LKB1 and Peutz-Jeghers Syndrome Josh Lawrimore

Gene Specifics

Location: 19p LKB1

Protein Specifics

LKB1 encodes a kinase 433 amino acids 433 amino acids 48 kDa 48 kDa Serine-Threonine Kinase Activity Serine-Threonine Kinase Activity Yoo L. I. et al. Nature. 2002

Other features of the protein suggest mechanisms of localization and regulation Nuclear Localization Sites Phosphorylation Sites Prenylation Site Yoo L. I. et al. Nature N-Terminal C-Terminal

Mainly cytoplasmic Mainly cytoplasmic Can also be localized in the nucleus Can also be localized in the nucleus Yoo L. I. et al. Nature Other features of the protein suggest mechanisms of localization and regulation

LBK1 Protein’s Cellular Function

“LKB1 Kinase: Master and Commander of Metabolism and Polarity” Spicer and Ashworth, Current Biology, 2004

The study of LKB1 homologs in model organisms suggest important roles in cell polarity C. elegans C. elegans –Par-4 genes  anterior-posterior axis in embryo Drosophila Drosophila –lkb1 gene  anterior-posterior polarity of oocyte and repolarization of the oocyte cytoskeleton

LBK1 Activation can polarize individual cells Bass et al. TRENDS in cell Biology, 2004

LKB1 leaves the nucleus to form a heterotrimeric complex to regulate cell polarity

MO25 Spicer and Ashworth, Current Biology, 2004 ? LBK1 is an upstream regulator of AMPK and Cell Metabolism

MO25 Spicer and Ashworth, Current Biology, 2004 Loss of LKB1 leads to loss of cell polarity and increased protein synthesis

LKB1 has other functions as well Apoptosis via p53 Apoptosis via p53 Cell cycle arrest via cyclin-dependent kinase inhibitor WAF1 (p21) Cell cycle arrest via cyclin-dependent kinase inhibitor WAF1 (p21) Sensor of microtubule integrity Sensor of microtubule integrity

Possible Apoptosis Model Yoo L. I. et al. Nature. 2002

LBK1 is Broadly expressed in Adults and Embryos Sanchez-Cespedes, Oncogene, 2007

Homozygous Knock-Outs Are Lethal KO mice die at mid-gestation KO mice die at mid-gestation Sever neural-tube defects Sever neural-tube defects Excessive mesenchymal cell death Excessive mesenchymal cell death Abnormal vasculature Abnormal vasculature Phenotype looks like Cowden’s disease (a PTEN KO mutation) Phenotype looks like Cowden’s disease (a PTEN KO mutation) Bass et al. TRENDS in cell Biology, 2004

LBK1 is expressed in differentiated cells in the Small Intestine Yoo L. I. et al. Nature. 2002

Peutz-Jeghers Syndrome First described in a Dutch Family by Peutz in 1921 and later by Jeghers First described in a Dutch Family by Peutz in 1921 and later by Jeghers Rare Autosomal-dominant polyposis disorder Rare Autosomal-dominant polyposis disorder Yoo L. I. et al. Nature

home.htm?system/abdomen/colonic_polyp.htm~right Symptoms

Symptoms The Johns Hopkins Guide for Patients and Families: Peutz-Jeghers Syndrome

Zbuk KM and Eng C (2007) Hamartomatous polyposis syndromes Nat Clin Pract Gastroenterol Hepatol 4: 492–502 doi: /ncpgasthep0902 Figure 1 A typical Peutz–Jeghers syndrome polyp demonstrating the arborizing pattern of smooth-muscle proliferation Permission obtained from Macmillan Publishers Ltd © Bronner (2003)79 Modern Pathology 16: 359–365

Mutation is loss of function Mutation is loss of function PJS hamartomatous polyps have typically shown LOH at LKB1 PJS hamartomatous polyps have typically shown LOH at LKB1 But recently shown that as many as 60% of PJS polyps fails to show LOH But recently shown that as many as 60% of PJS polyps fails to show LOH Indicates Possible Halpoinsufficiency Indicates Possible Halpoinsufficiency PJS and LKB1 Mutations Yoo L. I. et al. Nature The Johns Hopkins Guide for Patients and Families: Peutz-Jeghers Syndrome

Inheritance and Cancer Germ line mutation in 70% of classic families Germ line mutation in 70% of classic families Nearly 100% penetrance in inherited cases Nearly 100% penetrance in inherited cases 93% risk of getting cancer 93% risk of getting cancer Cancer around age 43 Cancer around age 43 Yoo L. I. et al. Nature. 2002

Colon Cancer 84-fold increase Gastric Cancer Small-intestinal Cancer 213-fold increase 520-fold increase PJS and Cancer Yoo L. I. et al. Nature. 2002