Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Biochem J
2002 Dec 01;368Pt 2:507-16. doi: 10.1042/BJ20021284.
Show Gene links
Show Anatomy links
Ionizing radiation induces ataxia telangiectasia mutated kinase (ATM)-mediated phosphorylation of LKB1/STK11 at Thr-366.
Sapkota GP
,
Deak M
,
Kieloch A
,
Morrice N
,
Goodarzi AA
,
Smythe C
,
Shiloh Y
,
Lees-Miller SP
,
Alessi DR
.
???displayArticle.abstract???
The serine/threonine protein kinase LKB1 functions as a tumour suppressor, and mutations in this enzyme lead to the inherited Peutz-Jeghers cancer syndrome. We previously found that LKB1 was phosphorylated at Thr-366 in vivo, a residue conserved in mammalian, Xenopus and Drosophila LKB1, located on a C-terminal non-catalytic moiety of the enzyme. Mutation of Thr-366 to Ala or Asp partially inhibited the ability of LKB1 to suppress growth of G361 melanoma cells, but did not affect LKB1 activity in vitro or LKB1 localization in vivo. As a first step in exploring the role of this phosphorylation further, we have generated a phosphospecific antibody specifically recognizing LKB1 phosphorylated at Thr-366 and demonstrate that exposure of cells to ionizing radiation (IR) induced a marked phosphorylation of LKB1 at Thr-366 in the nucleus. Thr-366 lies in an optimal phosphorylation motif for the phosphoinositide 3-kinase-like kinases DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated kinase (ATM) and ataxia telangiectasia-related kinase (ATR), which function as sensors for DNA damage in cells and mediate cellular responses to DNA damage. We demonstrate that both DNA-PK and ATM efficiently phosphorylate LKB1 at Thr-366 in vitro and provide evidence that ATM mediates this phosphorylation in vivo. This is based on the finding that LKB1 is not phosphorylated in a cell line lacking ATM in response to IR, and that agents which induce cellular responses via ATR in preference to ATM poorly induce phosphorylation of LKB1 at Thr-366. These observations provide the first link between ATM and LKB1 and suggest that ATM could regulate LKB1.
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001, Pubmed
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001,
Pubmed
Achari,
Detection of DNA-dependent protein kinase in extracts from human and rodent cells.
2000,
Pubmed
Ahn,
Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation.
2000,
Pubmed
Anderson,
DNA damage and the DNA-activated protein kinase.
1993,
Pubmed
Banin,
Enhanced phosphorylation of p53 by ATM in response to DNA damage.
1998,
Pubmed
Bardeesy,
Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation.
2002,
Pubmed
Chan,
Purification and characterization of the double-stranded DNA-activated protein kinase, DNA-PK, from human placenta.
1996,
Pubmed
Chan,
The DNA-dependent protein kinase is inactivated by autophosphorylation of the catalytic subunit.
1996,
Pubmed
Ching,
Analysis of the specificity of the AMP-activated protein kinase by site-directed mutagenesis of bacterially expressed 3-hydroxy 3-methylglutaryl-CoA reductase, using a single primer variant of the unique-site-elimination method.
1996,
Pubmed
Collins,
LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo.
2000,
Pubmed
Dong,
Frequent somatic mutations in serine/threonine kinase 11/Peutz-Jeghers syndrome gene in left-sided colon cancer.
1998,
Pubmed
Durocher,
DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme?
2001,
Pubmed
Feijoo,
Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing.
2001,
Pubmed
Gasch,
Genomic expression responses to DNA-damaging agents and the regulatory role of the yeast ATR homolog Mec1p.
2001,
Pubmed
Gruber,
Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome.
1998,
Pubmed
Guo,
Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence.
1999,
Pubmed
Hemminki,
A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.
1998,
Pubmed
,
Xenbase
Hemminki,
The molecular basis and clinical aspects of Peutz-Jeghers syndrome.
1999,
Pubmed
Jenne,
Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.
1998,
Pubmed
Jishage,
Role of Lkb1, the causative gene of Peutz-Jegher's syndrome, in embryogenesis and polyposis.
2002,
Pubmed
Karpova,
Interferon regulatory factor-3 is an in vivo target of DNA-PK.
2002,
Pubmed
Karuman,
The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death.
2001,
Pubmed
Kim,
Substrate specificities and identification of putative substrates of ATM kinase family members.
1999,
Pubmed
Lavin,
The genetic defect in ataxia-telangiectasia.
1997,
Pubmed
Lees-Miller,
Human DNA-activated protein kinase phosphorylates serines 15 and 37 in the amino-terminal transactivation domain of human p53.
1992,
Pubmed
Liu,
Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.
2000,
Pubmed
Marignani,
LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest.
2001,
Pubmed
Mihaylova,
The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway.
1999,
Pubmed
Nakau,
Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice.
2002,
Pubmed
Olschwang,
Peutz-Jeghers families unlinked to STK11/LKB1 gene mutations are highly predisposed to primitive biliary adenocarcinoma.
2001,
Pubmed
O'Neill,
Utilization of oriented peptide libraries to identify substrate motifs selected by ATM.
2000,
Pubmed
Park,
Mutations of the STK11 gene in sporadic gastric carcinoma.
1998,
Pubmed
Resta,
STK11 mutations in Peutz-Jeghers syndrome and sporadic colon cancer.
1998,
Pubmed
Rossi,
Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis.
2002,
Pubmed
Sanchez,
Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25.
1997,
Pubmed
Sapkota,
Identification and characterization of four novel phosphorylation sites (Ser31, Ser325, Thr336 and Thr366) on LKB1/STK11, the protein kinase mutated in Peutz-Jeghers cancer syndrome.
2002,
Pubmed
Sapkota,
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.
2001,
Pubmed
Shiloh,
Ataxia-telangiectasia and the ATM gene: linking neurodegeneration, immunodeficiency, and cancer to cell cycle checkpoints.
1996,
Pubmed
Shiloh,
ATM: genome stability, neuronal development, and cancer cross paths.
2001,
Pubmed
Smith,
Purification and DNA binding properties of the ataxia-telangiectasia gene product ATM.
1999,
Pubmed
Smith,
LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1.
2001,
Pubmed
,
Xenbase
Smith,
The mouse Peutz-Jeghers syndrome gene Lkb1 encodes a nuclear protein kinase.
1999,
Pubmed
Su,
Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers.
1999,
Pubmed
Tiainen,
Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest.
1999,
Pubmed
Tiainen,
Growth arrest by the LKB1 tumor suppressor: induction of p21(WAF1/CIP1).
2002,
Pubmed
Tibbetts,
Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress.
2000,
Pubmed
Vanhaesebroeck,
The PI3K-PDK1 connection: more than just a road to PKB.
2000,
Pubmed
Wang,
Germline mutations of the LKB1 (STK11) gene in Peutz-Jeghers patients.
1999,
Pubmed
Westerman,
Peutz-Jeghers syndrome: 78-year follow-up of the original family.
1999,
Pubmed
Williams,
The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells.
2000,
Pubmed
Yarden,
BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage.
2002,
Pubmed
Ylikorkala,
Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer.
1999,
Pubmed
Yoo,
LKB1--a master tumour suppressor of the small intestine and beyond.
2002,
Pubmed
Yoon,
Germline mutations of the STK11 gene in Korean Peutz-Jeghers syndrome patients.
2000,
Pubmed
Zhao,
ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1.
2001,
Pubmed
Ziv,
Recombinant ATM protein complements the cellular A-T phenotype.
1997,
Pubmed
