Download LKB1

Peutz-Jeghers Syndrome (PJS)
and LKB1
Sarah Bass
March 28, 2006
www.smu.org.uy
Peutz-Jeghers Syndrome
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Rare autosomal dominant disorder
Benign hamartomatous polyps through gastrointestinal tract
Tumors can develop in

Lung, breast, pancreas, uterus, ovary, cervix, testis
Polyps in the jejunum
alf3.urz.unibas.ch
Normal jejunum
www3.umdnj.edu
Multiple Processes LKB1 Regulates
LKB1 is a kinase and it is regulated by phosphorylation
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Control of cell-cycle arrest (G1)
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p53-mediated apoptosis
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Wnt signaling
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TFG-β signaling
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Ras-induced cell transformation
Polyps
145.253.118.170/roche5/ pics/a22030.000-1_big.gif
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Energy metabolism
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Cell polarity
Multiple Processes LKB1 Regulates
LKB1 is a kinase and it is regulated by phosphorylation

Control of cell-cycle arrest (G1)

p53-mediated apoptosis

Wnt signaling

TFG-β signaling

Ras-induced cell transformation
Polyps
145.253.118.170/roche5/ pics/a22030.000-1_big.gif

Energy metabolism
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Cell polarity
Location of LKB1
Located on chromosome 19p13.3
http://genecards.bcgsc.ca/cgi-bin/carddisp?STK11
Most of the point mutations in LKB1 are in the kinase domain
Yoo, Chung, Yuan
Determined location of LBK1 by linkage analysis using families with PJS
Homologues of LKB1 in Model
Organisms
Caenorhabditis elegans
•
LKB1 homologue controls cellular polarity (PAR4)
•
Six PAR genes and all are required to regulate polarity of first two
asymmetric cell divisions
•
Polarity is required to determine cell fate
www.sih.m.u-tokyo.ac.jp
Baas, Smit, Clevers
Homologues of LKB1 in Model
Organisms
Mice
• LKB1 -/- mice died midgestation
• Neural tube defects
• Impaired vascular development
www.scenta.co.uk
• Defects in extra-embryonic development
•
LKB1 +/• Viable, fertile, and appear healthy at birth
• At 20 weeks, hamartomatous polyps in the stomach
and small intestine appear
• At 40 weeks, 100% of these mice develops gastric
hamartomas
Cell Polarity in Mammalian Cells

Cell-extracellular matrix contacts and cell-cell contacts are spatial cues that
lead to polarization
Activated LKB1 can induce polarity in
single, isolated cells
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Actin (red) distributed equally →
(before LKB1 activation)
Baas, Smit, Clevers
←Actin reorganizing forming a border
at the apical site (after LKB1 activation)
Baas, Smit, Clevers
LKB1 and Metabolic Regulation
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LKB1 activates AMPK (AMP-activated protein kinase) by phosphorylating
Thr172 in the T-loop
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Phosphorylation of the T-loop is required for AMPK to be activated
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AMPK responds to metabolic stress when AMP/ATP ratios increase
cellsignaling.lanl.gov
Structure of
LKB1
Kinases that LKB1
can phosphorylate and
their T-loop sequences
Baas, Smith, Clevers
LKB1 and Cancer
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LKB1 is a tumor suppressor
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According to Lee Witters, normal cells will not divide when the energy levels
are low, but cancer cells will divide
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When there is low energy in the cell, LKB1 will turn on AMPK
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According to a theory by Witters, LKB1 helps
control cell growth because a normal cell will
not divide if there are low energy stores
Lee Witters
http://dartmed.dartmouth.edu/winter05/html/disc_enzyme.php
LKB1 and Cancer
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Germ-line mutations often inactivate the protein
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Hamartomas and cancers generally have LOH at LKB1
locus
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Studies to determine if both alleles need to be mutated
have led to different conclusions
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There is evidence to support the role of LKB1 in PeutzJeghers syndrome (familial), but there is not evidence to
support a possible role of LKB1 in sporadic cancers
LKB1 and Cancer
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Loss of polarity of differentiated epithelia leads to loss of tissue organization
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Can be priming step for cancer
Could also have loss of polarity in epithelial stem cells to begin with
Before a polarization signal
LKB1 is in the nucleus →
← After polarization signal,
LKB1 is activated and moves to
the cytoplasm
Baas, Smit, Clevers

Tissues defective in LKB1 develop hamartomas and polyps that have fewer
cells undergo apoptosis
Treatment
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LKB1 overexpression . . . .
Induces apoptosis in cells with p53
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Stops cell growth in cells without LKB1
Activating LKB1 will not be a significant help in slowing tumors
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Need to learn how LKB1 is suppressed in the cell
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Cancer cells have an inhibitor that can block activation of LKB1
Sources
Baas, A., Smit, L., Clevers, H. LKB1 tumor suppressor protein: PARtaker in cell polarity. TRENDS in Cell Biology.
14, 312-319 (2004).
Carethers, J. Peutz-Jeghers Syndrome. (2003). E-Medicine. Retrieved March 11, 2006 from
http://www.emedicine.com/med/topic1807.htm
Garner, Kristen. (2005). Once-obscure enzyme is now a hot property. [Electronic version]. Dartmouth Medicine.
Retrieved March 19, 2006 from http://dartmed.dartmouth.edu/winter05/html/disc_enzyme.php
GeneCard for STK11. (2001). Weizmann Institute of Science. Retrieved March 11, 2006 from
http://genecards.bcgsc.ca/cgi-bin/carddisp?STK11
Peutz-Jeghers Syndrome. (2006). UpToDate. Retrieved March 11, 2006 from
http://www.utdol.com.libproxy.lib.unc.edu/utd/content/topic.do?file=gi_dis/10563&type=A&selectedTitle=1~13
Peutz-Jeghers Syndrome, PJS. (2006). NCBI with Johns Hopkins University. Retrieved March 11, 2006 from
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=175200
Yoo,L., Chung, D., & Yuan, J. LKB1-A Master Tumour Suppressor of the Small Intestine and Beyond. Nature
Reviews. 2, 529-535 (2002).