Download LKB-1 / STK-11

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:




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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
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Some may not show LOH
Yoo, L.I. et al (2002) Nature Reviews 2. 529-535
Inheritance of PJS
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Polyps typically show LOH at the LKB-1 locus
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Some may not show LOH
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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
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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
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Severe neural-tube defects
Excessive mesenchymal cell death
Abnormal vasculature
Lkb-1+/- mice are viable
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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
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Suppression of Cell Proliferation
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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
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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
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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
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Cell polarity
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Polarity Signals
PAR protein pathway:
Baas, A.F. et al (2004) Cell 14: 312-319
OFF
ON
Role of LKB-1 in cancer
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Mutations are inactivating
Yoo, L.I. et al (2002) Nature Reviews 2. 529-535
Role of LKB-1 in cancer
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Inactivation may cause:
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Decreased apoptosis
Role of LKB-1 in cancer
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Inactivation may cause:
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Decreased apoptosis
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Increased cell proliferation
Role of LKB-1 in cancer
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Inactivation may cause:
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Decreased apoptosis
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Increased cell proliferation
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Loss of cell polarity may contribute to metastasis
Thiery, J.P. (2002) Nature Reviews Cancer 2, 442-454
References
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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.
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Baas AF, Smit L, Clevers H. LKB1 tumor supressor protein: PARtaker in cell polarity. TRENDS in
Cell Biology 2004; 14: 312-319.
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Thiery, J.P. (2002) Epithelial-mesenchymal transitions in tumour progression. Nature Reviews
Cancer 2, 442–454.