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FLASH GENE
Symbol STK11 contributors: mct/pgu/shn - updated : 14-06-2016
HGNC name serine/threonine kinase 11
HGNC id 11389
Corresponding disease
PJS1 Peutz-Jeghers syndrome 1
Location 19p13.3      Physical location : 1.205.797 - 1.228.434
Synonym name
  • polarized related protein LKB1
  • serine/threonine kinase 11 (Peutz-Jeghers syndrome)
  • renal carcinoma antigen NY-REN-19
  • serine/threonine-protein kinase LKB1
  • liver kinase B1 homolog
    • Synonym symbol(s) LKB1, PJS, STII
    EC.number 2.7.11.1
    DNA
    TYPE functioning gene
    STRUCTURE 22.64 kb     10 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map pter - D19S883 - STK11 - D19S883 - D19S878 - cen
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    10 - 3286 48 433 predominantly expressed in testis 2005 1562750
  • different C-terminal sequences generating LKB1S and LKB1L, but similar patterns of subcellular localization
  • presence of a farnesylation site (Cys-430/433) in LKB1L that is not conserved in LKB1S
    		•
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly
     salivary gland   highly
    Endocrinepancreas   highly
    Reproductivemale systemtestis  moderately
     male systemprostate  highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text liver (highly)
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal nuclear localization signal
  • two nuclear localization sequences,
  • a central kinase domain, tyrosine kinase catalytic domain
  • C-terminal prenylation motif (CAAX-box), region with a crucial role in the regulation of AMPK pathway and cell polarity, and farnesylation motif
    • conjugated PhosphoP
    HOMOLOGY
    interspecies ortholog to Stk11, Rattus norvegicus
    ortholog to STK11, Pan troglodytes
    ortholog to Stk11, Mus musculus
    Homologene
    FAMILY
  • protein kinase superfamily
  • CAMK Ser/Thr protein kinase family
    • CATEGORY enzyme , tumor suppressor , signaling , receptor membrane G serine/threonine kinase
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,interspace
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm
    text
  • mostly cytoplasmic when coexpressed with LIP1
  • translocated to the cytoplasm when coexpressed with LYK5
  • STRADA induces relocalization of STK11 from the nucleus to the cytoplasm and stimulates its catalytic activity
  • cytosolic localization appears to be important for its tumor suppressor functions
    • basic FUNCTION
  • essential role in G1 cell cycle arrest, maybe acting as a tumor suppressor
  • has a role in embryogenesis and polyposis
  • playing a key role in controlling cell polarity
  • highly activated in pyknotic intestinal epithelial cells
  • playing a key role in colorectal tumorigenesis (tumor suppressor in the small intestine)
  • may mediate glucose homeostasis in liver through the regulation of AMPKs and SIKs which regulate TORC2
  • is necessary for metformin to lower blood glucose
  • increasing beta-catenin phosphorylation leading to transcriptional inhibition of a canonical Wnt reporter gene
  • required for axon specification during neuronal polarization in the cerebral cortex and for neuronal polarization of cortical neurons
  • required for axon formation and its specific PKA-dependent phosphorylation is essential
  • plays a negative regulatory role in cancer, a finding that may lead to a new therapeutic strategy
  • STK11, TP53, TUSC3 might play a role in the development of metastasis in larynx and pharynx squamous cell carcinomas
  • plays a critical role in neuronal migration and neuronal differentiation (proper neuronal migration and differentiation are intimately coupled to the precise control of the centrosomal positioning/movement directed by STK11)
  • acting as a master kinase regulating the activity of a wide range of downstream kinases, which themselves have diverse physiological roles
  • is required for adiponectin-mediated modulation of AMPK-S6K axis and inhibition of adhesion, migration and invasion of breast cancer cells
  • plays an important role in maintaining cardiac structure and function
  • its activity requires complex formation with the pseudokinase STRADA and the adaptor protein CAB39
  • with CAMKK2, catalyzing activation of PRKAB1 by phosphorylation at Thr172
  • regulates LOX transcription directly through MTOR-HIF1A signaling axis (
  • cilium-basal body compartment as a spatially restricted activation site for Lkb1 signalling (
  • required for haematopoietic stem cell maintenance through AMPK-dependent and AMPK-independent mechanisms (
  • critical for the maintenance of energy homeostasis in haematopoietic cells (
  • has an essential role in haematopoietic stem cell homeostasis and critical for coupling energy metabolism (
  • role of STK11 and AMPK in cellular responses to stress and damage
  • serine/threonine kinase that has critical roles in cell growth, polarity and metabolism
  • STK11-loss facilitates oncogenic proliferation by releasing epithelial cells from structural BM boundaries
  • has a tumor suppressor function in the mammary gland, which is coupled to the maintenance of epithelial integrity
  • is necessary for formation of normal epithelial polarity and glandular architecture
  • importance of STK11 signaling in Sertoli cell biology and spermatogenesis
  • is a key regulator of cellular energy, proliferation, and polarity
  • STK11 and ARHGEF18 control RHOA activity in the bronchial epithelial cells to promote apical junction assembly
  • STK11 and NUAK1, are required for cortical axon branching
  • STK11 and NUAK1 are necessary and sufficient to immobilize mitochondria specifically at nascent presynaptic sites
  • novel function of STK11 in the maintenance of genomic stability through the regulation of centrosome mediated by PLK1
  • central role of STK11 in muscle stem cell homeostasis, muscle development, and regeneration
  • in the mammalian skeleton, regulates the transition between immature and hypertrophic chondrocytes
  • acts through PRKAA1 to limit lipid deposition in muscle stem cells and their derivative mature muscles
  • STK11-mediated metabolic shift during Schwann cells (SCs) differentiation increases mitochondrial metabolism and lipogenesis, necessary for normal myelination
  • may inhibit tumorigenesis by regulating the Hh signaling pathway in certain cancers
  • is a central regulator of T-cell-dependent humoral immunity
  • is essential for mitochondrial homeostasis in beta cells and in parallel is a powerful negative regulator of insulin secretion
  • play crucial roles in cell differentiation, proliferation, and the establishment of cell polarity
  • is required for the development and maintenance of stereocilia in the inner ear
    • CELLULAR PROCESS cell cycle
    cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • PI3K pathway
  • STK11 signaling in cardiac myocytes is essential for normal development of the atria and ventricles
  • STRADA-STK11 pathway plays critical roles in epithelial cell polarity, neuronal polarity, and cancer metastasis
  • STK11-NUAK1 pathway controls mitochondria immobilization in axons
  • LKB1-SIK pathway functions as a key gluconeogenic gatekeeper in the liver
    • a component
  • core heterotrimeric STK11-STRADA-CAB39 complex, implicated in unusual allosteric mechanism of STK11 activation
  • de-regulated STK11-CRTC1 signaling might represent a crucial mechanism for esophageal cancer progression
    • INTERACTION
    DNA
    RNA
    small molecule metal binding, nucleotide,
  • ATP binding
  • ions Mg2+ binding
    • protein
  • TP53 (regulation of apoptosis pathway)
  • LYK5 (critical for establishing epithelial polarity, in an undifferentiated neurite correlates with its subsequent axon differentiation)
  • p53 (
  • brahma-related gene 1, Brg1 (
  • LYST-interacting protein 1, LIP1 (
  • Heat-shock protein 90 and Cdc37 (
  • fetal liver LKB1-interacting protein, FLIP1 (
  • STRAD, MO25, LIM domain protein PINCH, BRG-1, FLJ21908/mSpaghetti and PAPK (
  • phosphorylates and activates NUAK1, NUAK2, BRSK1, BRSK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4 and MELK kinases (
  • dominant regulator of AMPK activation by its phosphorylation (
  • activates SNRK by phosphorylating (
  • phosphatase and tensin homolog, PTEN (
  • WD repeat domain 6 (WDR6) (coexpression of WDR6 and STK11 induces CDKN1B)
  • STE20-related kinase adaptor alpha (STRADA) STK11–STRADA complex could regulate neuronal polarization involving phosphorylation and activation of BRSK2 and BRSK1
  • SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4)
  • SMAD family member 4 (SMAD4)
  • TNFAIP3 interacting protein 2 (TNIP2)
  • STRADA normally binds and exports the protein kinase STK11 out of the nucleus, leading to suppression of the MTOR pathway
  • controls thymocyte survival via regulation of AMPK activation
  • predominately interacted with LAT and PLCG1 following TCR stimulation
  • striking cooperation between MYC activation and STK11 loss in mammary tumorigenesis
  • HPN is a key factor mediating STK11 loss-induced structural alterations in mammary epithelium and basement membrane (BM) fragmentation
  • loss of STK11 induces desmosomal defects and such junctional defects associate with mislocalization of HPN
  • STRADA regulates PAK1 in STK11-null cells to oversee cancer cell polarity and invasion
  • DCLRE1C promote STK11-mediated phosphorylation and activation of AMPK by stabilizing the STK11–PRKAA2 complex
  • STK11 acts through SIK2 and SIK3 to promote nucleocytoplasmic trafficking of class IIa HDACs
  • serves as a PTK2 repressor to stabilize focal adhesion sites
  • PARD3B binds to the tumour suppressor protein STK11 and inhibits its kinase activity
  • MAP3K11 serves as a common upstream kinase of PRKAA1 and JNK and functions as a direct upstream kinase for PRKAA1 independent of STK11
  • during metabolic stress, SUMO1 modification of STK11 lysine 178 is essential in promoting its interaction with PRKAA1 via a SUMO-interacting motif (SIM) essential for PRKAA1 activation
  • BHLHE40 negatively regulates PRKAA1 activity via STK11
  • STK11 controls brown adipose tissue growth and thermogenesis by regulating the intracellular localization of CRTC3
  • SIRT2 promotes AMPK activation by deacetylating the kinase STK11
    • cell & other
    REGULATION
    activated by binding of a complex consisting of CAB39 and STRAD or CAB39 and ALS2CR2
    PKC-zeta dependent phosphorylation at S307, leading to its nucleocytoplasmic transport and endothelial cell angiogenesis
    STE20-like pseudokinase STRAD
    STRADA (activates the STK11 tumour suppressor by forming a heterotrimeric complex with STK111 and the scaffolding protein CAB39
    Other up-regulated by adiponectin treatment in breast cancer cells
    phosphorylated by ataxia telangiectasia mutated kinase, ATM (
    SP1, NFYC and FOXO3, FOXO4 transcription factors are involved in the regulation of STK11 transcription
    ASSOCIATED DISORDERS
    corresponding disease(s) PJS1
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    in sporadic testicular cancer, malignant skin melanoma and laryngeal tumor
    tumoral somatic mutation      
    in gastrointestinal hamartomatous polyps in PJS1(familial forms)
    tumoral germinal mutation      
    in gastrointestinal hamartomatous polyps in PJS1(familial forms)
    tumoral   LOH    
    in PJS1 with polyposis resistant to transformation
    tumoral somatic mutation      
    in lung adenocarcinomas
    tumoral       loss of function
    in ovarian, intestinal and pancreatic cancer
    tumoral germinal mutation      
    in head and neck squamous cell carcinoma
    tumoral     --low  
    in breast cancer
    tumoral     --over  
    in breast cancer cells resulted in significant inhibition of invasion and significantly associated with a decrease in microvessel density
    tumoral somatic mutation      
    and homozygous inactivating mutations in non-small-cell lung cancers
    tumoral   LOH    
    in &8764;30p100 of lung adenocarcinomas, contribute significantly to lung cancer malignancy progression (
    tumoral   deletion    
    frequent homozygous deletion in non-small cell lung cancer
    Susceptibility
  • to malignancies, to pancreatic cancer
  • to absence of ovulatory response to treatment with metformin in polycystic ovary syndrome (PCOS)
    • Variant & Polymorphism SNP , other C allele of a single nucleotide polymorphism associated with a significantly decreased chance of ovulation in PCOS women treated with metformin
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerdigestivecolon
    COX-2 as a potential target for chemoprevention in Peutz-Jeghers polyposis patients
    ANIMAL & CELL MODELS
  • mice with a targeted disruption of Lkb1 die at midgestation, with the embryos showing neural tube defects, mesenchymal cell death and deregulation of vascular endothelial growth factor (VEGF) expression
  • Lkb1 (+/-) mice develop hamartomatous polyps in the glandular stomach
  • Lkb1(-/-) mice died in utero between 8.5 and 9.5 days postcoitum with developmental retardation and multiple gastric adenomatous polyps
  • in somatically activatable mutant Kras- driven model of mouse lung cancer, pulmonary tumorigenesis was accelerated by hemizygous inactivation of Lkb1 (STK11)
  • LKB1-deficient murine embryonic fibroblasts show nearly complete loss of Thr-172 phosphorylation and downstream AMPK signaling in response to a variety of stimuli that activate AMPK (
  • deletion of LKB1 in liver of adult mice result in a loss of AMPK activityand hyperglycemia with increased gluconeogenic and lipogenic gene expression
  • LKB1-KO mice displayed biatrial enlargement with atrial fibrillation and cardiac dysfunction at 4 weeks of age
  • deletion of Stk11 gene in mice caused increased haematopoietic stem cell (HSC) division, rapid HSC depletion and pancytopenia (
  • Lkb1-deficient haematopoietic stem cell have reduced mitochondrial membrane potential and ATP levels, exhibit defects in centrosomes and mitotic spindles in culture, and become aneuploid (
  • Lkb1 inactivation in adult mice causes loss of haematopoietic stem cell quiescence followed by rapid depletion of all haematopoietic subpopulations (
  • Lkb1-deficient bone marrow cells exhibit mitochondrial defects, alterations in lipid and nucleotide metabolism, and depletion of cellular ATP (
  • ablation of Lkb1 in adult mice results in severe pancytopenia and subsequent lethality (