The Full Wiki

STK11: Wikis

Advertisements

Note: Many of our articles have direct quotes from sources you can cite, within the Wikipedia article! This article doesn't yet, but we're working on it! See more info or our list of citable articles.

Encyclopedia

From Wikipedia, the free encyclopedia

edit
Serine/threonine kinase 11 (LKB1)

Structure of the heterotrimeric LKB1-STRADα-MO25α complex.
Available structures
2WTK
Identifiers
Symbols STK11; LKB1; PJS
External IDs OMIM602216 MGI1341870 HomoloGene393 GeneCards: STK11 Gene
EC number 2.7.11.9
RNA expression pattern
PBB GE STK11 41657 at tn.png
PBB GE STK11 204292 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6794 20869
Ensembl ENSG00000118046 ENSMUSG00000003068
UniProt Q15831 Q3V4A1
RefSeq (mRNA) NM_000455 NM_011492
RefSeq (protein) NP_000446 NP_035622
Location (UCSC) Chr 19:
1.16 - 1.18 Mb
Chr 10:
79.52 - 79.53 Mb
PubMed search [1] [2]

Serine/threonine kinase 11 or LKB1 is a protein kinase which in humans is encoded by the STK11 gene.[1]

Contents

Function

The STK11/LKB1 gene, which encodes a member of the serine/threonine kinase, regulates cell polarity and functions as a tumour suppressor.

LKB1 is a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), a necessary element in cell metabolism that is required for maintaining energy homeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of other ~14 kinases, comprising AMPK and AMPK-related kinases. Activation of AMPK by LKB1 suppresses growth and proliferation when energy and nutrient levels are scarce. Activation of AMPK-related kinases by LKB1 plays vital roles maintaining cell polarity thereby inhibiting inappropriate expansion of tumour cells. A picture from current research is emerging that loss of LKB1 leads to disorganization of cell polarity and facilitates tumour growth under energetically unfavorable conditions.

Clinical significance

Germline mutations in this gene have been associated with Peutz-Jeghers syndrome, an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms.[2][3][4] Recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in Lung, Cervial, Breast, Intestinal, Testicular, Pancreatic and Skin cancer. [5]

Activation

LKB1 is activated allosterically by binding to the pseudokinase STRAD and the adaptor protein MO25. The LKB1-STRAD-MO25 heterotrimeric complex represents the biologically active unit, that is capable of phosphorylating and activating AMPK and at least 12 other kinases that belong to the AMPK-related kinase family.

Structure

The crystal structure of the LKB1-STRAD-MO25 complex was elucidated using X-ray crystallography,[6] and revealed the mechanism by which LKB1 is allosterically activated. LKB1 has a structure typical of other protein kinases, with two (small and large) lobes on either side of the ligand ATP-binding pocket. STRAD and MO25 together cooperate to promote LKB1 active conformation. The LKB1 activation loop, a critical element in the process of kinase activation, is held in place by MO25, thus explaining the huge increase in LKB1 activity in the presence of STRAD and MO25 .

Splice variants

Alternate transcriptional splice variants of this gene have been observed and characterized. There are two main splice isoforms denoted LKB1 long (LKB1L) and LKB1 short (LKB1S). The short LKB1 variant is predominantly found in testes.

Interactions

STK11 has been shown to interact with MO25α/β and STRADα/β (LYK5) isoforms[7][8] SMARCA4,[9] CDC37[10] and Heat shock protein 90kDa alpha (cytosolic), member A1.[10]

References

  1. ^ Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Müller O, Back W, Zimmer M (January 1998). "Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase". Nature genetics 18 (1): 38–43. doi:10.1038/ng0198-38. PMID 9425897.  
  2. ^ Hemminki A, Tomlinson I, Markie D, et al. (1997). "Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis.". Nat. Genet. 15 (1): 87–90. doi:10.1038/ng0197-87. PMID 8988175.  
  3. ^ Hemminki A, Markie D, Tomlinson I, et al. (1998). "A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.". Nature 391 (6663): 184–7. doi:10.1038/34432. PMID 9428765.  
  4. ^ Scott R, Crooks R, Meldrum C (October 2008). "Gene symbol: STK11. Disease: Peutz-Jeghers Syndrome". Human genetics 124 (3): 300. PMID 18846624.  
  5. ^ "Distribution of somatic mutations in STK11". Catalogue of Somatic Mutations in Cancer. Wellcome Trust Genome Campus, Hinxton, Cambridge. http://www.sanger.ac.uk/perl/genetics/CGP/cosmic?action=bygene&ln=STK11&start=1&end=434&coords=AA:AA. Retrieved 2009-11- 11.  
  6. ^ PDB 2WTK; Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM (November 2009). "Structure of the LKB1-STRAD-MO25 Complex Reveals an Allosteric Mechanism of Kinase Activation". Science. doi:10.1126/science.1178377. PMID 19892943.  
  7. ^ Boudeau, Jérôme; Scott John W, Resta Nicoletta, Deak Maria, Kieloch Agnieszka, Komander David, Hardie D Grahame, Prescott Alan R, van Aalten Daan M F, Alessi Dario R (Dec. 2004). "Analysis of the LKB1-STRAD-MO25 complex". J. Cell. Sci. (England) 117 (Pt 26): 6365–75. doi:10.1242/jcs.01571. ISSN 0021-9533. PMID 15561763.  
  8. ^ Baas, A F; Boudeau J, Sapkota G P, Smit L, Medema R, Morrice N A, Alessi D R, Clevers H C (Jun. 2003). "Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD". EMBO J. (England) 22 (12): 3062–72. doi:10.1093/emboj/cdg292. ISSN 0261-4189. PMID 12805220.  
  9. ^ Marignani, P A; Kanai F, Carpenter C L (Aug. 2001). "LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest". J. Biol. Chem. (United States) 276 (35): 32415–8. doi:10.1074/jbc.C100207200. ISSN 0021-9258. PMID 11445556.  
  10. ^ a b Boudeau, Jérôme; Deak Maria, Lawlor Margaret A, Morrice Nick A, Alessi Dario R (Mar. 2003). "Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability". Biochem. J. (England) 370 (Pt 3): 849–57. doi:10.1042/BJ20021813. ISSN 0264-6021. PMID 12489981.  

Further reading

  • Yoo LI, Chung DC, Yuan J (2002). "LKB1--a master tumour suppressor of the small intestine and beyond.". Nat. Rev. Cancer 2 (7): 529–35. doi:10.1038/nrc843. PMID 12094239.  
  • Baas AF, Smit L, Clevers H (2004). "LKB1 tumor suppressor protein: PARtaker in cell polarity.". Trends Cell Biol. 14 (6): 312–9. doi:10.1016/j.tcb.2004.04.001. PMID 15183188.  
  • Katajisto P, Vallenius T, Vaahtomeri K, et al. (2007). "The LKB1 tumor suppressor kinase in human disease.". Biochim. Biophys. Acta 1775 (1): 63–75. doi:10.1016/j.bbcan.2006.08.003. PMID 17010524.  
  • Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery.". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.  
  • Hemminki A, Tomlinson I, Markie D, et al. (1997). "Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis.". Nat. Genet. 15 (1): 87–90. doi:10.1038/ng0197-87. PMID 8988175.  
  • Jenne DE, Reimann H, Nezu J, et al. (1998). "Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.". Nat. Genet. 18 (1): 38–43. doi:10.1038/ng0198-38. PMID 9425897.  
  • Hemminki A, Markie D, Tomlinson I, et al. (1998). "A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.". Nature 391 (6663): 184–7. doi:10.1038/34432. PMID 9428765.  
  • Bignell GR, Barfoot R, Seal S, et al. (1998). "Low frequency of somatic mutations in the LKB1/Peutz-Jeghers syndrome gene in sporadic breast cancer.". Cancer Res. 58 (7): 1384–6. PMID 9537235.  
  • Nakagawa H, Koyama K, Miyoshi Y, et al. (1998). "Nine novel germline mutations of STK11 in ten families with Peutz-Jeghers syndrome.". Hum. Genet. 103 (2): 168–72. doi:10.1007/s004390050801. PMID 9760200.  
  • Mehenni H, Gehrig C, Nezu J, et al. (1999). "Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity.". Am. J. Hum. Genet. 63 (6): 1641–50. doi:10.1086/302159. PMID 9837816.  
  • Guldberg P, thor Straten P, Ahrenkiel V, et al. (1999). "Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma.". Oncogene 18 (9): 1777–80. doi:10.1038/sj.onc.1202486. PMID 10208439.  
  • Su GH, Hruban RH, Bansal RK, et al. (1999). "Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers.". Am. J. Pathol. 154 (6): 1835–40. PMID 10362809.  
  • Westerman AM, Entius MM, Boor PP, et al. (1999). "Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families.". Hum. Mutat. 13 (6): 476–81. doi:10.1002/(SICI)1098-1004(1999)13:6<476::AID-HUMU7>3.0.CO;2-2. PMID 10408777.  
  • Scanlan MJ, Gordan JD, Williamson B, et al. (1999). "Antigens recognized by autologous antibody in patients with renal-cell carcinoma.". Int. J. Cancer 83 (4): 456–64. doi:10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5. PMID 10508479.  
  • Collins SP, Reoma JL, Gamm DM, Uhler MD (2000). "LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo.". Biochem. J. 345 Pt 3: 673–80. doi:10.1042/0264-6021:3450673. PMID 10642527.  
  • Sapkota GP, Kieloch A, Lizcano JM, et al. (2001). "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.". J. Biol. Chem. 276 (22): 19469–82. doi:10.1074/jbc.M009953200. PMID 11297520.  
  • Karuman P, Gozani O, Odze RD, et al. (2001). "The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death.". Mol. Cell 7 (6): 1307–19. doi:10.1016/S1097-2765(01)00258-1. PMID 11430832.  
  • Marignani PA, Kanai F, Carpenter CL (2001). "LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest.". J. Biol. Chem. 276 (35): 32415–8. doi:10.1074/jbc.C100207200. PMID 11445556.  
  • Abed AA, Günther K, Kraus C, et al. (2002). "Mutation screening at the RNA level of the STK11/LKB1 gene in Peutz-Jeghers syndrome reveals complex splicing abnormalities and a novel mRNA isoform (STK11 c.597(insertion mark)598insIVS4).". Hum. Mutat. 18 (5): 397–410. doi:10.1002/humu.1211. PMID 11668633.  
  • Sato N, Rosty C, Jansen M, et al. (2001). "STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas.". Am. J. Pathol. 159 (6): 2017–22. PMID 11733352.  

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Advertisements

Advertisements






Got something to say? Make a comment.
Your name
Your email address
Message