LMTK2 is a 1,503-amino-acid, two-pass integral membrane serine/threonine protein kinase whose amino terminus, carboxyl-terminal tail, and kinase active site face the cytoplasm. It functions on early and Rab11-positive recycling endosomes. LMTK2 docks protein phosphatase 1 catalytic subunits and associates with PPP1R2/inhibitor-2, phosphorylating PP1C at Thr320 to inhibit phosphatase activity. Through direct binding to unconventional myosin VI/MYO6, it supports cargo delivery from early endosomes to the endocytic recycling compartment. In human airway epithelial cells, LMTK2 also binds and phosphorylates CFTR at Ser737 and promotes CFTR endocytosis. Kinesin-linked axonal transport is supported in orthologous mouse and rat neuronal models, whereas TGF-beta/Smad signaling is supported in human airway epithelium; neither is established as a universal LMTK2 function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004672 protein kinase activity | IBA GO_REF:0000033 | MODIFY | Summary: PAINT transfers generic protein kinase activity across the LMTK family, but direct human biochemical studies resolve LMTK2 as a serine/threonine kinase. Reason: The broad kinase term is true but unnecessarily weak for LMTK2. Recombinant KPI-2/LMTK2 was reported to be strictly serine/threonine-specific, so replace this parent term with GO:0004674. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:1197518 · mouse Aatk/Lmtk1 SUPPORTS TRANSFER LMTK-family paralog that supports the broad ancestral kinase function. PANTHER:PTN004704357 · PANTHER ancestral LMTK node SUPPORTS TRANSFER PAINT node supports conserved kinase activity across this LMTK branch. UniProtKB:Q8IWU2 · human LMTK2 target SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own IDA annotation to GO:0004674 (protein serine/threonine kinase activity), a descendant of this term, is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. UniProtKB:Q96Q04 · human LMTK3 SUPPORTS TRANSFER LMTK paralog with conserved serine/threonine kinase activity. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:16887929 We found that KPI-2 is strictly a Ser/Thr kinase that reacts with Ser either preceded by or followed by Pro residues but unlike other Pro-directed kinases does not strictly require an adjacent Pro residue. |
| GO:0032456 endocytic recycling | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT assigns endocytic recycling to LMTK2, consistent with direct depletion phenotypes and localization along the early-endosome-to-recycling-endosome route. Reason: This is a core LMTK2 process. Independent human experiments show that loss of LMTK2 blocks transferrin-receptor cargo delivery from early endosomes to the endocytic recycling compartment. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002814775 · PANTHER ancestral LMTK2 node SUPPORTS TRANSFER The phylogenetic node transfers a process independently corroborated in human cells. UniProtKB:Q8IWU2 · human LMTK2 target SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own IMP annotation to this term is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. Supporting Evidence: PMID:18029400 When either myosin VI or LMTK2 is depleted by siRNAs, the transferrin receptor (TfR) is trapped in swollen endosomes and tubule formation in the endocytic recycling pathway is dramatically reduced, showing that both proteins are required for the transport of cargo, such as the TfR, from early endosomes to the endocytic recycling compartment. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro domains establish a protein-kinase fold, but direct substrate assays support the more informative serine/threonine kinase term. Reason: GO:0004672 is correct but too broad. The tyrosine-kinase-like sequence signature does not override biochemical evidence that LMTK2 is strictly a Ser/Thr kinase; replace with GO:0004674. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR001245 · protein kinase catalytic domain SUPPORTS TRANSFER Correctly detects the catalytic kinase domain but maps only to the generic parent term. InterPro:IPR008266 · tyrosine-protein kinase active-site signature SUPPORTS SOURCE BUT NOT TARGET Sequence signature supports a kinase fold but not LMTK2 substrate-residue specificity. Proposed replacements: protein serine/threonine kinase activity Supporting Evidence: PMID:12393858 However, it only exhibited serine/threonine kinase activity in autophosphorylation reactions or with added substrates. |
| GO:0004674 protein serine/threonine kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC mapping assigns protein serine/threonine kinase activity, matching direct biochemical characterization of human LMTK2. Reason: The mapping is specific and correct: recombinant LMTK2 phosphorylates serine and threonine residues and lacks demonstrated tyrosine-kinase activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: EC:2.7.11.1 · non-specific serine/threonine protein kinase EC class SUPPORTS TRANSFER The EC assignment agrees with direct LMTK2 biochemistry. Supporting Evidence: PMID:16887929 We found that KPI-2 is strictly a Ser/Thr kinase that reacts with Ser either preceded by or followed by Pro residues but unlike other Pro-directed kinases does not strictly require an adjacent Pro residue. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Conserved protein-kinase features predict ATP binding, a real but generic mechanistic property of LMTK2 catalysis. Reason: Retain as a valid non-core molecular function. ATP binding is inherent to the phosphotransfer reaction but is less informative than the specific catalytic activity GO:0004674. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR000719 · protein kinase domain SUPPORTS TRANSFER Kinase-domain match includes the conserved ATP-binding machinery. InterPro:IPR017441 · protein kinase ATP-binding region signature SUPPORTS TRANSFER Directly supports nucleotide binding but not a distinct core role. |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping places LMTK2 at membranes, consistent with its two N-terminal transmembrane helices and experimental membrane targeting. Reason: Membrane localization is a defining feature of LMTK2 and provides the platform for its endosomal trafficking function. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0162 · UniProt membrane subcellular-location vocabulary SUPPORTS TRANSFER Correct conservative mapping of the experimentally supported membrane location. Supporting Evidence: PMID:12393858 The transmembrane helices were sufficient for targeting proteins to the membrane. |
| GO:0106310 protein serine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea maps LMTK2's ATP-dependent protein-serine phosphorylation reaction to protein serine kinase activity. Reason: Serine-directed protein kinase activity is directly demonstrated and is a core subactivity of the broader serine/threonine kinase function. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:17989 · ATP-dependent protein-serine phosphorylation reaction SUPPORTS TRANSFER The mapped reaction is directly supported by serine-substrate assays. Supporting Evidence: PMID:16887929 The most reactive peptide in the library corresponds to Ser-737 of cystic fibrosis transmembrane conductance regulator, and the recombinant R domain of cystic fibrosis transmembrane conductance regulator was a preferred substrate. |
| GO:0005515 protein binding | IPI PMID:12393858 A novel transmembrane Ser/Thr kinase complexes with protein ... | MARK AS OVER ANNOTATED | Summary: LMTK2 directly associates with protein phosphatase inhibitor-2/PPP1R2, but the root-level protein-binding term does not describe the functional interaction. Reason: The interaction is experimentally supported, yet GO:0005515 is uninformative and no suitable partner-specific GO molecular-function term captures inhibitor-2 binding. Do not treat this generic term as a core function. Supporting Evidence: PMID:12393858 Inh2 associated with KPI-2 C-terminal domain with and without PP1C. |
| GO:0005515 protein binding | IPI PMID:24366813 Interaction proteome of human Hippo signaling: modular contr... | MODIFY | Summary: This interaction-proteomics row records LMTK2 binding to PPP1CC, the catalytic gamma isoform of protein phosphatase 1. Reason: The interaction is valid and independently established as direct, but generic protein binding should be replaced by GO:0008157 protein phosphatase 1 binding. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:12393858 KPI-2 C-terminal domain directly associated with PP1C, and this required a VTF motif. |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MODIFY | Summary: Quantitative interactome evidence reports association of LMTK2 with PPP1CC, consistent with the established LMTK2-PP1 regulatory complex. Reason: The generic term obscures the partner class. Replace it with GO:0008157 protein phosphatase 1 binding, supported independently by direct domain-level association. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:12393858 KPI-2 C-terminal domain directly associated with PP1C, and this required a VTF motif. |
| GO:0005515 protein binding | IPI PMID:28065597 A Global Analysis of the Receptor Tyrosine Kinase-Protein Ph... | MODIFY | Summary: Phosphatase-interactome evidence records LMTK2 association with PPP1CC, matching the directly characterized LMTK2-PP1 complex. Reason: Replace generic protein binding with the informative and experimentally supported GO:0008157 protein phosphatase 1 binding term. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:12393858 KPI-2 C-terminal domain directly associated with PP1C, and this required a VTF motif. |
| GO:0005515 protein binding | IPI PMID:28330616 Systematic Analysis of Human Protein Phosphatase Interaction... | MODIFY | Summary: Systematic phosphatase-interaction mapping reports LMTK2 with PPP1CC and corroborates the known LMTK2-PP1 regulatory complex. Reason: The interaction is sound, but GO:0005515 is uninformative. Replace it with GO:0008157 protein phosphatase 1 binding. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:12393858 KPI-2 C-terminal domain directly associated with PP1C, and this required a VTF motif. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: Proteome-scale interaction mapping detects LMTK2 with PPP1CC, one of several datasets corroborating the established LMTK2-PP1 association. Reason: Use the informative GO:0008157 protein phosphatase 1 binding term instead of generic protein binding; direct biochemical evidence confirms PP1C association. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:12393858 KPI-2 C-terminal domain directly associated with PP1C, and this required a VTF motif. |
| GO:0005515 protein binding | IPI PMID:35384245 Physical and functional interactome atlas of human receptor ... | MARK AS OVER ANNOTATED | Summary: Interaction-atlas evidence corroborates LMTK2 association with PPP1R2/inhibitor-2, already established in the LMTK2-PP1 regulatory complex. Reason: The interaction is credible but generic protein binding is not an informative molecular function, and no appropriate partner-specific GO term is available. Supporting Evidence: PMID:12393858 Inh2 associated with KPI-2 C-terminal domain with and without PP1C. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MODIFY | Summary: Multimodal interaction mapping reports LMTK2 association with PPP1CC, consistent with prior direct biochemical characterization. Reason: Replace generic GO:0005515 with GO:0008157 protein phosphatase 1 binding; the partner identity and direct LMTK2-PP1C evidence justify the more specific term. Proposed replacements: protein phosphatase 1 binding Supporting Evidence: PMID:12393858 KPI-2 C-terminal domain directly associated with PP1C, and this required a VTF motif. |
| GO:0030426 growth cone | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfers growth-cone localization from rat Lmtk2 to the human ortholog. Reason: The orthology transfer is biologically plausible and fits neuronal LMTK2 localization, but growth-cone residence is a cell-context-specific location rather than the gene's general core compartment. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:D3ZBH5 · rat Lmtk2 SUPPORTS TRANSFER Rat ortholog carrying the experimentally grounded neuronal localization. ensembl:ENSRNOP00000050872 · rat Lmtk2 Ensembl protein CIRCULAR OR REDUNDANT Same rat donor protein as D3ZBH5, not an independent second source. |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfers neuronal-cell-body localization from rat Lmtk2 to the human ortholog. Reason: The transfer is consistent with broad neuronal expression and localization but is tissue-specific, so it is retained as a non-core cellular context. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:D3ZBH5 · rat Lmtk2 SUPPORTS TRANSFER Rat ortholog carrying the experimentally grounded neuronal localization. ensembl:ENSRNOP00000050872 · rat Lmtk2 Ensembl protein CIRCULAR OR REDUNDANT Same rat donor protein as D3ZBH5, not an independent second source. Supporting Evidence: PMID:12832520 Cprk is expressed in a number of tissues but is enriched in brain and muscle and within the brain is found in a wide range of neuronal populations. |
| GO:0001881 receptor recycling | IMP PMID:18029400 Myosin VI and its interacting protein LMTK2 regulate tubule ... | ACCEPT | Summary: LMTK2 depletion traps transferrin receptor in swollen endosomes and disrupts transport through the endocytic recycling route. Reason: A direct loss-of-function phenotype supports a core role in recycling receptors from early endosomes through the recycling compartment. Supporting Evidence: PMID:18029400 When either myosin VI or LMTK2 is depleted by siRNAs, the transferrin receptor (TfR) is trapped in swollen endosomes and tubule formation in the endocytic recycling pathway is dramatically reduced, showing that both proteins are required for the transport of cargo, such as the TfR, from early endosomes to the endocytic recycling compartment. |
| GO:0001881 receptor recycling | IMP PMID:18429820 BREK/LMTK2 is a myosin VI-binding protein involved in endoso... | ACCEPT | Summary: BREK/LMTK2 knockdown permits transferrin uptake to early endosomes but blocks its onward movement to perinuclear recycling endosomes. Reason: This experimentally supports receptor recycling as a central LMTK2 trafficking process, independently corroborating PMID:18029400. Supporting Evidence: PMID:18429820 Notably, cells in which BREK was depleted by siRNA were still able to internalize transferrin molecules and to transport them to early endosomes, but were unable to transport them to perinuclear recycling endosomes. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:16887929 Peptide microarray analysis of substrate specificity of the ... | ACCEPT | Summary: Recombinant LMTK2 kinase domain was profiled against 1,154 peptides and shown to phosphorylate serine/threonine rather than tyrosine substrates. Reason: This direct biochemical assay establishes the core molecular function at the appropriate GO specificity. Supporting Evidence: PMID:16887929 We found that KPI-2 is strictly a Ser/Thr kinase that reacts with Ser either preceded by or followed by Pro residues but unlike other Pro-directed kinases does not strictly require an adjacent Pro residue. |
| GO:0005515 protein binding | IPI PMID:12832520 Identification of a novel, membrane-associated neuronal kina... | MARK AS OVER ANNOTATED | Summary: LMTK2/cprk binds CDK5R1/p35 in yeast two-hybrid and pull-down assays and colocalizes with it in cells. Reason: The interaction is real but generic protein binding is uninformative, and the evidence does not establish a more specific binding molecular function for LMTK2. Supporting Evidence: PMID:12832520 Cprk interacts with p35 in the yeast-two hybrid system, binds to p35 in glutathione S-transferase fusion pull-down assays, and colocalizes with p35 in cultured neurons and transfected cells. |
| GO:0005769 early endosome | IDA PMID:18029400 Myosin VI and its interacting protein LMTK2 regulate tubule ... | ACCEPT | Summary: Imaging places LMTK2 on a subset of Rab5- and EEA1-positive early endosomes. Reason: Direct colocalization supports early-endosome residence as part of LMTK2's core endocytic-recycling route. Supporting Evidence: PMID:18029400 Double labelling experiments show that LMTK2 is present on a subset of early endosomes as revealed by colocalisation with Rab5 and EEA1 (Fig. 4, d-j) and also associated with the Rab11-positive endocytic recycling compartment (Fig. 4, k-m). |
| GO:0005769 early endosome | IDA PMID:18429820 BREK/LMTK2 is a myosin VI-binding protein involved in endoso... | ACCEPT | Summary: This source assigns early-endosome localization in the same trafficking route in which LMTK2 depletion blocks early-to-recycling-endosome transport. Reason: The cached record is abstract-only and does not expose the localization experiment, so the curator's experimental annotation is retained; independent full-text imaging in PMID:18029400 directly confirms LMTK2 on early endosomes. Supporting Evidence: PMID:18029400 Double labelling experiments show that LMTK2 is present on a subset of early endosomes as revealed by colocalisation with Rab5 and EEA1 (Fig. 4, d-j) and also associated with the Rab11-positive endocytic recycling compartment (Fig. 4, k-m). |
| GO:0005794 Golgi apparatus | IDA PMID:12832520 Identification of a novel, membrane-associated neuronal kina... | MARK AS OVER ANNOTATED | Summary: The earlier study assigned perinuclear LMTK2/cprk signal to the Golgi apparatus, but later direct imaging found very little overlap with the Golgi marker GM130. Reason: The original localization interpretation is reported, but independent imaging places LMTK2 chiefly on early and recycling endosomes and directly challenges a general Golgi assignment. Retain the source record while marking the organelle interpretation as over-annotated. Supporting Evidence: PMID:12832520 In these cells, cprk is present with p35 in the Golgi apparatus. PMID:18029400 However, we found very little overlap between LMTK2 and GM130, a marker protein of the Golgi matrix (supplementary materials Fig. S1A). |
| GO:0018105 peptidyl-serine phosphorylation | IDA PMID:16887929 Peptide microarray analysis of substrate specificity of the ... | ACCEPT | Summary: Peptide-array and recombinant-substrate assays establish LMTK2-mediated phosphorylation of protein serine residues. Reason: Direct substrate profiling supports this core biological process and matches the accepted serine/threonine kinase molecular function. Supporting Evidence: PMID:16887929 The most reactive peptide in the library corresponds to Ser-737 of cystic fibrosis transmembrane conductance regulator, and the recombinant R domain of cystic fibrosis transmembrane conductance regulator was a preferred substrate. |
| GO:0018107 peptidyl-threonine phosphorylation | IDA PMID:16887929 Peptide microarray analysis of substrate specificity of the ... | ACCEPT | Summary: This experimental annotation records the threonine-directed arm of LMTK2's serine/threonine protein kinase activity. Reason: The publication is abstract-only in the cache, so the curator's direct annotation is retained; the reported strict Ser/Thr specificity supports the process and does not suggest tyrosine phosphorylation. Supporting Evidence: PMID:16887929 We found that KPI-2 is strictly a Ser/Thr kinase that reacts with Ser either preceded by or followed by Pro residues but unlike other Pro-directed kinases does not strictly require an adjacent Pro residue. |
| GO:0032456 endocytic recycling | IMP PMID:18029400 Myosin VI and its interacting protein LMTK2 regulate tubule ... | ACCEPT | Summary: LMTK2 and myosin VI are required for delivery of receptor cargo from early endosomes to the endocytic recycling compartment and for recycling tubules. Reason: Multiple localization and knockdown experiments make endocytic recycling a core LMTK2 process. Supporting Evidence: PMID:18029400 LMTK2 is the first transmembrane protein and kinase that binds directly to myosin VI. Our functional studies demonstrate that both proteins, myosin VI and LMTK2, are required for delivery of cargo such as the transferrin receptor from the early endosome to the endocytic recycling compartment. |
| GO:0033572 transferrin transport | IMP PMID:18029400 Myosin VI and its interacting protein LMTK2 regulate tubule ... | KEEP AS NON CORE | Summary: Transferrin receptor was used as cargo to reveal an LMTK2-dependent block between early endosomes and the recycling compartment. Reason: The phenotype is experimentally sound, but transferrin is an assay cargo and this cargo-specific term is secondary to the core process of endocytic recycling. Supporting Evidence: PMID:18029400 When either myosin VI or LMTK2 is depleted by siRNAs, the transferrin receptor (TfR) is trapped in swollen endosomes and tubule formation in the endocytic recycling pathway is dramatically reduced, showing that both proteins are required for the transport of cargo, such as the TfR, from early endosomes to the endocytic recycling compartment. |
| GO:0033572 transferrin transport | IMP PMID:18429820 BREK/LMTK2 is a myosin VI-binding protein involved in endoso... | KEEP AS NON CORE | Summary: LMTK2 depletion selectively prevents transferrin movement from early to perinuclear recycling endosomes. Reason: This is a valid experimental cargo phenotype but represents a transferrin-receptor assay of the broader, core endocytic-recycling function. Supporting Evidence: PMID:18429820 Notably, cells in which BREK was depleted by siRNA were still able to internalize transferrin molecules and to transport them to early endosomes, but were unable to transport them to perinuclear recycling endosomes. |
| GO:0045022 early endosome to late endosome transport | IMP PMID:18429820 BREK/LMTK2 is a myosin VI-binding protein involved in endoso... | MODIFY | Summary: The experiment follows endocytosed cargo from early endosomes to perinuclear recycling endosomes, not to late endosomes. Reason: The source explicitly supports early-to-recycling-endosome traffic. Replace the wrong-destination term with GO:0032456 endocytic recycling; the issue is term scoping, not failure of the experimental evidence. Proposed replacements: endocytic recycling Supporting Evidence: PMID:18429820 Our results show that BREK is critical for the transition of endocytosed membrane vesicles from early endosomes to recycling endosomes and also suggest an involvement of myosin VI in this pathway. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:12832520 Identification of a novel, membrane-associated neuronal kina... | KEEP AS NON CORE | Summary: The study reports a perinuclear LMTK2/cprk signal, although its interpretation as Golgi was challenged by later endosomal imaging. Reason: Keep the broad spatial observation as contextual localization rather than creating a duplicate Golgi recommendation. Later work supports a perinuclear endosomal pool while finding very little overlap with the Golgi marker GM130. Supporting Evidence: PMID:12832520 In these cells, cprk is present with p35 in the Golgi apparatus. PMID:18029400 LMTK2 was present at the plasma membrane, in a vesicular staining pattern throughout the cell, but concentrated in cell extensions and in the perinuclear area (Fig. 3, 4). |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:18429820 BREK/LMTK2 is a myosin VI-binding protein involved in endoso... | KEEP AS NON CORE | Summary: The source localizes LMTK2 to perinuclear recycling endosomes and therefore also supports the broader perinuclear-region observation. Reason: Keep the true but nonspecific spatial term as contextual. A separate source row for this same paper already captures the more informative GO:0055037 recycling endosome location, so a MODIFY recommendation would create a duplicate. Supporting Evidence: PMID:18429820 Immunocytochemical analyses revealed that BREK localizes to cytoplasmic membrane vesicles and to perinuclear recycling endosomes. |
| GO:0055037 recycling endosome | IDA PMID:18029400 Myosin VI and its interacting protein LMTK2 regulate tubule ... | ACCEPT | Summary: Imaging places LMTK2 on the Rab11-positive endocytic recycling compartment. Reason: Direct colocalization and loss-of-function trafficking phenotypes make the recycling endosome a core LMTK2 location. Supporting Evidence: PMID:18029400 Double labelling experiments show that LMTK2 is present on a subset of early endosomes as revealed by colocalisation with Rab5 and EEA1 (Fig. 4, d-j) and also associated with the Rab11-positive endocytic recycling compartment (Fig. 4, k-m). |
| GO:0055037 recycling endosome | IDA PMID:18429820 BREK/LMTK2 is a myosin VI-binding protein involved in endoso... | ACCEPT | Summary: Immunocytochemistry localizes LMTK2/BREK to perinuclear recycling endosomes. Reason: This is the appropriate specific compartment for the experimentally demonstrated early-to-recycling-endosome trafficking function. Supporting Evidence: PMID:18429820 Immunocytochemical analyses revealed that BREK localizes to cytoplasmic membrane vesicles and to perinuclear recycling endosomes. |
| GO:0070853 myosin VI binding | IPI PMID:18029400 Myosin VI and its interacting protein LMTK2 regulate tubule ... | ACCEPT | Summary: LMTK2 directly binds unconventional myosin VI, but the raw GOA WITH/FROM accession P13533 resolves to MYH6 rather than MYO6. Reason: GO:0070853 and the IPI evidence are correct: the paper demonstrates direct LMTK2- myosin VI binding. Preserve P13533 as raw provenance but flag it as a homonym-driven source miscitation; the correct human MYO6 accession is UniProtKB:Q9UM54 and is cited only as additional evidence. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE MISCITATION Sources checked: UniProtKB:P13533 · human MYH6 cardiac myosin heavy chain 6 SOURCE BAD Raw WITH/FROM is a name-confused accession for MYH6; the assayed unconventional myosin VI/MYO6 protein is UniProtKB:Q9UM54. Supporting Evidence: PMID:18029400 LMTK2 binds to the WWY site in the C-terminal myosin VI tail, the same site as the endocytic adaptor protein Dab2. |
| GO:0070853 myosin VI binding | IPI PMID:18429820 BREK/LMTK2 is a myosin VI-binding protein involved in endoso... | ACCEPT | Summary: Multiple binding assays establish LMTK2/BREK interaction with unconventional myosin VI, although the GOA WITH/FROM accession P13533 incorrectly denotes MYH6. Reason: Retain the correct myosin VI binding term and experimental evidence. Preserve the raw P13533 source value for provenance while classifying it as a miscitation; the correct human MYO6 accession is UniProtKB:Q9UM54 and is cited only as additional evidence. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE MISCITATION Sources checked: UniProtKB:P13533 · human MYH6 cardiac myosin heavy chain 6 SOURCE BAD Raw WITH/FROM is a name-confused accession for MYH6; the assayed unconventional myosin VI/MYO6 protein is UniProtKB:Q9UM54. Supporting Evidence: PMID:18429820 Several binding experiments confirmed the interaction of myosin VI with BREK in vivo and in vitro. |
| GO:0004674 protein serine/threonine kinase activity | IDA PMID:12393858 A novel transmembrane Ser/Thr kinase complexes with protein ... | ACCEPT | Summary: Human KPI-2/LMTK2 exhibits serine/threonine kinase activity in autophosphorylation and added-substrate assays. Reason: Direct biochemical evidence establishes this as LMTK2's core catalytic molecular function at the correct specificity. Supporting Evidence: PMID:12393858 However, it only exhibited serine/threonine kinase activity in autophosphorylation reactions or with added substrates. |
| GO:0004864 protein phosphatase inhibitor activity | IDA PMID:12393858 A novel transmembrane Ser/Thr kinase complexes with protein ... | MODIFY | Summary: LMTK2 phosphorylates PP1C at Thr320 and attenuates phosphatase activity. Reason: The inhibitory activity is real but the existing term is broader than the assayed target class. Replace it with GO:0004865 protein serine/threonine phosphatase inhibitor activity. Proposed replacements: protein serine/threonine phosphatase inhibitor activity Supporting Evidence: PMID:12393858 KPI-2 kinase domain phosphorylated protein phosphatase-1 (PP1C) at Thr(320), which attenuated PP1C activity. |
| GO:0005524 ATP binding | NAS PMID:12393858 A novel transmembrane Ser/Thr kinase complexes with protein ... | KEEP AS NON CORE | Summary: ATP binding is inferred from LMTK2's kinase domain and ATP-dependent phosphotransfer assays rather than measured as a distinct function. Reason: Retain this valid generic catalytic cofactor property as non-core; the informative function is protein serine/threonine kinase activity. |
| GO:0006468 protein phosphorylation | IDA PMID:12393858 A novel transmembrane Ser/Thr kinase complexes with protein ... | MODIFY | Summary: LMTK2 phosphorylates protein substrates on serine and threonine residues, so the broad protein-phosphorylation term is true but underspecified. Reason: Replace the generic process with the experimentally supported specific processes GO:0018105 peptidyl-serine phosphorylation and GO:0018107 peptidyl-threonine phosphorylation. Proposed replacements: peptidyl-serine phosphorylation peptidyl-threonine phosphorylation Supporting Evidence: PMID:12393858 However, it only exhibited serine/threonine kinase activity in autophosphorylation reactions or with added substrates. |
| GO:0016020 membrane | IDA PMID:12393858 A novel transmembrane Ser/Thr kinase complexes with protein ... | ACCEPT | Summary: LMTK2 contains two N-terminal transmembrane helices that target the protein to membranes. Reason: Membrane localization is directly supported and is integral to LMTK2's endosomal trafficking role. Supporting Evidence: PMID:12393858 The transmembrane helices were sufficient for targeting proteins to the membrane. |
| GO:0046777 protein autophosphorylation | IDA PMID:12393858 A novel transmembrane Ser/Thr kinase complexes with protein ... | KEEP AS NON CORE | Summary: LMTK2 undergoes serine/threonine autophosphorylation in vitro. Reason: Autophosphorylation is a valid regulatory property of the kinase but is secondary to its core catalytic activity and endocytic-recycling function. Supporting Evidence: PMID:12393858 However, it only exhibited serine/threonine kinase activity in autophosphorylation reactions or with added substrates. |
| GO:0010008 endosome membrane | IDA PMID:23114966 Determination of the membrane topology of lemur tyrosine kin... | NEW | Summary: Fluorescence protease protection establishes LMTK2 as an integral protein of endosomal membranes with its catalytic domain exposed to the cytoplasm. Reason: GO:0010008 captures the membrane-specific location implied jointly by direct topology and endosome-localization experiments and is absent from the fetched GOA set. It is more precise than generic membrane while complementing the early- and recycling-endosome annotations. Supporting Evidence: PMID:23114966 In conclusion, we have, for the first time, formally demonstrated the topology and orientation of LMTK2 within endosomal membranes. PMID:18029400 Double labelling experiments show that LMTK2 is present on a subset of early endosomes as revealed by colocalisation with Rab5 and EEA1 (Fig. 4, d-j) and also associated with the Rab11-positive endocytic recycling compartment (Fig. 4, k-m). |
| GO:0045807 positive regulation of endocytosis | IMP PMID:24727471 LMTK2-mediated phosphorylation regulates CFTR endocytosis in... | NEW | Summary: LMTK2 kinase activity promotes CFTR endocytosis in human airway epithelial cells; loss or catalytic inactivation of LMTK2 reduces uptake and raises surface CFTR. Reason: This direct human perturbation supports GO:0045807, which is absent from the source annotations. The assignment is deliberately bounded to CFTR trafficking in airway epithelium and is not elevated to a universal core role. Supporting Evidence: PMID:24727471 LMTK2 knockdown or expression of inactive LMTK2 kinase domain increases cell surface density of CFTR by attenuating its endocytosis in human airway epithelial cells. |
| GO:0019894 kinesin binding | ISO PMID:31068217 LMTK2 binds to kinesin light chains to mediate anterograde a... | NEW | Summary: Mouse Lmtk2 binds kinesin-1 light chains KLC1 and KLC2 through a C-terminal WD motif and uses this interaction for anterograde axonal transport. Reason: GO:0019894 captures a specific binding activity absent from human GOA. Because the binding and transport experiments used mouse Lmtk2 and rat neurons, this is an ISO transfer to human LMTK2 and is retained as a neuronal, non-core context. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q3TYD6 · mouse Lmtk2 SUPPORTS TRANSFER The ortholog was used directly in binding and neuronal-transport experiments; transfer is plausible but the role remains context-specific. Supporting Evidence: PMID:31068217 Binding to KLC1/2 involves a C-terminal tryptophan/aspartate (WD) motif in LMTK2 and the tetratricopeptide repeat (TPR) domains in KLC1/2, and this interaction facilitates axonal transport of LMTK2. |
| GO:0030511 positive regulation of transforming growth factor beta receptor signaling pathway | IMP PMID:39316683 LMTK2 switches on canonical TGF-β1 signaling in human bronch... | NEW | Summary: LMTK2-dependent inhibition of PP1C permits canonical Smad3 signaling downstream of TGF-beta1 in human bronchial epithelial cells. Reason: Knockdown and pathway assays support positive regulation of TGF-beta receptor signaling. This recent finding is absent from GOA and is recorded as a bounded airway-epithelial role rather than part of the universal core function. Supporting Evidence: PMID:39316683 Third, TGF-β1 used LMTK2 to activate canonical Smad3-mediated signaling. |
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Download this section (compressed HTML)Q: Which direct LMTK2 substrate or noncatalytic interaction couples the LMTK2-MYO6 module to endosomal tubule formation and general receptor-cargo recycling beyond the demonstrated airway-epithelial CFTR substrate?
Q: Which sequence signal and cytosolic targeting factor deliver ER-exported LMTK2 to early and recycling endosome membranes, and is this targeting regulated by PP1C, MYO6, or phosphorylation of LMTK2 itself?
Q: How broadly do the CFTR-endocytosis, KLC1/2-dependent axonal-transport, and TGF-beta/Smad signaling mechanisms operate across human tissues, and which are physiological cargo-specific roles rather than shared functions of LMTK2?
Experiment: Introduce an acute endogenous LMTK2 degron in human cells and rescue with wild-type, kinase-dead, PP1C-docking-motif, or MYO6-binding-region mutants. Quantify transferrin receptor flux, Rab11/EHD tubule dynamics, and endosome morphology by pulse-chase and live imaging, then couple each rescue to phosphoproteomics to identify candidate trafficking substrates.
Hypothesis: LMTK2 kinase activity and its PP1C- and MYO6-binding interfaces make separable contributions to early-to-recycling-endosome transport.
Type: endogenous acute-depletion, separation-of-function rescue, live-cell trafficking, and phosphoproteomics
Experiment: Compare endogenous-proximity labeling and quantitative interactomes of wild-type LMTK2 with an ER-export-motif mutant and endosome-targeting-defective truncations; validate candidate targeting factors by knockout, rescue, and organelle-resolved trafficking assays.
Hypothesis: A post-ER targeting factor recognizes LMTK2 downstream of its di-acidic export motif and is required for stable delivery to early and recycling endosome membranes.
Type: proximity labeling, domain mapping, and organelle trafficking
Experiment: Generate isogenic airway organoids carrying endogenous CFTR-S737A together with LMTK2 knockout or kinase-dead knock-in, then measure CFTR internalization, recycling, apical surface lifetime, and chloride transport with wild-type rescue.
Hypothesis: LMTK2-dependent CFTR Ser737 phosphorylation is sufficient to tune CFTR endocytosis and surface stability in differentiated human airway epithelium.
Type: endogenous genome editing and airway-organoid transport physiology
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The mechanism that targets newly synthesized LMTK2 from the endoplasmic reticulum specifically to early and recycling endosome membranes remains unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: LMTK2 is established as a two-pass integral membrane protein with a cytoplasmic kinase domain, and a di-acidic motif is required for ER export. What is unresolved is the post-ER signal, adaptor, or membrane interaction that specifies its terminal endosomal destination.
Significance: Endosomal targeting is prerequisite for the MYO6-linked recycling function and for placing LMTK2 near cargo-specific substrates such as CFTR.
What would resolve it: Identify proteins or lipids that bind the cytoplasmic tail or transmembrane region after ER exit, and test candidate factors with endogenous localization and recycling assays using targeting-defective separation-of-function alleles.
Provenance (the field's own admissions):
Gap: The direct effector mechanism by which the LMTK2-MYO6 module drives endosomal tubule formation and broad cargo movement is unresolved; MYO6 binding is proven, but MYO6 has not been shown to be an LMTK2 substrate, and known PP1C and CFTR phosphorylation events do not yet explain the general recycling phenotype.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Direct LMTK2-MYO6 binding, early/recycling-endosome localization, and knockdown defects in transferrin-receptor delivery and tubulation are firmly established. PP1C Thr320 and CFTR Ser737 are direct substrates in defined contexts.
Significance: Resolving this link would distinguish catalytic signaling from motor recruitment and explain how one membrane kinase controls the physical remodeling of the recycling compartment.
What would resolve it: Use kinase-dead, PP1C-docking-deficient, and MYO6-binding-deficient endogenous alleles with live tubulation assays, cargo flux, and compartment-resolved phosphoproteomics; test candidate substrates by phosphosite knock-in rescue.
Provenance (the field's own admissions):
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