Download Peutz-Jeghers Syndrome: LBK1/STK11

Peutz-Jeghers Syndrome:
LBK1/STK11
By Matt Wheeler
Peutz-Jeghers Syndrome
• Rare autosomal
dominant disorder
• formation of benign
hamartomatous
polyps throughout
the gastrointestinal
track
• melanin deposits
Jishage, K et al (2002) PNAS 89: 8903-8908
Choi, HS et al (1999) J Korean Med Sci 14: 2-7
Clinical Characteristics of PJS
•
Abdominal pain, bowel obstruction,
and bleeding
• Increased lifetime risk of cancer
LKB1/STK11 is mutated in PJS
• Encodes a serine/threonine kinase
• A tumor suppressor gene
• Inherited mutation in LKB1/STK11
Identification of the gene involved
• Previously identified but unmapped gene
• Gene mapped to short arm of
chromosome 19 (19p13.3)
Connolly, DC et al (2000) Am J Pathology 156: 339-345
LKB1/STK11 is a
serine-threonine protein kinase
Boudeau, J et al (2003) FEBS letters 546:159-165
Mutations in LKB1/STK11
• Mutations inactivate the protein
• 75 mutations have been identified
• Nearly all occur in the conserved kinase domain
Yoo, YI et al (2002) Nature Reviews 2: 529-535
Mouse Model of PJS
• LKB1 -/- mice die by embryonic day 8
• Failure of embryo to turn, severe neural
tube defects, and abnormal vasculature
PJS Mouse model contd
LKB1 +/- mice develop normally and share
characteristics of human PJS patients
Gastrointestinal polyps without neoplastic
growths in other organs
100% penetrance by week 40
Cellular functions of LKB1/STK11
• Specific biological roles remain unclear
• Regulates multiple cellular processes
• These include: cell cycle arrest, apoptosis,
Wnt signaling, TGF-ß signaling, Ras
regulation, energy metabolism, and cell
polarity
Apoptosis regulation
Yoo, YI et al (2002) Nature Reviews 2: 529-535
+Z
V
N
1
+
1
LK
B
LK
B
Ca
sp
9D
AD
1
LK
B
K7
6M
KD
A
G
FP
LK
B1
LK
B1
G
FP
G
FP
K78M LKB1 = Mutant
LKB1 with no kinase
activity
co
nt
ro
l
KDA = version of LKB1
That only contains a
Kinase domain
45
40
35
30
25
20
15
10
5
0
G
FP
zVAD and casp9DN =
Caspase inhibitors
% cell death
Expression of WT LKB1 in fibrosarcoma cells
leads to increased apoptosis
Karuman, P et al (2001) Molecular Cell 7: 1307-1319
LKB1 and Cell Metabolism
Kyriakis, JM (2003) Journal of Biology 2: 26
Function in Cellular Growth Control:
Inhibition of mTOR pathway
Hardie, GD (2004) Journal of Cell Science 117: 5479-5487
Cell polarity
• Important during embryonic development
• Assymetry necessary for proper cellular
function
• Loss of polarity is a key factor in cancer
progression
Cell polarity contd
Epithelial Cell Diagram
Muller, HJ (2000) Developmental Dynamics 218: 52-67
LKB1 and Cell Polarity
• Activation of LKB1 in single intestinal epithelial
cells induces complete polarization
Prior to LKB1 Activation
After LKB1 activation
Bass, AF et al (2004) Cell 116: 457-466
•
•
•
•
Conclusions
Tumor Supressor
Serine threonine kinase
Biological roles unclear
Possible roles of LKB1 in cancer progression
- Inactivation -> decreased apoptosis and
increased cell proliferation
- Loss of polarity promotes tumor metastasis
References
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Choi HS, Park YJ, Park JG. PeutzJeghers Syndrome: A New Understanding. J Korean Med Sci
1999; 14: 2-7
Yoo LI, Chung DC, Yuan J. LKB1- A Master Tumor Supressor of the Small Intestine and Beyond.
Nature Reviews; 2: 529-535
Hardie GD. The AMP-activated protein kinase pathway-new players upstream and downstream.
Journal of Cell Science2004; 117: 5479-5487
Kyriakis JM. At the crossroads: AMP activated kinase and the LKB1 tumor supressor link cell
proliferation to metabolic regulation. Journal of Biology 2003; 2: 26
Shaw RJ, Bardeesy N, Manning BD et al. The LKB1 tumor supressor negatively regulated mTOR
signaling. Cancer Cell 2004; 6: 91-99
Karuman P, Gozani O, Odze RD et al. The Peutz-Jegher gene product LKB1 is a mediator of p53Dependent cell death. Molecular Cell 2001; 7: 1307-1319
Muller HJ. Genetic control of epithelial cell polarity: Lessons from drosophila. Developmental
Dynamics 2000; 218: 52-67
Bass AF, Kuipers J, Van Der Wel NN et al. Complete polarization of single intestinal epithelial cells
upon activation of LKB1 by STRAD. Cell 2004; 116: 457-466
Bass AF, Smit L, Clevers H. LKB1 tumor supressor protein: PARtaker in cell polarity. TRENDS in
Cell Biology 2004; 14:312-319
Boudeau J, Sapkota G, Alessi DR. LKB1, a protein kinase regulating cell proliferation and polarity.
FEBS letters 2003; 546: 159-165
Ylikorkala A, Rossi DJ, Korsisaari N et al. Vascular abnormalities and deregulation of VEGF in
LKB1- deficient mice. Science 2001; 1323-1326