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STK11 (serine/threonine kinase 11)

Identity

Other namesLKB1
PJS (Peutz-Jeghers syndrome)
EC 2.7.11.1
NY-REN-19 antigen
HGNC (Hugo) STK11
LocusID (NCBI) 6794
Location 19p13.3
Location_base_pair Starts at 1205798 and ends at 1228434 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description 10 Exons spanning 23 kb, the 10th exon occurs within the 3' untranslated region of the gene. The gene is transcribed in telomere to centromere direction.
Transcription The length of this transcript has not been reconciled. The curated human Vega transcript is the longest transcript reported to date (3,627 bp, Vega external transcript). The GeneBank sequence is the same but is shorter (3,286 bp) at the 3' end (NM_000455.4). The exon/intron structures in GeneBank are given for 2 alternative assemblies (aligned with NT_011255.14 and NW_927173.1), of which the NT_0112255.14 is consistent with the Vega annotation. Alternative transcripts although shown to occur, have not be been well characterized.

Protein

 
  Diagram of STK11 protein (not drawn to scale). The kinase domain is depicted by the green box. The second box outlined by the dashed lines illustrates the location of the nuclear localization signal (NLS) and the purple box indicates the prenylation motif. This protein is believed to contain a putative cytoplasmic retention signal (not shown).
Description 433 amino acids, 48.6 kDa; N-term with a nuclear localization domain and a putative cytoplasmic retention signal, a kinase domain, and a C-terminal CAAX box prenylation motif.
Expression Ubiquitous, especially high expression in the testis and fetal liver.
Localisation Found in both the nucleus and the cytoplasm. Localization is thought to be dependent on interaction with proteins such as BRG1, LIP1, STRAD, MO25.
Function A serine/threonine protein kinase, recently classified as a part of the Ca2+/ calmodulin kinase group of kinases. STK11 was shown to associate and activate the pseudokinase, STRAD, resulting in the reorganization of non-polarized cells so they form asymmetrical apical and basal structures. Another mechanism by which this may occur is by the interaction of STK11 with the PAR1 family of serine/threonine kinases. AMPK is a protein kinase cascade that plays an important role in regulating energy homeostasis. The first report of an upstream regulator came when it was discovered that STK11, in complex with STRAD and the scaffolding protein MO25, can phosphorylate and activate AMPK. Subsequently, it was demonstrated that STK11 can phosphorylate the T-loop of 12 other AMPK related human kinases. In addition it has been implicated in a range of processes including, chromatin remodeling, cell cycle arrest, ras-induced cell transformation, p53-mediated apoptosis and Wnt signaling.
Homology Orthologs found in several species and include:
Xenopus laevis egg and embryonic kinase 1(XEEK1),
Caenorhabditis elegans partitioning defective gene 4 (PAR4),
mouse LKB1
and drosophila LKB1.

Mutations

Germinal Most mutations identified to date are in the catalytic domain of STK11, indicating that kinase activity is likely essential for its function as a tumor suppressor. Several types of mutations including insertions, deletions, nonsense, missense and splice site alterations have been identified to date. One family has been identified with complete germline deletion of this gene.
Somatic Many of the polyps that develop in Peutz-Jeghers syndrome (see below) show loss of heterozygosity and sometimes somatic mutations. Somatic mutations rarely occur in sporadic tumours, with the exception of adenocarcinoma of the lung. The inactivation of the LKB1 can also occur through promoter hypermethylation.

Implicated in

Entity Peutz-Jeghers syndrome (PJS)
Disease Autosomal dominant syndrome associated with mucocutaneous hyperpigmentation and benign intestinal polyps known as hamartomas. The relative incidence is estimated to vary from 1/29 000 to 1/120 000 births. Patients are at an increased risk of developing malignancies in epithelial tissues, for example it has been estimated that there is a about 84, about 213 and about 520 fold increased risk of developing colon, gastric and small intestinal cancers respectively. PJS patients are also at an increased risk of developing cancers in the breast, lung, ovaries, uterus, cervix and testes.
Hybrid/Mutated Gene A majority (60-70%) of Peutz-Jeghers patients show germline mutations in STK11. Genetic locus heterogeneity may exist for this disease. A small percentage of families with no mutations in STK11/LKB1 have been identified, however no other candidate genes that predispose to Peutz-Jeghers syndrome have been identified to date.
Oncogenesis Patients inherit mutations in one allele, and the remaining allele is later inactivated generally by LOH or sometimes somatic mutation. This biallelic inactivation of STK11 leads to a loss of tumour suppressor activity, thereby promoting tumourigenesis.
  
Entity Lung adenocarcinoma
Disease Adenocarcinoma is the most common non-small-cell lung cancer accounting for about 30-40% of all cases diagnosed to date. These tumors are thought to derive from epithelial cells that line the peripheral small airways and the heterogeneity of lung tumours is well documented. The outcome of non-small cell lung cancer is more difficult to predict, and about 50% of patients die from metastatic disease even after surgery of the primary tumour.
Hybrid/Mutated Gene As many as 33% of sporadic lesions analyzed display somatic mutations in STK11.
Oncogenesis Loss of protein function is seen in sporadic lung adenocarcinoma tumours.
  

External links

Nomenclature
HGNC (Hugo)STK11   11389
Cards
AtlasSTK11ID292
Entrez_Gene (NCBI)STK11  6794  serine/threonine kinase 11
GeneCards (Weizmann)STK11
Ensembl (Hinxton)ENSG00000118046 [Gene_View]  chr19:1205798-1228434 [Contig_View]  STK11 [Vega]
AceView (NCBI)STK11
Genatlas (Paris)STK11
WikiGenes6794
SOURCE (Princeton)NM_000455
Genomic and cartography
GoldenPath (UCSC)STK11  -  19p13.3   chr19:1205798-1228434 +  19p13.3   [Description]    (hg19-Feb_2009)
EnsemblSTK11 - 19p13.3 [CytoView]
Mapping of homologs : NCBISTK11 [Mapview]
OMIM175200   260350   273300   602216   
Gene and transcription
Genbank (Entrez)AB209553 AF035625 AF217978 AJ844634 AK128518
RefSeq transcript (Entrez)NM_000455
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NG_007460 NT_011255 NW_001838476 NW_004929412
Consensus coding sequences : CCDS (NCBI)STK11
Cluster EST : UnigeneHs.515005 [ NCBI ]
CGAP (NCI)Hs.515005
Alternative Splicing : Fast-db (Paris)GSHG0014421
Alternative Splicing GalleryENSG00000118046
Gene ExpressionSTK11 [ NCBI-GEO ]     STK11 [ SEEK ]   STK11 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ15831 (Uniprot)
NextProtQ15831  [Medical]
With graphics : InterProQ15831
Splice isoforms : SwissVarQ15831 (Swissvar)
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ]   2.7.11.12.7.11.1 [ IntEnz-EBI ]   2.7.11.1 [ BRENDA ]   2.7.11.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Ca/CaM-dep_Ca-dep_prot_Kinase    Kinase-like_dom    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_dual-sp_kinase_dom    Ser/Thr_kinase_AS   
Related proteins : CluSTrQ15831
Domain families : Pfam (Sanger)Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00069   
Domain families : Smart (EMBL)S_TKc (SM00220)  
DMDM Disease mutations6794
Blocks (Seattle)Q15831
PDB (SRS)2WTK   
PDB (PDBSum)2WTK   
PDB (IMB)2WTK   
PDB (RSDB)2WTK   
Human Protein AtlasENSG00000118046
Peptide AtlasQ15831
HPRD03740
IPIIPI01024704   IPI01024909   IPI00219072   
Protein Interaction databases
DIP (DOE-UCLA)Q15831
IntAct (EBI)Q15831
FunCoupENSG00000118046
BioGRIDSTK11
InParanoidQ15831
Interologous Interaction database Q15831
IntegromeDBSTK11
STRING (EMBL)STK11
Ontologies - Pathways
Ontology : AmiGOmagnesium ion binding  regulation of cell growth  tissue homeostasis  vasculature development  p53 binding  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  cytoplasm  mitochondrion  cytosol  cytosol  energy reserve metabolic process  protein phosphorylation  autophagy  cellular response to DNA damage stimulus  cell cycle arrest  cell cycle arrest  spermatid development  axonogenesis  negative regulation of cell proliferation  insulin receptor signaling pathway  response to ionizing radiation  membrane  establishment of cell polarity  regulation of Wnt receptor signaling pathway  LRR domain binding  protein kinase activator activity  negative regulation of cell growth  positive regulation of transforming growth factor beta receptor signaling pathway  activation of protein kinase activity  protein complex binding  response to glucagon  response to lipid  regulation of fatty acid biosynthetic process  glucose homeostasis  protein complex  anoikis  small molecule metabolic process  positive regulation of gluconeogenesis  positive regulation of protein kinase activity  protein autophosphorylation  positive regulation of axonogenesis  protein heterooligomerization  Golgi localization  regulation of protein kinase B signaling cascade  canonical Wnt receptor signaling pathway  negative regulation of epithelial cell proliferation involved in prostate gland development  intrinsic apoptotic signaling pathway by p53 class mediator  
Ontology : EGO-EBImagnesium ion binding  regulation of cell growth  tissue homeostasis  vasculature development  p53 binding  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  cytoplasm  mitochondrion  cytosol  cytosol  energy reserve metabolic process  protein phosphorylation  autophagy  cellular response to DNA damage stimulus  cell cycle arrest  cell cycle arrest  spermatid development  axonogenesis  negative regulation of cell proliferation  insulin receptor signaling pathway  response to ionizing radiation  membrane  establishment of cell polarity  regulation of Wnt receptor signaling pathway  LRR domain binding  protein kinase activator activity  negative regulation of cell growth  positive regulation of transforming growth factor beta receptor signaling pathway  activation of protein kinase activity  protein complex binding  response to glucagon  response to lipid  regulation of fatty acid biosynthetic process  glucose homeostasis  protein complex  anoikis  small molecule metabolic process  positive regulation of gluconeogenesis  positive regulation of protein kinase activity  protein autophosphorylation  positive regulation of axonogenesis  protein heterooligomerization  Golgi localization  regulation of protein kinase B signaling cascade  canonical Wnt receptor signaling pathway  negative regulation of epithelial cell proliferation involved in prostate gland development  intrinsic apoptotic signaling pathway by p53 class mediator  
Pathways : KEGGFoxO signaling pathway    mTOR signaling pathway    PI3K-Akt signaling pathway    Adipocytokine signaling pathway   
REACTOMESTK11
Protein Interaction DatabaseSTK11
Wikipedia pathwaysSTK11
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)STK11
SNP (GeneSNP Utah)STK11
SNP : HGBaseSTK11
Genetic variants : HAPMAPSTK11
1000_GenomesSTK11 
ICGC programENSG00000118046 
Cancer Gene: CensusSTK11 
Somatic Mutations in Cancer : COSMICSTK11 
CONAN: Copy Number AnalysisSTK11 
Mutations and Diseases : HGMDSTK11
OMIM175200    260350    273300    602216   
GENETestsSTK11
Disease Genetic AssociationSTK11
Huge Navigator STK11 [HugePedia]  STK11 [HugeCancerGEM]
Genomic VariantsSTK11  STK11 [DGVbeta]
Exome VariantSTK11
dbVarSTK11
ClinVarSTK11
snp3D : Map Gene to Disease6794
General knowledge
Homologs : HomoloGeneSTK11
Homology/Alignments : Family Browser (UCSC)STK11
Phylogenetic Trees/Animal Genes : TreeFamSTK11
Chemical/Protein Interactions : CTD6794
Chemical/Pharm GKB GenePA36198
Drug Sensitivity STK11
Clinical trialSTK11
Cancer Resource (Charite)ENSG00000118046
Other databases
Probes
Litterature
PubMed247 Pubmed reference(s) in Entrez
CoreMineSTK11
iHOPSTK11

Bibliography

A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.
Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hglund P, Jrvinen H, Kristo P, Pelin K, Ridanp M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA
Nature. 1998 ; 391 (6663) : 184-187.
PMID 9428765
 
Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.
Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Mller O, Back W, Zimmer M
Nature genetics. 1998 ; 18 (1) : 38-43.
PMID 9425897
 
Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest.
Tiainen M, Ylikorkala A, Mkel TP
Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (16) : 9248-9251.
PMID 10430928
 
Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome.
Esteller M, Avizienyte E, Corn PG, Lothe RA, Baylin SB, Aaltonen LA, Herman JG
Oncogene. 2000 ; 19 (1) : 164-168.
PMID 10644993
 
The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death.
Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, Brien TP, Bozzuto CD, Ooi D, Cantley LC, Yuan J
Molecular cell. 2001 ; 7 (6) : 1307-1319.
PMID 11430832
 
LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest.
Marignani PA, Kanai F, Carpenter CL
The Journal of biological chemistry. 2001 ; 276 (35) : 32415-32418.
PMID 11445556
 
Phosphorylation of the protein kinase mutated in Peutz-Jeghers cancer syndrome, LKB1/STK11, at Ser431 by p90(RSK) and cAMP-dependent protein kinase, but not its farnesylation at Cys(433), is essential for LKB1 to suppress cell vrowth.
Sapkota GP, Kieloch A, Lizcano JM, Lain S, Arthur JS, Williams MR, Morrice N, Deak M, Alessi DR
The Journal of biological chemistry. 2001 ; 276 (22) : 19469-19482.
PMID 11297520
 
LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1.
Smith DP, Rayter SI, Niederlander C, Spicer J, Jones CM, Ashworth A
Human molecular genetics. 2001 ; 10 (25) : 2869-2877.
PMID 11741830
 
Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice.
Ylikorkala A, Rossi DJ, Korsisaari N, Luukko K, Alitalo K, Henkemeyer M, Mkel TP
Science (New York, N.Y.). 2001 ; 293 (5533) : 1323-1326.
PMID 11509733
 
Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation.
Bardeesy N, Sinha M, Hezel AF, Signoretti S, Hathaway NA, Sharpless NE, Loda M, Carrasco DR, DePinho RA
Nature. 2002 ; 419 (6903) : 162-167.
PMID 12226664
 
Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD.
Baas AF, Boudeau J, Sapkota GP, Smit L, Medema R, Morrice NA, Alessi DR, Clevers HC
The EMBO journal. 2003 ; 22 (12) : 3062-3072.
PMID 12805220
 
Regulation of the Wnt signalling component PAR1A by the Peutz-Jeghers syndrome kinase LKB1.
Spicer J, Rayter S, Young N, Elliott R, Ashworth A, Smith D
Oncogene. 2003 ; 22 (30) : 4752-4756.
PMID 12879020
 
Genotype-phenotype correlations in Peutz-Jeghers syndrome.
Amos CI, Keitheri-Cheteri MB, Sabripour M, Wei C, McGarrity TJ, Seldin MF, Nations L, Lynch PM, Fidder HH, Friedman E, Frazier ML
Journal of medical genetics. 2004 ; 41 (5) : 327-333.
PMID 15121768
 
Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD.
Baas AF, Kuipers J, van der Wel NN, Batlle E, Koerten HK, Peters PJ, Clevers HC
Cell. 2004 ; 116 (3) : 457-466.
PMID 15016379
 
LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1.
Lizcano JM, Gransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Mkel TP, Hardie DG, Alessi DR
The EMBO journal. 2004 ; 23 (4) : 833-843.
PMID 14976552
 
LKB1 kinase: master and commander of metabolism and polarity.
Spicer J, Ashworth A
Current biology : CB. 2004 ; 14 (10) : R383-R385.
PMID 15186763
 
LKB1, the multitasking tumour suppressor kinase.
Marignani PA
Journal of clinical pathology. 2005 ; 58 (1) : 15-19.
PMID 15623475
 
The tumor suppressor LKB1 induces p21 expression in collaboration with LMO4, GATA-6, and Ldb1.
Setogawa T, Shinozaki-Yabana S, Masuda T, Matsuura K, Akiyama T
Biochemical and biophysical research communications. 2006 ; 343 (4) : 1186-1190.
PMID 16580634
 
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Contributor(s)

Written02-2002Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated01-2007Bharati Bapat, Sheron Perera
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Lab Medicine and Pathobiology, University of Toronto, Canada

Citation

This paper should be referenced as such :
Huret JL . STK11 (serine/threonine kinase 11). Atlas Genet Cytogenet Oncol Haematol. February 2002 .
Bapat B, Perera S . STK11 (serine/threonine kinase 11). Atlas Genet Cytogenet Oncol Haematol. January 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/STK11ID292.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/37843/1/02-2002-STK11ID292.pdf   [ Bibliographic record ]
http://documents.irevues.inist.fr/bitstream/2042/38417/1/01-2007-STK11ID292.pdf   [ Bibliographic record ]

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indexed on : Fri Apr 18 17:25:47 CEST 2014

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