Download LKB1 and Peutz-Jeghers Syndrome

LKB1 and Peutz-Jeghers
Syndrome
Josh Lawrimore
Gene Specifics
Location: 19p13.3
LKB1
http://www.lbl.gov/Publications/Currents/Archive/Apr-02-2004.html
Protein Specifics
LKB1 encodes a kinase
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433 amino acids
48 kDa
Serine-Threonine Kinase Activity
Yoo L. I. et al. Nature. 2002
Other features of the protein
suggest mechanisms of localization
and regulation
Phosphorylation Sites
N-Terminal
Nuclear
Localization Sites
Yoo L. I. et al. Nature. 2002
C-Terminal
Prenylation Site
Other features of the protein
suggest mechanisms of localization
and regulation
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Mainly cytoplasmic
Can also be localized in the nucleus
Yoo L. I. et al. Nature. 2002
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
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C. elegans
– Par-4 genes anterior-posterior axis in
embryo
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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
Bass et al. TRENDS in cell 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
MO25
synthesis
Spicer and Ashworth, Current
Biology, 2004
LKB1 has other functions
as well
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Apoptosis via p53
Cell cycle arrest via cyclin-dependent
kinase inhibitor WAF1 (p21)
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
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KO mice die at mid-gestation
Sever neural-tube defects
Excessive mesenchymal cell death
Abnormal vasculature
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
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First described in a Dutch Family by
Peutz in 1921 and later by Jeghers
Rare Autosomal-dominant polyposis
disorder
Yoo L. I. et al. Nature. 2002
http://home.megapass.co.kr/~faldo/diseases/peutzjeghers.html
Symptoms
http://www.surgical-tutor.org.uk/defaulthome.htm?system/abdomen/colonic_polyp.htm~right
Symptoms
The Johns Hopkins Guide for Patients and
Families: Peutz-Jeghers Syndrome
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
Zbuk KM and Eng C (2007) Hamartomatous polyposis syndromes
Nat Clin Pract Gastroenterol Hepatol 4: 492–502 doi:10.1038/ncpgasthep0902
PJS and LKB1 Mutations
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Mutation is loss of function
PJS hamartomatous polyps have
typically shown LOH at LKB1
But recently shown that as many as
60% of PJS polyps fails to show LOH
Indicates Possible Halpoinsufficiency
Yoo L. I. et al. Nature. 2002
The Johns Hopkins Guide for Patients and
Families: Peutz-Jeghers Syndrome
Inheritance and Cancer
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Germ line mutation in 70% of classic
families
Nearly 100% penetrance in inherited
cases
93% risk of getting cancer
Cancer around age 43
Yoo L. I. et al. Nature. 2002
PJS and Cancer
Colon Cancer
84-fold
increase
Gastric Cancer
Small-intestinal Cancer
Yoo L. I. et al. Nature. 2002
213-fold
increase
520-fold
increase