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LKB-1 / STK-11 Peutz-Jeghers Syndrome By: Sarah Dyer Peutz-Jeghers Syndrome (PJS) Causes benign hamartomatous polyp formation throughout the GI tract ©1999 Division of Gastroenterology, Johns Hopkins Hospital Peutz-Jeghers Syndrome (PJS) Causes benign hamartomatous polyp formation throughout the GI tract Polyps can lead to cancer in the small-intestine and colon ©1999 Division of Gastroenterology, Johns Hopkins Hospital Peutz-Jeghers Syndrome (PJS) Also associated with an increased risk for many other cancers: Lung Pancreas Breast Uterus Cervix Ovary Testis Mehenni et al. (2006) Gut 55: 984-900 Inheritance of PJS PJS is inherited as an autosomal dominant trait Mehenni et al (1997) Am J Hum Genet; 61: 1327-1334. Inheritance of PJS PJS is inherited as an autosomal dominant trait Penetrance is over 90% Mehenni et al (1997) Am J Hum Genet; 61: 1327-1334. Inheritance of PJS PJS is inherited as an autosomal dominant trait Penetrance is over 90% 70% of families with PJS carry LKB-1 mutations Mehenni et al (1997) Am J Hum Genet; 61: 1327-1334. Inheritance of PJS Polyps typically show LOH at the LKB-1 locus Yoo, L.I. et al (2002) Nature Reviews 2. 529-535 Inheritance of PJS Polyps typically show LOH at the LKB-1 locus Some may not show LOH Yoo, L.I. et al (2002) Nature Reviews 2. 529-535 Inheritance of PJS Polyps typically show LOH at the LKB-1 locus Some may not show LOH A 50% reduction of Lkb-1 protein expression might be sufficient to cause hamartomas Yoo, L.I. et al (2002) Nature Reviews 2. 529-535 LKB-1 in Mice Necessary for embryonic development Yoo, L.I. et al (2002) Nature Reviews 2. 529-535 LKB-1 in Mice Necessary for embryonic development Lkb-1-/- mice die at mid-gestation Severe neural-tube defects Excessive mesenchymal cell death Abnormal vasculature Yoo, L.I. et al (2002) Nature Reviews 2. 529-535 LKB-1 in Mice Necessary for embryonic development Lkb-1-/- mice die at mid-gestation Severe neural-tube defects Excessive mesenchymal cell death Abnormal vasculature Lkb-1+/- mice are viable 100% developed gastric hamartomas Yoo, L.I. et al (2002) Nature Reviews 2. 529-535 Normal role of Lkb-1 protein Serine-threonine kinase Present in the nucleus and cytoplasm of the cells Lkb-1 is phosphorylated at Ser31, Ser325, Thr336, Thr366 and Ser431 Yoo, L.I. et al (2002) Nature Reviews 2. 529-535 Normal role of Lkb-1 protein Apoptosis LKB-1 expression in the small intestine: LKB-1 expression is highest in the cells undergoing apoptosis Yoo, L.I. et al. (2002) Nature Reviews 2. 529-535 Normal role of Lkb-1 protein Suppression of Cell Proliferation Overexpressed wild-type LKB-1 has been shown to suppress cell proliferation in some cell lines. Yoo, L.I. et al (2002) Nature Reviews 2. 529-535 Normal role of Lkb-1 protein Establishing Cell Polarity: Before LKB-1 Activation After LKB-1 Activation Baas, A.F. et al (2004) Cell 14: 312-319 Normal role of Lkb-1 protein Cell polarity PAR protein family homologs in C. elegans, Drosophila and mammals Baas, A.F. et al (2004) Cell 14: 312-319 Normal role of Lkb-1 protein Cell polarity C. elegans: PAR proteins set up polarity of zygotes Mammalian epithelial cells: Cause formation of brush borders, adherens junctions and tight junctions Baas, A.F. et al (2004) Cell 14: 312-319 Normal role of Lkb-1 protein Cell polarity Polarity Signals PAR protein pathway: Baas, A.F. et al (2004) Cell 14: 312-319 OFF ON Role of LKB-1 in cancer Mutations are inactivating Yoo, L.I. et al (2002) Nature Reviews 2. 529-535 Role of LKB-1 in cancer Inactivation may cause: Decreased apoptosis Role of LKB-1 in cancer Inactivation may cause: Decreased apoptosis Increased cell proliferation Role of LKB-1 in cancer Inactivation may cause: Decreased apoptosis Increased cell proliferation Loss of cell polarity may contribute to metastasis Thiery, J.P. (2002) Nature Reviews Cancer 2, 442-454 References Mehenni H, Resta N, Park J-G, Miyaki M, Guanti G, Costanza MC. Cancer risks in LKB1 germline mutation carriers. Gut 2006; 55: 984-990 Mehenni H, Blouin JL, Radhakrishna U, Bhardwaj SS, Bhardwaj K, Dixit VB, Richards KF, Bermejo-Fenoll A, Leal AS, Raval RC, Antonarakis SE. Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19q13.4. Am J Hum Genet. 1997; 61: 1327-1334. Yoo LI, Chung DC, Yuan J. LKB1- A Master Tumor Suppressor of the Small Intestine and Beyond. Nature Reviews; 2: 529-535. Baas AF, Smit L, Clevers H. LKB1 tumor supressor protein: PARtaker in cell polarity. TRENDS in Cell Biology 2004; 14: 312-319. Thiery, J.P. (2002) Epithelial-mesenchymal transitions in tumour progression. Nature Reviews Cancer 2, 442–454.