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LKB1/STK11

LKB1/STK11. Kate Bradford BIOL 445 March 5, 2009. Overview. LKB1 Roles in the cell Peutz-Jeghers Syndrome Tumor Suppression Future Research. LKB1/STK11. Serine/threonine kinase 19p13.3 Found in the nucleus and cytoplasm Ubiquitously expressed LKB1-STRAD-MO25 complex. Structure.

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LKB1/STK11

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  1. LKB1/STK11 Kate Bradford BIOL 445 March 5, 2009

  2. Overview • LKB1 • Roles in the cell • Peutz-Jeghers Syndrome • Tumor Suppression • Future Research

  3. LKB1/STK11 • Serine/threonine kinase • 19p13.3 • Found in the nucleus and cytoplasm • Ubiquitously expressed • LKB1-STRAD-MO25 complex

  4. Structure http://www.nature.com/nrc/journal/v2/n7/fig_tab/nrc843_F3.html

  5. Animal Model • LKB1-/- mutation in mice is lethal • Midgestation • Neural-tube defects • Severely impaired vascular development • LKB1+/- mice: gastrointestinal polyposis, similar to PJS patients • Different distribution of polyps in GI tract • Similar histology of polyps • Mouse model for PJS

  6. Roles in the cell • LKB1-STRAD-MO25 complex • Multiple cellular pathways • Motility • Metabolism • Polarity • Cell cycle • Positively regulates activity of AMPKs • Embryonic Development

  7. Roles in the Cell POLARITY METABOLISM http://www.nature.com/onc/journal/v27/n55/full/onc2008342a.html

  8. AMPK • Maintenance of cellular energy homeostasis AMPK http://www.csc.mrc.ac.uk/d/image/ResearchImages/Carling2.gif

  9. Cell Polarity • What is cell polarity? • “Master regulator of cell polarity” • Catalytic function required • STRAD mediated translocation to cytoplasm • AMPKs • MARKs

  10. Peutz-Jeghers Syndrome • ~70% of PJS patients have LKB1 mutation • Autosomal dominant • Benign harmatomatous polyps • Mucocutaneous hyperpigmentation on lips and hands • Increased risk of cancer • Treatments

  11. Peutz-Jeghers Syndrome http://www.ispub.com/ostia/index.php?xmlFilePath=journals/ijs/vol16n2/peutz.xml

  12. Peutz-Jeghers Syndrome http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T23-4KNF254-1&_user=130907&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000004198&_version=1&_urlVersion=0&_userid=130907&md5=c43ebfdac004762133d066d28d9babd2

  13. LKB1 Mutations in Cancer • Germ line mutations in PJS • Somatic mutations in LKB1 • Pancreatic • Pulmonary • Biliary • Melanomas

  14. How do metabolism defects lead to tumorigenesis? • LKB1 is a low-energy checkpoint tumor suppressor • Absence of LKB1/AMPk pathway could increase activity of proliferation pathways • mTOR • Loss of AMPK activation could promote immortalization

  15. How do polarity defects lead to tumorigenesis? • Malignant cells • Impair genomic stability • Polarity defects promote oncogenic activity of c-myc • Polarity restrains cell proliferation by mitogenic stimuli

  16. Cell cycle arrest • Overexpression in LKB1 deficient cell lines can suppress cell growth • WAF1/p21 http://www.nature.com/nrc/journal/v2/n7/fig_tab/nrc843_F3.html

  17. Apoptosis and p53 • Physical interaction between p53 and LKB1 http://www.nature.com/nrc/journal/v2/n7/fig_tab/nrc843_F3.html

  18. Future Research • Examine LKB1’s expression and function in other types of cancer • Determine how LKB1 deficiency leads to tumorigenesis • Stage-specific functions • Interaction with other tumor suppressors and oncogenes • Drug therapies • Melanoma

  19. References • Bass, A.F. et al. (2004) LKB1 tumor suppressor protein: PARtaker in cell polarity. TRENDS in Cell Bio. 14, 312-319. • Hezel, A.F. and Bardeesy, N. (2007) LKB1; linking cell structure and tumor suppression. Onco. 27, 6908-6919. • Katajisto, P. et al (2007) The LKB1 tumor suppressor kinase in human disease. Biochem. et biophys. 1775, 63-75. • Shah, U. et al (2008) LKB1 and Lung Cancer: More than the Usual Suspects. Cancer Res. 68, 3562-3565. • Shaw, R.G. et al (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 6, 91-99. • Shaw, R.J. et al (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. PNAS. 101, 3329-3335 • Yoo, L.I. et al. (2002) LKB1—A Master Tumour Suppressor of the Small Intestine and Beyond. Nature. 2, 529-535.

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