Peutz-Jeghers Syndrome: LBK1/STK11 By Matt Wheeler

Peutz-Jeghers Syndrome Rare autosomal dominant disorder Rare autosomal dominant disorder formation of benign hamartomatous polyps throughout the gastrointestinal track formation of benign hamartomatous polyps throughout the gastrointestinal track melanin deposits melanin deposits Jishage, K et al (2002) PNAS 89: Choi, HS et al (1999) J Korean Med Sci 14: 2-7

Clinical Characteristics of PJS Abdominal pain, bowel obstruction, and bleeding Abdominal pain, bowel obstruction, and bleeding Increased lifetime risk of cancer Increased lifetime risk of cancer

LKB1/STK11 is mutated in PJS Encodes a serine/threonine kinase Encodes a serine/threonine kinase A tumor suppressor gene A tumor suppressor gene Inherited mutation in LKB1/STK11 Inherited mutation in LKB1/STK11

Identification of the gene involved Previously identified but unmapped gene Previously identified but unmapped gene Gene mapped to short arm of chromosome 19 (19p13.3) Gene mapped to short arm of chromosome 19 (19p13.3) Connolly, DC et al (2000) Am J Pathology 156:

LKB1/STK11 is a serine-threonine protein kinase Boudeau, J et al (2003) FEBS letters 546:

Mutations in LKB1/STK11 Mutations inactivate the protein Mutations inactivate the protein 75 mutations have been identified 75 mutations have been identified Nearly all occur in the conserved kinase domain Nearly all occur in the conserved kinase domain Yoo, YI et al (2002) Nature Reviews 2:

Mouse Model of PJS LKB1 -/- mice die by embryonic day 8 LKB1 -/- mice die by embryonic day 8 Failure of embryo to turn, severe neural tube defects, and abnormal vasculature Failure of embryo to turn, severe neural tube defects, and abnormal vasculature

PJS Mouse model contd LKB1 +/- mice develop normally and share characteristics of human PJS patients Gastrointestinal polyps without neoplastic growths in other organs 100% penetrance by week 40

Cellular functions of LKB1/STK11 Specific biological roles remain unclear Specific biological roles remain unclear Regulates multiple cellular processes Regulates multiple cellular processes These include: cell cycle arrest, apoptosis, Wnt signaling, TGF-ß signaling, Ras regulation, energy metabolism, and cell polarity These include: cell cycle arrest, apoptosis, Wnt signaling, TGF-ß signaling, Ras regulation, energy metabolism, and cell polarity

Apoptosis regulation Apoptosis regulation Yoo, YI et al (2002) Nature Reviews 2:

Expression of WT LKB1 in fibrosarcoma cells leads to increased apoptosis zVAD and casp9DN = Caspase inhibitors KDA = version of LKB1 That only contains a Kinase domain Karuman, P et al (2001) Molecular Cell 7: K78M LKB1 = Mutant LKB1 with no kinase activity

LKB1 and Cell Metabolism Kyriakis, JM (2003) Journal of Biology 2: 26

Function in Cellular Growth Control: Inhibition of mTOR pathway Function in Cellular Growth Control: Inhibition of mTOR pathway Hardie, GD (2004) Journal of Cell Science 117:

Cell polarity Important during embryonic development Important during embryonic development Assymetry necessary for proper cellular function Assymetry necessary for proper cellular function Loss of polarity is a key factor in cancer progression Loss of polarity is a key factor in cancer progression

Cell polarity contd Epithelial Cell Diagram Muller, HJ (2000) Developmental Dynamics 218: 52-67

LKB1 and Cell Polarity Activation of LKB1 in single intestinal epithelial cells induces complete polarization Activation of LKB1 in single intestinal epithelial cells induces complete polarization Prior to LKB1 ActivationAfter LKB1 activation Bass, AF et al (2004) Cell 116:

Conclusions Tumor Supressor Tumor Supressor Serine threonine kinase Serine threonine kinase Biological roles unclear Biological roles unclear Possible roles of LKB1 in cancer progression Possible roles of LKB1 in cancer progression - Inactivation -> decreased apoptosis and increased cell proliferation - Inactivation -> decreased apoptosis and increased cell proliferation - Loss of polarity promotes tumor metastasis - Loss of polarity promotes tumor metastasis

References Choi HS, Park YJ, Park JG. PeutzJeghers Syndrome: A New Understanding. J Korean Med Sci 1999; 14: 2-7 Choi HS, Park YJ, Park JG. PeutzJeghers Syndrome: A New Understanding. J Korean Med Sci 1999; 14: 2-7 Yoo LI, Chung DC, Yuan J. LKB1- A Master Tumor Supressor of the Small Intestine and Beyond. Nature Reviews; 2: Yoo LI, Chung DC, Yuan J. LKB1- A Master Tumor Supressor of the Small Intestine and Beyond. Nature Reviews; 2: Hardie GD. The AMP-activated protein kinase pathway-new players upstream and downstream. Journal of Cell Science2004; 117: Hardie GD. The AMP-activated protein kinase pathway-new players upstream and downstream. Journal of Cell Science2004; 117: Kyriakis JM. At the crossroads: AMP activated kinase and the LKB1 tumor supressor link cell proliferation to metabolic regulation. Journal of Biology 2003; 2: 26 Kyriakis JM. At the crossroads: AMP activated kinase and the LKB1 tumor supressor link cell proliferation to metabolic regulation. Journal of Biology 2003; 2: 26 Shaw RJ, Bardeesy N, Manning BD et al. The LKB1 tumor supressor negatively regulated mTOR signaling. Cancer Cell 2004; 6: Shaw RJ, Bardeesy N, Manning BD et al. The LKB1 tumor supressor negatively regulated mTOR signaling. Cancer Cell 2004; 6: Karuman P, Gozani O, Odze RD et al. The Peutz-Jegher gene product LKB1 is a mediator of p53- Dependent cell death. Molecular Cell 2001; 7: Karuman P, Gozani O, Odze RD et al. The Peutz-Jegher gene product LKB1 is a mediator of p53- Dependent cell death. Molecular Cell 2001; 7: Muller HJ. Genetic control of epithelial cell polarity: Lessons from drosophila. Developmental Dynamics 2000; 218: Muller HJ. Genetic control of epithelial cell polarity: Lessons from drosophila. Developmental Dynamics 2000; 218: Bass AF, Kuipers J, Van Der Wel NN et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 2004; 116: Bass AF, Kuipers J, Van Der Wel NN et al. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 2004; 116: Bass AF, Smit L, Clevers H. LKB1 tumor supressor protein: PARtaker in cell polarity. TRENDS in Cell Biology 2004; 14: Bass AF, Smit L, Clevers H. LKB1 tumor supressor protein: PARtaker in cell polarity. TRENDS in Cell Biology 2004; 14: Boudeau J, Sapkota G, Alessi DR. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS letters 2003; 546: Boudeau J, Sapkota G, Alessi DR. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS letters 2003; 546: Ylikorkala A, Rossi DJ, Korsisaari N et al. Vascular abnormalities and deregulation of VEGF in LKB1- deficient mice. Science 2001; Ylikorkala A, Rossi DJ, Korsisaari N et al. Vascular abnormalities and deregulation of VEGF in LKB1- deficient mice. Science 2001;