Biology:STK11

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.

Expression

Testosterone and DHT treatment of murine 3T3-L1 or human SGBS adipocytes for 24 h significantly decreased the mRNA expression of LKB1 via the androgen receptor and consequently reduced the activation of AMPK by phosphorylation. In contrast, 17β-estradiol treatment increased LKB1 mRNA, an effect mediated by oestrogen receptor alpha.

However, in ER-positive breast cancer cell line MCF-7, estradiol caused a dose-dependent decrease in LKB1 transcript and protein expression leading to a significant decrease in the phosphorylation of the LKB1 target AMPK. ERα binds to the STK11 promoter in a ligand-independent manner and this interaction is decreased in the presence of estradiol. Moreover, STK11 promoter activity is significantly decreased in the presence of estradiol.

Function

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

LKB1 is a primary upstream kinase of adenosine 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 ~14 other 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. A study in rats showed that LKB1 expression is upregulated in cardiomyocytes after birth and that LKB1 abundance negatively correlates with proliferation of neonatal rat cardiomyocytes.

Loss of LKB1 activity is associated with highly aggressive HER2+ breast cancer. HER2/neu mice were engineered for loss of mammary gland expression of Lkb1 resulting in reduced latency of tumorgenesis. These mice developed mammary tumors that were highly metabolic and hyperactive for MTOR. Pre-clinical studies that simultaneously targeted mTOR and metabolism with AZD8055 (inhibitor of mTORC1 and mTORC2) and 2-DG, respectively inhibited mammary tumors from forming. Mitochondria function In control mice that did not have mammary tumors were not affected by AZD8055/2-DG treatments.

LKB1 catalytic deficient mutants found in Peutz–Jeghers syndrome activate the expression of cyclin D1 through recruitment to response elements within the promoter of the oncogene. LKB1 catalytically deficient mutants have oncogenic properties.

Clinical significance

At least 51 disease-causing mutations in this gene have been discovered. 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. However, the LKB1 gene was also found to be mutated in lung cancer of sporadic origin, predominantly adenocarcinomas. Further, more recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in cervical, breast, intestinal, testicular, pancreatic and skin cancer.

LKB1 has been implicated as a potential target for inducing cardiac regeneration after injury as the regenerative potential of cardiomyocytes is limited in adult mammals. Knockdown of Lkb1 in rat cardiomyocytes suppressed phosphorylation of AMPK and activated Yes-associated protein, which subsequently promoted cardiomyocyte proliferation.

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. Several novel splice isoforms of STRADα that differentially affect LKB1 activity, complex assembly, subcellular localization of LKB1 and the activation of the LKB1-dependent AMPK pathway.

Structure

The crystal structure of the LKB1-STRAD-MO25 complex was elucidated using X-ray crystallography, 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 (LKB1_L) and LKB1 short (LKB1_S). The short LKB1 variant is predominantly found in testes.

Interactions

STK11 has been shown to interact with:

• CDC37,
• * FYN
• HSP90AA1
• LYK5
• SMARCA4
• ESR1

Further reading

• "LKB1--a master tumour suppressor of the small intestine and beyond". Nature Reviews. Cancer 2 (7): 529–35. July 2002. doi:10.1038/nrc843. PMID 12094239. 
• "LKB1 tumor suppressor protein: PARtaker in cell polarity". Trends in Cell Biology 14 (6): 312–9. June 2004. doi:10.1016/j.tcb.2004.04.001. PMID 15183188. 
• "The LKB1 tumor suppressor kinase in human disease". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1775 (1): 63–75. January 2007. doi:10.1016/j.bbcan.2006.08.003. PMID 17010524. 
• "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. September 1996. doi:10.1101/gr.6.9.791. PMID 8889548. 
• "Low frequency of somatic mutations in the LKB1/Peutz-Jeghers syndrome gene in sporadic breast cancer". Cancer Research 58 (7): 1384–6. April 1998. PMID 9537235. 
• "Nine novel germline mutations of STK11 in ten families with Peutz-Jeghers syndrome". Human Genetics 103 (2): 168–72. August 1998. doi:10.1007/s004390050801. PMID 9760200. 
• "Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity". American Journal of Human Genetics 63 (6): 1641–50. December 1998. doi:10.1086/302159. PMID 9837816. 
• "Somatic mutation of the Peutz-Jeghers syndrome gene, LKB1/STK11, in malignant melanoma". Oncogene 18 (9): 1777–80. March 1999. doi:10.1038/sj.onc.1202486. PMID 10208439. 
• "Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers". The American Journal of Pathology 154 (6): 1835–40. June 1999. doi:10.1016/S0002-9440(10)65440-5. PMID 10362809. 
• "Novel mutations in the LKB1/STK11 gene in Dutch Peutz-Jeghers families". Human Mutation 13 (6): 476–81. 1999. doi:10.1002/(SICI)1098-1004(1999)13:6<476::AID-HUMU7>3.0.CO;2-2. PMID 10408777. 
• "Antigens recognized by autologous antibody in patients with renal-cell carcinoma". International Journal of Cancer 83 (4): 456–64. November 1999. doi:10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5. PMID 10508479. 
• "LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo". The Biochemical Journal 345 Pt 3 (3): 673–80. February 2000. doi:10.1042/0264-6021:3450673. PMID 10642527. 
• "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". The Journal of Biological Chemistry 276 (22): 19469–82. June 2001. doi:10.1074/jbc.M009953200. PMID 11297520. 
• "The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death". Molecular Cell 7 (6): 1307–19. June 2001. doi:10.1016/S1097-2765(01)00258-1. PMID 11430832. 
• "Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene". Oncogene 23 (22): 4037–40. May 2004. doi:10.1038/sj.onc.1207502. PMID 15021901. 
• "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)". Human Mutation 18 (5): 397–410. November 2001. doi:10.1002/humu.1211. PMID 11668633. 
• "STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas". The American Journal of Pathology 159 (6): 2017–22. December 2001. doi:10.1016/S0002-9440(10)63053-2. PMID 11733352. 

External links

• GeneReviews/NCBI/NIH/UW entry on Peutz-Jeghers syndrome
• OMIM entries on Peutz-Jeghers syndrome

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