| 2009 |
LKB1 directly phosphorylates and activates AMPK, a central metabolic sensor, linking cell metabolism to growth control and cell polarity. LKB1 acts as an upstream kinase for AMPK and 14 related AMPK subfamily kinases. |
Biochemical kinase assays, genetic epistasis, and multiple experimental systems reviewed |
Nature reviews. Cancer |
High |
19629071
|
| 2004 |
LKB1 forms a heterotrimeric complex with the pseudokinase STRAD and the armadillo-repeat scaffold protein MO25. Binding to STRAD-MO25 activates LKB1 kinase activity and re-localizes it from the nucleus to the cytoplasm. Two binding sites on MO25α are required for complex assembly, and LKB1 activation by STRADα-MO25α does not require phosphorylation of LKB1's own T-loop. STRADα binds ATP with high affinity but this is not required for LKB1 activation. Twelve of 34 cancer-derived LKB1 point mutants tested failed to interact with STRAD-MO25. |
Point mutagenesis of 34 LKB1 cancer mutants, co-immunoprecipitation, kinase activity assays, immunofluorescence localization |
Journal of cell science |
High |
15561763
|
| 2006 |
LKB1 kinase activity and cellular localization are controlled through interaction with the catalytically inactive pseudokinase STRAD and the armadillo-repeat protein MO25. LKB1 phosphorylates and activates 14 kinases related to AMPK, mediating effects on metabolism, polarity, and proliferation. |
Biochemical reconstitution, interaction studies, substrate phosphorylation assays (reviewed from primary experimental literature) |
Annual review of biochemistry |
High |
16756488
|
| 2007 |
In Drosophila, LKB1 is required in vivo for AMPK activation; lkb1 mutations phenocopy ampkalpha mutations (loss of epithelial polarity and overproliferation under energetic stress). A phosphomimetic AMPKα rescues lkb1 mutant phenotypes, establishing genetic epistasis: LKB1 signals through AMPK to coordinate epithelial polarity and proliferation with cellular energy status. |
Drosophila genetics: lkb1 and AMPKα mutant analysis, epistasis with phosphomimetic AMPKα, immunofluorescence |
The Journal of cell biology |
High |
17470638
|
| 2012 |
The orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, attenuating AMPK activation. The compound TMPA binds Nur77 with high affinity, releasing LKB1 to shuttle to the cytoplasm where it phosphorylates AMPKα. Nur77 knockout mice do not respond to TMPA's glucose-lowering effects, confirming on-pathway requirement. |
Co-immunoprecipitation, pulldown, subcellular fractionation, kinase assays, Nur77 knockout mouse model, glucose/insulin assays |
Nature chemical biology |
High |
22983157
|
| 2009 |
LKB1 regulates pancreatic beta cell size, polarity, and function through distinct downstream targets: cell size is controlled via mTOR pathway; nuclear position polarity is controlled via LKB1 target Par1b; insulin secretion is restricted via AMPK. LKB1-deficient beta cells show dramatic increase in insulin secretion, altered nuclear/cilia localization, and 65% increased cell volume. |
Beta cell-specific LKB1 conditional knockout mice; histology, immunofluorescence, insulin secretion assays, pathway-specific genetic dissection |
Cell metabolism |
High |
19808022
|
| 2014 |
LKB1 promotes RAB7-mediated trafficking of the angiogenic receptor NRP-1 from late endosomes to the lysosome for degradation, suppressing angiogenesis. LKB1 specifically binds GTP-bound (active) RAB7 but not GDP-bound RAB7. siRNA depletion of RAB7 disrupts NRP-1 lysosomal transfer and increases tumor growth and angiogenesis. |
Co-immunoprecipitation, pulldown with GTP/GDP-RAB7 forms, siRNA knockdown, live-cell trafficking assays, tumor xenograft models |
The Journal of clinical investigation |
High |
25180605
|
| 2019 |
FBXO22 interacts with LKB1 and mediates Lys-63-linked polyubiquitination of LKB1, inhibiting LKB1 kinase activity and thereby promoting NSCLC cell growth through inhibition of LKB1-AMPK-mTOR signaling. |
Co-immunoprecipitation, ubiquitination assays (linkage-specific), kinase activity assays, overexpression/knockdown in cell lines and xenografts |
Cell death & disease |
Medium |
31217475
|
| 2021 |
LKB1 directly binds Sirt1 in a resveratrol-stimulated manner and phosphorylates Sirt1 at three C-terminal serine residues, which increases intramolecular Sirt1 interactions (C-terminus binding to deacetylase core domain), eliminates DBC1 inhibition, and promotes Sirt1-substrate interaction. This LKB1-dependent Sirt1 activation increases mitochondrial biogenesis and respiration via PGC-1α deacetylation. |
Knockdown/rescue experiments, fluorometric Sirt1 activity assays, immunoprecipitation, pulldown assays, site-directed mutagenesis of phosphorylation sites |
The Journal of biological chemistry |
Medium |
34216621
|
| 2014 |
LKB1 activity is required for microtubule-dependent trafficking of the bile acid transporter ABCB11 to the canalicular membrane and for hepatocyte polarization and canalicular network formation. In LKB1 knockout hepatocytes, ABCB11 trafficking is greatly reduced and only restored by cAMP (via PKA, not AMPK), not by taurocholate. |
Liver-specific LKB1 knockout mice, live-cell imaging, FRAP, particle tracking, biochemical fractionation |
PloS one |
High |
24643070
|
| 2019 |
CRISPR/Cas9-based combinatorial knockout in a KRAS-driven lung adenocarcinoma mouse model demonstrated that SIK family kinases are critical downstream effectors of LKB1-mediated tumor suppression. SIK- and LKB1-deficient tumors share histologic and gene-expression similarities, placing SIKs in the same tumor-suppressive axis as LKB1. |
CRISPR/Cas9 combinatorial genome editing in vivo, histology, gene-expression profiling, genetic epistasis |
Cancer discovery |
High |
31350327
|
| 2014 |
LKB1 controls inflammatory gene expression through the CRTC2-SIK axis: LKB1 loss triggers elevated CRTC2-CREB signaling downstream of SIK kinases, increasing cytokine and chemokine production. Mechanistically, CRTC2 cooperates with histone acetyltransferases CBP/p300 to deposit H3K27ac marks at inflammatory gene loci. |
Genetic deletion of LKB1, ChIP for H3K27ac, transcriptomic analysis, CRTC2 overexpression/knockdown, cytokine measurements |
Molecular cell |
Medium |
37172591
|
| 2014 |
LKB1 reduces intracellular ROS and protects genome from oxidative damage independently of AMPK. Under elevated ROS, LKB1 binds to and maintains the activity of the cdc42-PAK1 complex, triggering p38 activation and downstream ATF-2 signaling, which enhances superoxide dismutase-2 and catalase activity. |
LKB1 KO/re-expression, ROS measurements, DNA damage assays, Co-IP of LKB1-PAK1 complex, kinase activity assays |
Oncogene |
Medium |
25263448
|
| 2016 |
LKB1 loss combined with KRAS activation induces mTOR-dependent upregulation of the serine-glycine-one-carbon pathway and S-adenosylmethionine generation. Simultaneously, DNA methyltransferases are upregulated, elevating DNA methylation at retrotransposon elements. LKB1-deficient cells and tumors are sensitized to inhibition of serine biosynthesis and DNA methylation. |
Genetically engineered mouse models, primary pancreatic epithelial cells, transcriptomics, proteomics, metabolic analyses, bisulfite sequencing for DNA methylation |
Nature |
High |
27799657
|
| 2021 |
LKB1 inactivation drives chromatin accessibility changes and acts as a master regulator of chromatin remodeling in lung adenocarcinoma primary tumors. Loss of LKB1 activates the endoderm transcription factor SOX17 in metastases, which drives a second wave of epigenetic changes enhancing metastatic ability; SOX17 expression is necessary and sufficient for this metastatic epigenetic reprogramming. |
CRISPR-Cas9 screening, single-cell multi-omic analysis (ATAC-seq, RNA-seq), in vivo metastasis models, SOX17 gain/loss-of-function |
Nature cell biology |
High |
34341533
|
| 2017 |
Lkb1 maintains regulatory T (Treg) cell lineage identity by stabilizing Foxp3 expression. Lkb1 prevents STAT4-mediated methylation of the conserved noncoding sequence 2 (CNS2) in the Foxp3 locus. Independently, Lkb1 programs immunosuppressive gene expression through augmentation of TGF-β signaling. Treg-specific deletion of Lkb1 causes fatal early-onset autoimmune disease with loss of Foxp3 expression. |
T cell-specific conditional knockout, bisulfite sequencing of CNS2, STAT4 mechanistic studies, TGF-β signaling assays, flow cytometry |
Nature communications |
High |
28621313
|
| 2022 |
LKB1 couples mitochondrial function to cytokine expression in TH17 cells by regulating TCA cycle metabolism. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in TH17 cells with disrupted mitochondrial membranes by rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD+, and preventing 2-hydroxyglutarate production. |
T cell-specific LKB1 deletion, multi-omics (metabolomics, transcriptomics, epigenomics), OPA1 deletion, functional cytokine assays |
Nature |
High |
36171294
|
| 2022 |
The Golgi-localized protein TBC1D23 directly interacts with LKB1 and recruits it to the Golgi, promoting Golgi-specific activation of AMPK upon energy stress. Golgi-targeted LKB1 expression rescues TBC1D23 deficiency in zebrafish. LKB1 loss causes neurodevelopmental abnormalities in zebrafish that partially recapitulate TBC1D23 deficiency phenotypes. |
Co-immunoprecipitation, subcellular fractionation, AMPK activity assays, Golgi-targeted LKB1 constructs, zebrafish genetic models |
Nature communications |
High |
38413626
|
| 2022 |
SCO1 constitutively interacts with LKB1; copper-loaded SCO1 directly tethers LKB1 to AMPK, activating AMPK and promoting mitochondrial biogenesis and fatty acid oxidation. This copper-SCO1-LKB1-AMPK complex assembly represents a mechanism by which copper as a signaling molecule regulates lipid catabolism. |
Co-immunoprecipitation of SCO1-LKB1-AMPK complex, biochemical copper-loading assays, AMPK activity assays, mouse models with Cp ablation |
Cell reports |
Medium |
36261001
|
| 2022 |
Intracellular midkine (MDK) disrupts the LKB1-STRAD-Mo25 complex by interacting with LKB1 and STRAD, decreasing LKB1 activity and dampening basal and stress-induced AMPK activation. |
Co-immunoprecipitation, AMPK activity assays, cell-based glucose starvation/2-DG stress assays, MDK overexpression |
Cell death & disease |
Medium |
35487917
|
| 2023 |
MKP1 promotes LKB1 nuclear retention through a MKP1-p38 MAPK-LKB1 signaling axis: under NASH conditions, oxidative stress induces MKP1 expression, leading to nuclear p38 MAPK dephosphorylation and decreased LKB1 phosphorylation at a site required for LKB1 nuclear export. Hepatic MKP1 deletion releases nuclear LKB1 to the cytoplasm, activating AMPKα and preventing NASH. |
Hepatic MKP1 conditional knockout mice, subcellular fractionation, phospho-specific antibodies, AMPK activity assays, NASH diet feeding |
Nature communications |
High |
37669951
|
| 2014 |
LKB1 post-transcriptionally stimulates BRCA1 expression by inhibiting the cytoplasmic localization of the RNA-binding protein HuR in an AMPK-dependent manner, thereby stabilizing BRCA1 mRNA. This maintains homology-directed DNA repair (HDR) capacity. Cells lacking LKB1 display defective HDR and increased DNA double-strand breaks. |
LKB1 knockdown/overexpression, HuR localization assays, BRCA1 mRNA stability assays, DNA damage (γ-H2AX) assays, HDR reporter assay |
Nucleic acids research |
Medium |
25488815
|
| 2014 |
LKB1 regulates synaptic remodeling in the aging retina: LKB1 and its substrate AMPK function in rod photoreceptors to maintain synaptic stability. Loss of either kinase in young adult mice produces retinal synaptic defects (aberrant axonal retraction, ectopic dendritic extension, ectopic synapses) resembling those in old wild-type animals. Genetic or pharmacological AMPK activation attenuates age-related synaptic alterations. |
Conditional KO of LKB1 and AMPK in rod photoreceptors, retinal immunofluorescence and EM morphology, ERG functional assays, pharmacological AMPK activation |
Nature neuroscience |
High |
25086610
|
| 2014 |
LKB1 activity in Schwann cells is central to axon stability. LKB1 deletion in Schwann cells causes abnormalities in nerve energy and lipid homeostasis and increased lactate release that compensatorily supports distressed axons. AMPK and mTOR in Schwann cells are largely dispensable for this support function. |
SC-specific LKB1 conditional knockout mice, molecular, structural and behavioral characterization, metabolic profiling |
Nature neuroscience |
High |
25195104
|
| 2018 |
In Purkinje cells, the LKB1-SIK1/SIK2 kinase pathway ensures dendritic localization of Robo2, a regulator of dendrite self-avoidance. PC-specific LKB1 deletion severely disrupts dendrite self-avoidance without affecting gross morphology. Restoration of dendritic Robo2 by overexpression largely rescues the self-avoidance defect in LKB1-deficient PCs. |
Conditional LKB1 KO in Purkinje cells, immunofluorescence for Robo2 localization, Robo2 rescue experiment, SIK1/SIK2 downstream validation |
Cell reports |
High |
30208308
|
| 2014 |
STRADα specifically maintains LKB1 protein levels via cytoplasmic compartmentalization (reciprocal protein-stabilizing relationship in vivo). STRADβ is also sufficient for axogenesis in cortical neurons but does not stabilize LKB1 protein levels. |
In vivo STRAD conditional expression studies in developing cortex, immunofluorescence, Western blotting for LKB1 levels |
Neural development |
Medium |
24594058
|
| 2019 |
LKB1 deficiency in periosteal mesenchymal progenitors (Ctsk+ cells) increases proliferation and osteoblast differentiation leading to osteogenic tumor formation. This effect is mediated via mTORC1, as raptor genetic deletion or mTORC1 inhibitor treatment ameliorates tumor progression in Ctsk-Cre Lkb1fl/fl mice. |
Conditional LKB1 KO in Ctsk-Cre cells, lineage tracing, mTORC1 genetic and pharmacological inhibition, xenograft models |
The Journal of clinical investigation |
High |
30830877
|
| 2018 |
LKB1 directly interacts with and phosphorylates PRMT5 at T132, T139, and T144 residues within the TIM-Barrel domain. Point mutation of T139/144 to A drastically decreases PRMT5 methyltransferase activity, likely due to loss of interaction with regulatory proteins MEP50, pICln, and RiOK1. |
Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis of PRMT5 phosphorylation sites, methyltransferase activity assay |
International journal of cancer |
Medium |
30289978
|
| 2007 |
LKB1 catalytically deficient mutants (when introduced into DLD1 colorectal cancer cells) activate cyclin D1 expression through recruitment to response elements in the cyclin D1 promoter, and allow cell cycle progression to S phase. Wild-type LKB1 causes G1 arrest independent of p21 or p53. |
Introduction of LKB1 WT and catalytic mutants into p21-/-p53-/- colorectal cancer cells, cell cycle analysis, promoter-binding assays, Western blotting |
Cancer research |
Medium |
17575127
|
| 2022 |
LKB1 stabilizes and activates p53 through the JNK pathway in response to cisplatin-induced DNA damage, promoting apoptosis. Conversely, AMPK (downstream of LKB1) negatively regulates cisplatin-induced apoptosis by suppressing ROS-mediated p53 activation, revealing reciprocal regulation of p53 by LKB1 and AMPK in DNA damage response. |
LKB1 and AMPKα1/α2 double knockout cells, cisplatin treatment, apoptosis assays, p53 stabilization assays, JNK pathway inhibition, antioxidant rescue |
International journal of molecular sciences |
Medium |
36077459
|
| 2014 |
LKB1 limits satellite cell proliferation through the AMPK/mTOR pathway but facilitates differentiation through phosphorylation of GSK-3β (a WNT signaling component). Lkb1 null satellite cells fail to maintain quiescence and show accelerated proliferation but reduced differentiation. |
MyoD-Cre and Pax7-CreER conditional LKB1 knockout mice, satellite cell isolation, proliferation/differentiation assays, pathway inhibitor treatments |
Stem cells (Dayton, Ohio) |
Medium |
25069613
|