Gene Ontology annotation through association of InterPro records with GO terms
Gene Ontology annotation based on Enzyme Commission mapping
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic Gene Ontology annotation based on Rhea mapping
Kinome screening for regulators of the estrogen receptor identifies LMTK3 as a new therapeutic target in breast cancer.
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LMTK3 phosphorylates ESR1/ERalpha in vitro and protects it from proteasomal degradation; the abstract does not identify the directly phosphorylated residue.
"LMTK3 phosphorylated ERα, protecting it from proteasomal degradation in vitro."
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In ERalpha-positive breast-cancer models, LMTK3 also regulates ESR1 abundance indirectly through the PKC-AKT-FOXO3 transcriptional pathway.
"LMTK3 acts by decreasing the activity of protein kinase C (PKC) and the phosphorylation of AKT (Ser473), thereby increasing binding of forkhead box O3 (FOXO3) to the ESR1 promoter."
UniProtKB record for human LMTK3 (Q96Q04)
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The reviewed human Q96Q04 record displays a 1460-amino-acid LMTK3 sequence.
"ID LMTK3_HUMAN Reviewed; 1460 AA."
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UniProt names human LMTK3 a serine/threonine-protein kinase.
"DE RecName: Full=Serine/threonine-protein kinase LMTK3;"
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The current sequence has a predicted signal peptide at residues 1-20.
"FT SIGNAL 1..20"
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The current sequence has a predicted transmembrane helix at residues 40-60.
"FT TRANSMEM 40..60"
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The current sequence has a predicted protein kinase domain at residues 133-411.
"FT DOMAIN 133..411"
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UniProt explicitly attributes the human membrane, axon, dendrite, and Golgi localization statements to similarity with mouse Lmtk3 Q5XJV6.
"CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250|UniProtKB:Q5XJV6}; Single-
CC pass membrane protein {ECO:0000250|UniProtKB:Q5XJV6}. Cell projection,
CC axon {ECO:0000250|UniProtKB:Q5XJV6}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:Q5XJV6}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:Q5XJV6}. Note=Punctate pattern in cell
CC projections."
LMTK3 deficiency causes pronounced locomotor hyperactivity and impairs endocytic trafficking.
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Lmtk3 knockout in mice alters behavior and dopamine turnover, while primary knockout neurons show impaired N-methyl-D-aspartate receptor endocytic trafficking.
"In addition, using cultured primary neurons from Lmtk3(-/-) mice, we found that LMTK3 is involved in the endocytic trafficking of N-methyl-d-aspartate receptors, a type of ionotropic glutamate receptor."
LMTK3 Represses Tumor Suppressor-like Genes through Chromatin Remodeling in Breast Cancer.
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Nuclear LMTK3 binds KAP1/TRIM28 in breast-cancer cells, with PP1alpha stabilizing the interaction and promoting KAP1 dephosphorylation at LMTK3-associated chromatin.
"The LMTK3/KAP1 interaction is stabilized by PP1α, which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3-bound tumor suppressor-like genes."
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The authors propose a nuclear scaffolding function for LMTK3 in chromatin remodeling and transcriptional repression.
"In summary, we propose a model where a scaffolding function of nuclear LMTK3 promotes cancer progression through chromatin remodeling."
Phosphorylation of Rab-coupling protein by LMTK3 controls Rab14-dependent EphA2 trafficking to promote cell:cell repulsion.
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Human cancer-cell perturbations attribute HGF-induced RCP/RAB11FIP1 Ser435 phosphorylation specifically to LMTK3 rather than LMTK1.
"The LMTK family comprises three members, and siRNA experiments indicated that LMTK3 is responsible for HGF-induced phosphorylation of RCP's Ser435. Indeed, siRNA of LMTK3 (Fig. 4c,d), but not LMTK1 (Fig. 4d) opposed HGF-driven phosphorylation of RCP at Ser435."
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LMTK3-dependent RCP Ser435 phosphorylation enables assembly of an RCP-Rab14-EphA2 complex, EphA2 accumulation in perinuclear endosomes, and HGF-induced cell repulsion.
"Taken together these data indicate that HGF signalling promotes LMTK3-mediated phosphorylation of RCP at Serine435 which leads to assembly of an RCP/Rab14/EphA2 complex and accumulation of EphA2 within perinuclear endosomes."
The lncRNA MIR2052HG regulates ERα levels and aromatase inhibitor resistance through LMTK3 by recruiting EGR1.
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MIR2052HG recruits EGR1 to the LMTK3 promoter and thereby regulates LMTK3 transcription in human ER-positive breast-cancer cells.
"Mechanistically, MIR2052HG interacts with EGR1 and facilitates its recruitment to the LMTK3 promoter."
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LMTK3 sustains ERalpha through PKC-AKT-FOXO3-dependent ESR1 transcription and the downstream PKC-MEK-ERK-RSK1 degradation pathway.
"LMTK3 sustains ERα levels by reducing protein kinase C (PKC) activity, resulting in increased ESR1 transcription mediated through AKT/FOXO3 and reduced ERα degradation mediated by the PKC/MEK/ERK/RSK1 pathway."
Lmtk3-KO Mice Display a Range of Behavioral Abnormalities and Have an Impairment in GluA1 Trafficking.
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Lmtk3 knockout mice have impaired long-term potentiation and abnormal stimulus-dependent GluA1 trafficking in neurons.
"Further investigation revealed abnormalities in GluA1 trafficking after AMPA stimulation in Lmtk3-KO neurons, along with a reduction in GluA1 expression in the post-synaptic density."
The structure-function relationship of oncogenic LMTK3.
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The human LMTK3 kinase-domain structure adopts an inactive DYG-out conformation.
"We find that LMTK3cat adopts an inactive conformation, with the key DYG motif (more commonly DFG motif) stabilized in the “DYG-out” conformation"
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Recombinant LMTK3 directly phosphorylates HSPB1/HSP27 in vitro, principally at Ser15 and Ser82.
"We also pinpointed Ser15 and Ser82 as the main HSP27 residues phosphorylated by LMTK3 in vitro, using site-directed mutagenesis"
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Recombinant LMTK3 phosphorylates CDC37 in vitro, although the CDC37 phosphosite was not mapped.
"LMTK3 was able to phosphorylate CDC37 in vitro, suggesting a previously unidentified role for LMTK3 within the chaperone regulatory pathway."
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LMTK3 is an HSP90 client, and the ATP-competitive compound C28 also promotes proteasome-mediated LMTK3 degradation.
"Functional and mechanistic studies reveal LMTK3 is a heat shock protein 90 (HSP90) client protein, requiring HSP90 for folding and stability, while C28 promotes proteasome-mediated degradation of LMTK3."
The brain-specific kinase LMTK3 regulates neuronal excitability by decreasing KCC2-dependent neuronal Cl(-) extrusion.
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The large disordered cytoplasmic C-terminal region of LMTK3 binds PP1.
"LMTK3 consists of 1,460 amino acids with a small extracellular N-terminus, a single transmembrane domain, an adjacent catalytic domain, and large highly disordered cytoplasmic C-terminus that binds PP1"
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In mouse neurons, LMTK3 acts as a scaffold that recruits PP1 to KCC2/SLC12A5 and promotes dephosphorylation of KCC2 Ser940, decreasing transporter activity.
"LMTK3 acts to promote the association of KCC2 with PP1 to promote the dephosphorylation of S940 within its C-terminal cytoplasmic domain, a process the diminishes KCC2 activity."
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The physiological loss-of-function analysis used adult Lmtk3 knockout mice and acute hippocampal slices.
"To investigate the effects of LMTK3 inactivation on KCC2 activity, we performed whole-cell patch-clamp Cl− loading experiments on dentate gyrus granule cells (DGGCs) in acute hippocampal slices from adult LMTK3 control and KO mice."
LMTK3 regulation of EV biogenesis and cargo sorting promotes tumour growth by reducing monocyte infiltration and driving pro-tumourigenic macrophage polarisation in breast cancer.
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Recombinant LMTK3 directly phosphorylates RAB7A in vitro, and site-specific assays identify RAB7A Ser72 as the phosphoacceptor.
"To elucidate if Rab7 is directly or indirectly phosphorylated by LMTK3, we performed in vitro kinase assays, using recombinant LMTK3 kinase domain as source of enzyme activity and Rab7 as substrate."
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Human T47D and MDA-MB-231 imaging places LMTK3 with RAB7A-positive late endosomes.
"Following immunofluorescence staining, our analysis showed overlapping localisation between LMTK3 and Rab7, confirming that LMTK3 is present in late endosomes"
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In human breast-cancer cells, LMTK3-dependent RAB7A Ser72 phosphorylation disrupts late-endosome trafficking and enlarges multivesicular bodies, producing larger EVs with altered cargo rather than necessarily increasing EV number.
"In summary, our findings demonstrate that LMTK3 overexpression in breast cancer cells promotes the phosphorylation of Rab7 at Ser72, which in turn disrupts late endosome trafficking and results in the formation of enlarged MVBs."