Peutz-Jeghers Syndrome and LKB1/STK11

Kathryn Satterfield

• Intestinal polyposis

• Increased risk of cancer in the gastrointestinal tract and reproductive organs

• Pigmented spots on the skin.

• Autosomal Dominant

THE DISEASE

Boudeau, J et al. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Letters 2003. 546:159-165.

Yoo L, et al. LKB1- A Master Tumour Suppresor of the Small Intestine and Beyond. Nature Reviews. 2002. 7:529- 535.

• Predisposed to development of hamartomatous polyps of the small intestine.

• Lifetime cancer risk: 93%.

THE DISEASE

Boudeau, J et al. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Letters 2003. 546:159-165.Yoo L, et al. LKB1- A Master Tumour Suppresor of the Small Intestine and Beyond. Nature Reviews. 2002. 7:529- 535.

LKB1 Gene

• In 1997 Peutz-Jeghers syndrome was linked to loss-of-function mutations both alleles of LKB1.

• Thus LKB1 might suppress tumorigenesis in the intestine

Boudeau, J et al. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Letters 2003. 546:159-165.Yoo L, et al. LKB1- A Master Tumour Suppresor of the Small Intestine and Beyond. Nature Reviews. 2002. 7:529- 535.

• LKB1 encodes a serine threonine kinase

• Homologs in mice, Drosophila, and C. elegans, but NOT in yeast.

• LKB1 is located both in the nucleus and the cytoplasm.

• LKB1 mutations in PJS patients are found in the Kinase domain and the C-terminal regulatory domain.

LKB1 PROTEIN STRUCTURE

Boudeau, J et al. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Letters 2003. 546:159-165.Yoo L, et al. LKB1- A Master Tumour Suppresor of the Small Intestine and Beyond. Nature Reviews. 2002. 7:529- 535.

• Has multiple phosphorylation sites- Regulated by phosphorylation??

• The C-terminus contains a CAAX box for prenylation.

LKB1 REGULATION

Boudeau, J et al. LKB1, a protein kinase regulating cell proliferation and polarity. FEBS Letters 2003. 546:159-165.Yoo L, et al. LKB1- A Master Tumour Suppresor of the Small Intestine and Beyond. Nature Reviews. 2002. 7:529- 535.

• An LKB1-specific adaptor protein and substrate.

• Translocates LKB1 from the nucleus to the cytoplasm.

• In some mutant cell lines LKB1 translocation does not occur.

Baas AF, et al. Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD. EMBO J. 2003. Jun 16;22(12):3062-72.

STRAD

• Interactions with p21

• Interactions with p53

• Interactions with wnt pathway

• Role in cell polarization

• Interactions with PTEN

• Possible regulation of ERK and COX-2

POSSIBLE FUNCTIONS OF LKB1

Tiainen M. et al. Growth Supprestion by Lkb1 is mediated by a G1 cell cycle arrest. 1999 Aug 3; PNAS 96 (16: 9248-51.

Karuman P. et al. The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death. Mol Cell. 2001 Jun;7(6): 1307-19.

Spicer J, et al. Regulation of the Wnt signalling component PAR1A by the Peutz-Jeghers syndrom kinase LKB1. Oncogene. 2003 Jul 24;22(30):2752-6.

Ossipova O et al. LKB2 (XEEK1) regulates Wnt signalling invertebrate development. Nat Cell Biol. 2003 Oct; 5(10):889-94.

Smith D et al. LIP2, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrom kinase LKB1. Human Molecular Genetics, 2001, 10(25): 2869-77.

Takeda H et al. Simultaneous expression of COX-2 and mPGES-1 in mouse gastrointestinal hamartomas. British Journal of Cancer. 2004 90: 701-704.

• LKB1 -/- mice are embryonic lethal.

• Death occurs at mid-gestation.

• Knockout leads to abnormal development of the neural tube, heart and placenta.

• LKB1+/- mice are useful for studying LKB1’s role in tumorigenesis.

MOUSE KNOCKOUTS

Ylikorkala A. et al. Vascular abnormalities and deregulations of VEGF in LKB1-deficient mice. Science. 2001 Aug 17; 293(5533): 1323-6.

Drosophila and C. elegans

• LKB1 is necessary for the formation of the A-P axis in c. elegans and Drosophila.

• LKB1 plays a role in apical-basal epithelial polarity in these models.

• Loss of cell polarity may contribute to tumor formation in PJS.

Kinesin label in fly oocytes

A) WT LKB1 B) LKB1 mutant

A

B

Martin SG et al. A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature. 2003 Jan 23;421(6921):379.

Recent Studies on LKB1 in cells

• Created cell line in which STRAD (an LKB1 activator) is inducible.

• Activation of LKB1 resulted in complete polarization in intestinal epithelial cell lines!

Baas AF, et al. Complete Polarization of Single Intestinal Epithelial Cells upon Activation of LKB1 by STRAD. Cell. 2004 Feb 6; 116:457-66.

Recent Studies on LKB1 in cells

Baas AF, et al. Complete Polarization of Single Intestinal Epithelial Cells upon Activation of LKB1 by STRAD. Cell. 2004 Feb 6; 116:457-66.

SUMMARY

• Not much is known about the endogenous function of LKB1 or how the mutations identified play a role in creating cancer.

• The most recent research implicates that LKB1 may play a role in cell polarity.

• Research continues in the investigation of the endogenous role of LKB1 in all the areas discussed as well as the role of LKB1 in tumorigenesis in heterozygous mice.