1. Kate Bradford BIOL 445 March 5, 2009
LKB1/STK11
Kate Bradford
BIOL 445
March 5, 2009

2. Peutz-Jeghers Syndrome
Overview
LKB1
Roles in the cell
Peutz-Jeghers Syndrome
Tumor Suppression
Future Research

3. Serine/threonine kinase 19p13.3 Found in the nucleus and cytoplasm
LKB1/STK11
Serine/threonine kinase
19p13.3
Found in the nucleus and cytoplasm
Ubiquitously expressed
LKB1-STRAD-MO25 complex

4. Structure

5. Animal Model LKB1-/- mutation in mice is lethal
Midgestation
Neural-tube defects
Severely impaired vascular development
LKB1+/- mice: gastrointestinal polyposis, similar to PJS patients
Different distribution of polyps in GI tract
Similar histology of polyps
Mouse model for PJS

6. Roles in the cell LKB1-STRAD-MO25 complex Multiple cellular pathways
Motility
Metabolism
Polarity
Cell cycle
Positively regulates activity of AMPKs
Embryonic Development

7. Roles in the Cell POLARITY METABOLISM

8. AMPK Maintenance of cellular energy homeostasis AMPK

9. Cell Polarity What is cell polarity?
“Master regulator of cell polarity”
Catalytic function required
STRAD mediated translocation to cytoplasm
AMPKs
MARKs

10. Peutz-Jeghers Syndrome
~70% of PJS patients have LKB1 mutation
Autosomal dominant
Benign harmatomatous polyps
Mucocutaneous hyperpigmentation on lips and hands
Increased risk of cancer
Treatments

11. Peutz-Jeghers Syndrome

12. Peutz-Jeghers Syndrome

13. LKB1 Mutations in Cancer
Germ line mutations in PJS
Somatic mutations in LKB1
Pancreatic
Pulmonary
Biliary
Melanomas

14. How do metabolism defects lead to tumorigenesis?
LKB1 is a low-energy checkpoint tumor suppressor
Absence of LKB1/AMPk pathway could increase activity of proliferation pathways
mTOR
Loss of AMPK activation could promote immortalization

15. How do polarity defects lead to tumorigenesis?
Malignant cells
Impair genomic stability
Polarity defects promote oncogenic activity of c-myc
Polarity restrains cell proliferation by mitogenic stimuli

16. Cell cycle arrest
Overexpression in LKB1 deficient cell lines can suppress cell growth
WAF1/p21

17. Apoptosis and p53 Physical interaction between p53 and LKB1

18. Future Research
Examine LKB1’s expression and function in other types of cancer
Determine how LKB1 deficiency leads to tumorigenesis
Stage-specific functions
Interaction with other tumor suppressors and oncogenes
Drug therapies
Melanoma

19. References
Bass, A.F. et al. (2004) LKB1 tumor suppressor protein: PARtaker in cell polarity. TRENDS in Cell Bio. 14,
Hezel, A.F. and Bardeesy, N. (2007) LKB1; linking cell structure and tumor suppression. Onco. 27,
Katajisto, P. et al (2007) The LKB1 tumor suppressor kinase in human disease. Biochem. et biophys. 1775,
Shah, U. et al (2008) LKB1 and Lung Cancer: More than the Usual Suspects. Cancer Res. 68,
Shaw, R.G. et al (2004) The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 6,
Shaw, R.J. et al (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. PNAS. 101,
Yoo, L.I. et al. (2002) LKB1—A Master Tumour Suppressor of the Small Intestine and Beyond. Nature. 2,