Peutz-Jeghers Syndrome (PJS) and LKB1

1. Peutz-Jeghers Syndrome (PJS)and LKB1 Sarah Bass March 28, 2006 www.smu.org.uy

2. Peutz-Jeghers Syndrome • Rare autosomal dominant disorder • Benign hamartomatous polyps through gastrointestinal tract • Tumors can develop in • Lung, breast, pancreas, uterus, ovary, cervix, testis Polyps in the jejunum Normal jejunum alf3.urz.unibas.ch www3.umdnj.edu

3. Multiple Processes LKB1 Regulates LKB1 is a kinase and it is regulated by phosphorylation • Control of cell-cycle arrest (G1) • p53-mediated apoptosis • Wnt signaling • TFG-β signaling • Ras-induced cell transformation • Energy metabolism • Cell polarity Polyps 145.253.118.170/roche5/ pics/a22030.000-1_big.gif

4. Multiple Processes LKB1 Regulates LKB1 is a kinase and it is regulated by phosphorylation • Control of cell-cycle arrest (G1) • p53-mediated apoptosis • Wnt signaling • TFG-β signaling • Ras-induced cell transformation • Energy metabolism • Cell polarity Polyps 145.253.118.170/roche5/ pics/a22030.000-1_big.gif

5. Location of LKB1 Located on chromosome 19p13.3 http://genecards.bcgsc.ca/cgi-bin/carddisp?STK11 Most of the point mutations in LKB1 are in the kinase domain Yoo, Chung, Yuan Determined location of LBK1 by linkage analysis using families with PJS

6. Homologues of LKB1 in Model Organisms Caenorhabditis elegans • LKB1 homologue controls cellular polarity (PAR4) • Six PAR genes and all are required to regulate polarity of first two asymmetric cell divisions • Polarity is required to determine cell fate www.sih.m.u-tokyo.ac.jp Baas, Smit, Clevers

7. Homologues of LKB1 in Model Organisms Mice • LKB1 -/- mice died midgestation • Neural tube defects • Impaired vascular development • Defects in extra-embryonic development • LKB1 +/- • Viable, fertile, and appear healthy at birth • At 20 weeks, hamartomatous polyps in the stomach and small intestine appear • At 40 weeks, 100% of these mice develops gastric hamartomas www.scenta.co.uk

8. Cell-extracellular matrix contacts and cell-cell contacts are spatial cues that lead to polarization Activated LKB1 can induce polarity in single, isolated cells Cell Polarity in Mammalian Cells Actin (red) distributed equally → (before LKB1 activation) Baas, Smit, Clevers ←Actin reorganizing forming a border at the apical site (after LKB1 activation) Baas, Smit, Clevers

9. LKB1 and Metabolic Regulation • LKB1 activates AMPK (AMP-activated protein kinase) by phosphorylating Thr172 in the T-loop • Phosphorylation of the T-loop is required for AMPK to be activated • AMPK responds to metabolic stress when AMP/ATP ratios increase Kinases that LKB1 can phosphorylate and their T-loop sequences Structure of LKB1 cellsignaling.lanl.gov Baas, Smith, Clevers

10. LKB1 and Cancer • LKB1 is a tumor suppressor • According to Lee Witters, normal cells will not divide when the energy levels are low, but cancer cells will divide • When there is low energy in the cell, LKB1 will turn on AMPK • According to a theory by Witters, LKB1 helps control cell growth because a normal cell will not divide if there are low energy stores Lee Witters http://dartmed.dartmouth.edu/winter05/html/disc_enzyme.php

11. LKB1 and Cancer • Germ-line mutations often inactivate the protein • Hamartomas and cancers generally have LOH at LKB1 locus • Studies to determine if both alleles need to be mutated have led to different conclusions • There is evidence to support the role of LKB1 in Peutz-Jeghers syndrome (familial), but there is not evidence to support a possible role of LKB1 in sporadic cancers

12. LKB1 and Cancer • Loss of polarity of differentiated epithelia leads to loss of tissue organization • Can be priming step for cancer • Could also have loss of polarity in epithelial stem cells to begin with • Tissues defective in LKB1 develop hamartomas and polyps that have fewer cells undergo apoptosis Before a polarization signal LKB1 is in the nucleus → ← After polarization signal, LKB1 is activated and moves to the cytoplasm Baas, Smit, Clevers

13. Treatment • LKB1 overexpression . . . . • Induces apoptosis in cells with p53 • Stops cell growth in cells without LKB1 Activating LKB1 will not be a significant help in slowing tumors • Need to learn how LKB1 is suppressed in the cell • Cancer cells have an inhibitor that can block activation of LKB1

14. Sources Baas, A., Smit, L., Clevers, H. LKB1 tumor suppressor protein: PARtaker in cell polarity. TRENDS in Cell Biology. 14, 312-319 (2004). Carethers, J. Peutz-Jeghers Syndrome. (2003). E-Medicine. Retrieved March 11, 2006 from http://www.emedicine.com/med/topic1807.htm Garner, Kristen. (2005). Once-obscure enzyme is now a hot property. [Electronic version]. Dartmouth Medicine. Retrieved March 19, 2006 from http://dartmed.dartmouth.edu/winter05/html/disc_enzyme.php GeneCard for STK11. (2001). Weizmann Institute of Science. Retrieved March 11, 2006 from http://genecards.bcgsc.ca/cgi-bin/carddisp?STK11 Peutz-Jeghers Syndrome. (2006). UpToDate. Retrieved March 11, 2006 from http://www.utdol.com.libproxy.lib.unc.edu/utd/content/topic.do?file=gi_dis/10563&type=A&selectedTitle=1~13 Peutz-Jeghers Syndrome, PJS. (2006). NCBI with Johns Hopkins University. Retrieved March 11, 2006 from http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175200 Yoo,L., Chung, D., & Yuan, J. LKB1-A Master Tumour Suppressor of the Small Intestine and Beyond. Nature Reviews. 2, 529-535 (2002).