Peutz-Jeghers Syndrome:Peutz-Jeghers Syndrome:LBK1/STK11LBK1/STK11

By Matt WheelerBy Matt Wheeler

Peutz-Jeghers SyndromePeutz-Jeghers Syndrome

• Rare autosomal Rare autosomal dominant disorderdominant disorder

• formation of benign formation of benign hamartomatous hamartomatous polyps throughout polyps throughout the gastrointestinal the gastrointestinal tracktrack

• melanin depositsmelanin deposits

Jishage, K et al (2002) PNAS 89: 8903-8908Choi, HS et al (1999) J Korean Med Sci 14: 2-7

Clinical Characteristics of PJSClinical Characteristics of PJS

• Abdominal pain, bowel obstruction, Abdominal pain, bowel obstruction, and bleedingand bleeding

• Increased lifetime risk of cancerIncreased lifetime risk of cancer

LKB1/STK11 is mutated in PJSLKB1/STK11 is mutated in PJS

• Encodes a serine/threonine kinase Encodes a serine/threonine kinase • A tumor suppressor geneA tumor suppressor gene• Inherited mutation in LKB1/STK11Inherited mutation in LKB1/STK11

Identification of the gene involvedIdentification of the gene involved

• Previously identified but unmapped genePreviously identified but unmapped gene

• Gene mapped to short arm of Gene mapped to short arm of chromosome 19 (19p13.3)chromosome 19 (19p13.3)

Connolly, DC et al (2000) Am J Pathology 156: 339-345

LKB1/STK11 is a LKB1/STK11 is a serine-threonine protein kinaseserine-threonine protein kinase

Boudeau, J et al (2003) FEBS letters 546:159-165

Mutations in LKB1/STK11Mutations in LKB1/STK11• Mutations inactivate the proteinMutations inactivate the protein

• 75 mutations have been identified 75 mutations have been identified

• Nearly all occur in the conserved kinase domainNearly all occur in the conserved kinase domain

Yoo, YI et al (2002) Nature Reviews 2: 529-535

Mouse Model of PJSMouse Model of PJS

• LKB1 -/- mice die by embryonic day 8LKB1 -/- mice die by embryonic day 8• Failure of embryo to turn, severe neural Failure of embryo to turn, severe neural

tube defects, and abnormal vasculature tube defects, and abnormal vasculature

PJS Mouse model contdPJS Mouse model contd

LKB1 +/- mice develop normally and share LKB1 +/- mice develop normally and share characteristics of human PJS patientscharacteristics of human PJS patients

Gastrointestinal polyps without neoplastic Gastrointestinal polyps without neoplastic growths in other organsgrowths in other organs

100% penetrance by week 40100% penetrance by week 40

Cellular functions of LKB1/STK11Cellular functions of LKB1/STK11

• Specific biological roles remain unclearSpecific biological roles remain unclear• Regulates multiple cellular processesRegulates multiple cellular processes• These include: cell cycle arrest, apoptosis, These include: cell cycle arrest, apoptosis,

Wnt signaling, TGF-ß signaling, Ras Wnt signaling, TGF-ß signaling, Ras regulation, energy metabolism, and cell regulation, energy metabolism, and cell polaritypolarity

Apoptosis regulationApoptosis regulation

Yoo, YI et al (2002) Nature Reviews 2: 529-535

Expression of WT LKB1 in fibrosarcoma cells leads to increased apoptosis

zVAD and casp9DN = Caspase inhibitors

KDA = version of LKB1That only contains a Kinase domain

Karuman, P et al (2001) Molecular Cell 7: 1307-1319

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ell d

eath

K78M LKB1 = Mutant LKB1 with no kinaseactivity

LKB1 and Cell MetabolismLKB1 and Cell Metabolism

Kyriakis, JM (2003) Journal of Biology 2: 26

Function in Cellular Growth Control: Function in Cellular Growth Control: Inhibition of mTOR pathwayInhibition of mTOR pathway

Hardie, GD (2004) Journal of Cell Science 117: 5479-5487

Cell polarityCell polarity

• Important during embryonic developmentImportant during embryonic development

• Assymetry necessary for proper cellular Assymetry necessary for proper cellular functionfunction

• Loss of polarity is a key factor in cancer Loss of polarity is a key factor in cancer progressionprogression

Cell polarity contdCell polarity contdEpithelial Cell Diagram

Muller, HJ (2000) Developmental Dynamics 218: 52-67

LKB1 and Cell PolarityLKB1 and Cell Polarity

• Activation of LKB1 in single intestinal epithelial Activation of LKB1 in single intestinal epithelial cells induces complete polarizationcells induces complete polarization

Prior to LKB1 Activation After LKB1 activation

Bass, AF et al (2004) Cell 116: 457-466

ConclusionsConclusions

• Tumor SupressorTumor Supressor• Serine threonine kinaseSerine threonine kinase• Biological roles unclearBiological roles unclear• Possible roles of LKB1 in cancer progressionPossible roles of LKB1 in cancer progression - Inactivation -> decreased apoptosis and - Inactivation -> decreased apoptosis and

increased cell proliferationincreased cell proliferation

- Loss of polarity promotes tumor metastasis - Loss of polarity promotes tumor metastasis

ReferencesReferences• Choi HS, Park YJ, Park JG. Choi HS, Park YJ, Park JG. PeutzJeghers Syndrome: A New Understanding. J Korean Med Sci PeutzJeghers Syndrome: A New Understanding. J Korean Med Sci

1999; 14: 2-7 1999; 14: 2-7 • Yoo LI, Chung DC, Yuan J. Yoo LI, Chung DC, Yuan J. LKB1- A Master Tumor Supressor of the Small Intestine and Beyond. LKB1- A Master Tumor Supressor of the Small Intestine and Beyond.

Nature Reviews; 2: 529-535Nature Reviews; 2: 529-535• Hardie GDHardie GD. The AMP-activated protein kinase pathway-new players upstream and downstream. . The AMP-activated protein kinase pathway-new players upstream and downstream.

Journal of Cell Science2004; 117: 5479-5487Journal of Cell Science2004; 117: 5479-5487• Kyriakis JMKyriakis JM. At the crossroads: AMP activated kinase and the LKB1 tumor supressor link cell . At the crossroads: AMP activated kinase and the LKB1 tumor supressor link cell

proliferation to metabolic regulation. Journal of Biology 2003; 2: 26proliferation to metabolic regulation. Journal of Biology 2003; 2: 26• Shaw RJ, Bardeesy N, Manning BDShaw RJ, Bardeesy N, Manning BD et al. The LKB1 tumor supressor negatively regulated et al. The LKB1 tumor supressor negatively regulated

mTOR signaling. Cancer Cell 2004; 6: 91-99mTOR signaling. Cancer Cell 2004; 6: 91-99• Karuman P, Gozani O, Odze RDKaruman P, Gozani O, Odze RD et al. The Peutz-Jegher gene product LKB1 is a mediator of et al. The Peutz-Jegher gene product LKB1 is a mediator of

p53-Dependent cell death. Molecular Cell 2001; 7: 1307-1319p53-Dependent cell death. Molecular Cell 2001; 7: 1307-1319• Muller HJMuller HJ. Genetic control of epithelial cell polarity: Lessons from drosophila. Developmental . Genetic control of epithelial cell polarity: Lessons from drosophila. Developmental

Dynamics 2000; 218: 52-67Dynamics 2000; 218: 52-67• Bass AF, Kuipers J, Van Der Wel NNBass AF, Kuipers J, Van Der Wel NN et al. Complete polarization of single intestinal epithelial et al. Complete polarization of single intestinal epithelial

cells upon activation of LKB1 by STRAD. Cell 2004; 116: 457-466cells upon activation of LKB1 by STRAD. Cell 2004; 116: 457-466• Bass AF, Smit L, Clevers HBass AF, Smit L, Clevers H. LKB1 tumor supressor protein: PARtaker in cell polarity. TRENDS in . LKB1 tumor supressor protein: PARtaker in cell polarity. TRENDS in

Cell Biology 2004; 14:312-319Cell Biology 2004; 14:312-319• Boudeau J, Sapkota G, Alessi DRBoudeau J, Sapkota G, Alessi DR. LKB1, a protein kinase regulating cell proliferation and . LKB1, a protein kinase regulating cell proliferation and

polarity. FEBS letters 2003; 546: 159-165polarity. FEBS letters 2003; 546: 159-165• Ylikorkala A, Rossi DJ, Korsisaari NYlikorkala A, Rossi DJ, Korsisaari N et al. Vascular abnormalities and deregulation of VEGF in et al. Vascular abnormalities and deregulation of VEGF in

LKB1- deficient mice. Science 2001; 1323-1326LKB1- deficient mice. Science 2001; 1323-1326