Peutz-Jeghers Syndrome (PJS)and LKB1

Sarah Bass

March 28, 2006

www.smu.org.uy

Peutz-Jeghers Syndrome

Rare autosomal dominant disorder Benign hamartomatous polyps through gastrointestinal tract Tumors can develop in

Lung, breast, pancreas, uterus, ovary, cervix, testis

alf3.urz.unibas.ch Polyps in the jejunum Normal jejunum

www3.umdnj.edu

Multiple Processes LKB1 Regulates Control of cell-cycle arrest (G1)

p53-mediated apoptosis

Wnt signaling

TFG-β signaling

Ras-induced cell transformation

Energy metabolism

Cell polarity

Polyps145.253.118.170/roche5/ pics/a22030.000-1_big.gif

LKB1 is a kinase and it is regulated by phosphorylation

Multiple Processes LKB1 Regulates Control of cell-cycle arrest (G1)

p53-mediated apoptosis

Wnt signaling

TFG-β signaling

Ras-induced cell transformation

Energy metabolism

Cell polarity

Polyps145.253.118.170/roche5/ pics/a22030.000-1_big.gif

LKB1 is a kinase and it is regulated by phosphorylation

Location of LKB1

http://genecards.bcgsc.ca/cgi-bin/carddisp?STK11

Located on chromosome 19p13.3

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 OrganismsCaenorhabditis 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 OrganismsMice• LKB1 -/- mice died midgestation

• Neural tube defects• Impaired vascular development• 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

www.scenta.co.uk

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

Baas, Smit, Clevers

Actin (red) distributed equally →(before LKB1 activation)

←Actin reorganizing forming a border at the apical site (after LKB1 activation)

Baas, Smit, Clevers

LKB1 and Metabolic Regulation LKB1 activates AMPK (AMP-activated protein kinase) by phosphorylating

Thr172 in the T-loop

Phosphorylation of the T-loop is required for AMPK to be activated

AMPK responds to metabolic stress when AMP/ATP ratios increase

Kinases that LKB1can phosphorylate andtheir T-loop sequences

Baas, Smith, Cleverscellsignaling.lanl.gov

Structure of LKB1

LKB1 and Cancer

LKB1 is a tumor suppressor

According to Lee Witters, normal cells will not divide when the energy levels are low, but cancer cells will divide

When there is low energy in the cell, LKB1 will turn on AMPK

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

Germ-line mutations often inactivate the protein

Hamartomas and cancers generally have LOH at LKB1 locus

Studies to determine if both alleles need to be mutated have led to different conclusions

There is evidence to support the role of LKB1 in Peutz-Jeghers syndrome (familial), but there is not evidence to support a possible role of LKB1 in sporadic cancers

LKB1 and Cancer

Loss of polarity of differentiated epithelia leads to loss of tissue organization Can be priming step for cancer

Could also have loss of polarity in epithelial stem cells to begin with

Tissues defective in LKB1 develop hamartomas and polyps that have fewer cells undergo apoptosis

Before a polarization signalLKB1 is in the nucleus → ← After polarization signal,

LKB1 is activated and moves tothe cytoplasm

Baas, Smit, Clevers

Treatment

LKB1 overexpression . . . . Induces apoptosis in cells with p53 Stops cell growth in cells without LKB1

Activating LKB1 will not be a significant help in slowing tumors

Need to learn how LKB1 is suppressed in the cell Cancer cells have an inhibitor that can block activation of LKB1

SourcesBaas, 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).