Atlas of Genetics and Cytogenetics in Oncology and Haematology
STK11 (serine/threonine kinase 11)
| Identity |
| Other names | LKB1 |
| PJS (Peutz-Jeghers syndrome) | |
| EC 2.7.11.1 | |
| NY-REN-19 antigen | |
| HGNC | STK11 |
| Location | 19p13.3 |
| 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 |
| 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, Hˆglund P, Jˆ§rvinen H, Kristo P, Pelin K, Ridanpˆ§ˆ§ 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, Mˆºller 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, Mˆ§kelˆ§ 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, Mˆ§kelˆ§ 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, Gˆransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Mˆ§kelˆ§ 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 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 02-2002 | Jean-Loup Huret |
| Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France | ||
| Updated | 01-2007 | Bharati 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 . URL : http://AtlasGeneticsOncology.org/Genes/STK11ID292.html |
| Bapat B, Perera S . STK11 (serine/threonine kinase 11). Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Genes/STK11ID292.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Mon Aug 11 21:17:45 2008 |
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