Disease relevance of STK11

• BACKGROUND & AIMS: There is limited data on the spectrum and risk for cancer associated with germline serine/threonine protein kinase 11 (STK11) mutations that cause Peutz-Jeghers syndrome (PJS) [1].
• Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors [2].
• Our data suggest that LKB1/STK11 may contribute to tumorigenesis in a small fraction of malignant melanomas [3].
• Mapping of a translocation breakpoint in a Peutz-Jeghers hamartoma to the putative PJS locus at 19q13.4 and mutation analysis of candidate genes in polyp and STK11-negative PJS cases [4].
• The recently discovered tumor suppressor genes, ALK-5, MKK4, and STK11 (the gene responsible for Peutz-Jeghers syndrome) are all targeted for mutation in a small proportion of sporadic pancreatic cancers [5].

High impact information on STK11

• We discuss evidence that the cellular localization and activity of LKB1 is controlled through its interaction with a catalytically inactive protein resembling a protein kinase, termed STRAD, and an armadillo repeat-containing protein, named mouse protein 25 (MO25) [6].
• The data suggest that LKB1 functions as a tumor suppressor by not only inhibiting proliferation, but also by exerting profound effects on cell polarity and, most unexpectedly, on the ability of a cell to detect and respond to low cellular energy levels [6].
• The LKB1 gene encodes a serine/threonine kinase that is mutated in the Peutz-Jeghers cancer syndrome [7].
• Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD [7].
• LKB1 is homologous to the Par-4 polarity genes in C. elegans and D. melanogaster [7].

Chemical compound and disease context of STK11

• Peutz-Jeghers Syndrome (PJS) is thought to be caused by mutations occurring in the widely expressed serine/threonine protein kinase named LKB1/STK11 [8].
• PJS and CNC share manifestations with Cowden syndrome (or Cowden disease) (CS, OMIM#158350) and Bannayan-Riley-Ruvalcaba syndrome (BRR, OMIM#153480) [9].
• Growth and molecular profile of lung cancer cells expressing ectopic LKB1: down-regulation of the phosphatidylinositol 3'-phosphate kinase/PTEN pathway [10].
• Mutations in LKB1/STK11, a gene mapping to chromosome 19p13.3 and encoding a widely expressed serine/threonine kinase, were recently identified as the cause of Peutz-Jeghers syndrome [3].
• Furthermore, these data draw attention to the possible adverse consequences of antitumor drugs that target Hsp90, such as antibiotics related to geldanamycin, which could disrupt LKB1 function and promote the development of polyps and carcinomatous lesions [11].

Biological context of STK11

• We conclude that germline mutations in STK11, probably in conjunction with acquired genetic defects of the second allele in somatic cells, cause the manifestations of PJ syndrome [12].
• In a three-generation PJ family, we found an STK11 allele with a deletion of exons 4 and 5 and an inversion of exons 6 and 7 segregating with the disease [12].
• Germline mutations of the LKB1 (STK11) tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS) and predisposition to cancer [13].
• Here we performed fine mapping of the short arm of chromosome 19 and found that the LKB1/STK11 gene mapped in the minimal-deleted region [14].
• Two somatic mutations were identified, a nonsense mutation (Glu170Stop) causing exon skipping and intron retention, and a missense mutation (Asp194Tyr) affecting an invariant residue in the catalytic subunit of LKB1/STK11 [3].

Anatomical context of STK11

• Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA [2].
• Prompted by another feature of the syndrome, lentigines of the lips and oral mucosa, we evaluated the status of LKB1/STK11 expression, deletion, and mutation in cell lines and tumour samples from 35 patients with sporadic malignant melanoma [3].
• In this study we investigated the possible direct role of STK11 in the development of MDA of the uterine cervix [15].
• Germline mutations of the PTEN/MMAC1/TEP and LKB1 genes cause hamartomas to develop in the gastrointestinal tracts of patients with Cowden syndrome and Peutz-Jeghers syndrome, respectively [16].
• Here, we demonstrate that stimulation of Rat-2 or embryonic stem cells with activators of ERK1/2 or of cAMP-dependent protein kinase induced phosphorylation of endogenously expressed LKB1 at Ser(431) [17].

Associations of STK11 with chemical compounds

• A serine threonine kinase gene, STK11, has been identified as the tumor suppressor gene responsible for the PJS [15].
• However, nonsense mediated mRNA decay must be blocked with puromycin to detect shortened STK11 gene products contained in the leucocytic mRNA pool of PJS patients [18].
• Mutation of the T-loop Thr phosphorylated by LKB1 to Ala prevented activation, while mutation to glutamate produced active forms of many of the AMPK-related kinases [19].
• LKB1 is a serine/threonine kinase which is inactivated by mutation in the Peutz-Jeghers polyposis and cancer predisposition syndrome (PJS) [20].
• The endocrine tumors of CS and PJS, which could classify these disorders as variant types of multiple endocrine neoplasias (MENs), are not present in most CS and BRR patients, but lentigines are shared by PJS, CNC and BRR [9].
• We also demonstrate that LKB1 wild-type cells are more resistant to cell death upon glucose withdrawal than their mutant counterparts [21].
• We conclude that PKCzeta mediates LKB1-dependent Akt inhibition in response to ONOO(-), resulting in endothelial apoptosis [22].

Physical interactions of STK11

• In vivo, LKB1 forms a complex with STRAD, an inactive pseudokinase, and MO25, an armadillo repeat scaffolding-like protein [23].
• We found that LKB1 binds to and regulates brahma-related gene 1 (Brg1), an essential component of chromatin remodeling complexes [24].
• Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37 [11].
• Heat-shock protein 90 and Cdc37 interact with LKB1 and regulate its stability [25].
• We showed that the PEA3 transcriptional factor interacted with LKB1, a serine/threonine kinase, which is somatically mutated in lung cancer [26].

Enzymatic interactions of STK11

• LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes [13].
• 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 [27].
• Recent work has shown that the LKB1 tumour suppressor protein kinase phosphorylates and activates protein kinases belonging to the AMP activated kinase (AMPK) subfamily [28].

Regulatory relationships of STK11

• LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1 [19].
• This suggests that LKB1-induced apoptosis is p53 independent but might be p73-mediated in the pancreatic tumor cell line, AsPC-1 [29].
• Our results imply that STRAD plays a key role in regulating the tumour suppressor activities of LKB1 [30].
• BI-D1870 is cell permeant and prevents the RSK-mediated phorbol ester- and EGF (epidermal growth factor)-induced phosphoryl-ation of glycogen synthase kinase-3beta and LKB1 in human embry-onic kidney 293 cells and Rat-2 cells [31].
• Ectopic expression of cyclooxygenase-2 and endogenous biosynthesis of eicosanoids also inhibited LKB1 activity in MCF-7 cells [32].
• These results suggest that LKB1 deacetylation is regulated by SIRT1 and that this in turn influences its intracellular localization, association with STRAD, kinase activity, and ability to activate AMPK [33].

Other interactions of STK11

• Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome [34].
• LKB1 catalytic activity and the presence of MO25 and STRAD are required for activation [19].
• Here we demonstrate that LKB1 can phosphorylate the T-loop of all the members of this subfamily, apart from MELK, increasing their activity >50-fold [19].
• Several LKB1 point mutations associated with PJS disrupt the interaction with PTEN suggesting that the loss of this interaction might contribute to PJS [13].
• LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1 [20].
• Conditional LKB1 mouse models have outlined a tissue-dependent context for pathway activation and suggest that LKB1 may affect different AMPK isoforms independently [35].

Analytical, diagnostic and therapeutic context of STK11

• Sequence analysis of STK11 exons in four unrelated PJ patients has identified three nonsense and one acceptor splice site mutations [12].
• Because the breakpoint in 19q13.4 may disrupt the putative PJS disease gene mapping to this region, we mapped the breakpoint and analyzed DNA from the case and a series of STK11-negative PJS cases [4].
• This study was intended to evaluate a diagnostic reverse transcriptase polymerase chain reaction based protein-truncation test for the identification of germline mutations in the serine/threonine protein kinase 11 (STK11, also designated LKB1) gene in Peutz-Jeghers syndrome (PJS) [18].
• To examine changes in gene expression profiles subsequent to exogenous wild-type LKB1 in A549 cells, we used cDNA microarrays [10].
• Site-directed mutagenesis implicated Cys210 in the LKB1 activation loop as the residue modified [32].

References