and sequence-defined isoform rescue in human neurons.
Gap: The direct neuronal substrate connecting LMTK1 kinase activity to TBC1D9B and Rab11A regulation is unknown.
OPEN BIOLOGY MF_DARK
What is known: Genetic and functional ordering places TBC1D9B downstream of LMTK1, but direct phosphorylation was not demonstrated.
Significance: Identifying the substrate is necessary to define the neuronal kinase mechanism.
What would resolve it: Combine LMTK1-dependent phosphoproteomics with purified-protein kinase assays and phosphosite-mutant rescue.
Gap: Reproducible intrinsic tyrosine kinase activity of human LMTK1 remains unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Direct human evidence establishes protein serine kinase activity, whereas the older tyrosine-activity evidence is from mouse and heterogeneous human phosphotyrosine profiles do not exclude weak dual specificity.
Significance: This resolves the conflict between legacy tyrosine annotations and modern serine-kinase evidence.
What would resolve it: Test purified human LMTK1 against defined serine, threonine, and tyrosine substrates with kinase-dead controls.
Gap: Whether recurrent human PP1 interactions represent a physiological PP1-STK39 scaffold is unknown, and the species of the PMID:17267545 AATYK1 construct is not stated in the cached abstract.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: PPP1CA and PPP1CC interactions recur in human screens, while PMID:17267545 reports motif-dependent PP1 and SPAK scaffolding in Xenopus oocytes without resolving the AATYK1 construct species in the cached text.
Significance: This distinguishes a conserved catalytic-independent function from recurrent screen binding.
What would resolve it: Identify the original construct sequence, validate endogenous human PP1 binding, map the docking motif, and test motif-dependent pathway output.
Provenance (the field's own admissions):
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