1. PTEN (a.k.a. MMAC1 and TEP1) and Cowden’s Disease
“Phosphatase and tensin homolog on Chromosome ten”
PTEN (a.k.a. MMAC1 and TEP1)
and
Cowden’s Disease

2. Cowden Disease Multiple benign growths – hamartomas
CD confers an increased susceptibility to malignant carcinomas
Breast cancer, thyroid cancers and glioblastoma
GLIOBLASTOMA

3. Cowden Disease 89% of females with CD get breast hamartomas
74% develop malignant breast tumors
(Schrager et al. 1998)
50% - 75% of people with CD develop thyroid disease
Prostate Cancer
Loss of PTEN and p27
In many of the cases of advanced metastatic tumors, the individual has also suffered additional mutations

4. Discovery of PTEN In 1996 Cowden Syndrome was mapped to the 10q22-23
This region is also commonly mutated in thyroid cancers

5. Phosphatase and Tensin Homologue on Chromosome 10
Either germline or sporadic mutation
80% have a germline mutation
PTEN acts as classic tumor suppressor
Inherited as an autosomal dominant trait
Must lose both copies to be affected - Loss of Heterozygosity (LOH)
81% of Cowden’s Disease patients have suffered a mutation in PTEN. 80% of CD patients with a PTEN mutation have a germline mutation, the remaining 20% lost the PTEN gene by sporadic mutation
Simpson and Parsons.(2001) Experimental Cell Research 264, 29-41

6. PTEN is a Phosphatase
High degree of sequence homology with typical protein phosphatase
Postulated dual specificity as a protein and lipid phosphatase
As a protein phosphatase PTEN is thought to regulate the MAP kinase pathway by dephosphorylating serine/threonine residues upstream of ERK and FAK

7. Phosphatase and Tensin Homologue on Chromosome 10
Component of the PIP3/PI3K/AKT pathway
NEGATIVE REGULATOR of this pathway
Antagonist of cell survival, cell growth, cell cycle and cell migration
FROM HERE ON OUT I WILL BE TALKING ABOUT PTEN AS A LIPID PHOSPHATASE
Since we’ve already established that it acts as a tumor suppressor it makes sense that it is a negative regulator of a pathway that promotes cell survival, growth, cycle progression and cell migration
Waite and Eng.(2002) Am. J. Hum. Genet. 70:

8. Biochemical Structure and Activity of PTEN
Phosphatase Catalytic Domain
Protein Protein Binding Domain
Lipid Binding Domain
Stability N C
403 aa

9. Biochemical Structure and Function of PTEN
Active site of the phosphatase domain

10. PTEN Intracellular role
PTEN functions in the PI3K/AKT pathway by negatively regulating the levels of PtdIns(3,4,5)P3 or PIP3
PIP3 is a potent secondary messenger that binds proteins with PH domains
1999. Coffee Break. PTEN and the Tumor Suppressor. 1-3

11. Biochemical Structure and Activity of PTEN
Found 8 different mutations in PTEN
Protein Protein Binding Domain
Phosphatase Catalytic Domain
Lipid Binding Domain
Stability
186
403
In studies on the CD patients they identified 8 different mutations scattered throughout the length of the protein with a clustering in Exon 5, which contains the phosphatase catalytic domain, specifically the substitution of an E for a G at amino acid 129
“Hot Spot” – 31% of all mutations
G129E
43% of all mutations

12. PTEN Intracellular role
1999. Coffee Break. PTEN and the Tumor Suppressor. 1-3

13. Cooper (2000) The CELL a Molecular Approach fig.15.3
Critical Role of Akt
AKT family proteins directly stimulate cell division, cell growth, angiogenesis and INHIBITS apoptosis
SUPPRESSES
CELL DEATH!!!
Cooper (2000) The CELL a Molecular Approach fig.15.3

14. Biochemical structure and function of PTEN
Converts PIP3  PIP2 = INACTIVATED
PIP2 can NOT signal AKT = Suppression of GROWTH
Loss of PTEN results in hyper-accumulation of PIP3
This leads to hyper-activation of AKT
Result = INCREASED GROWTH, DIVISION and the ability to EVADE APOPTOSIS
Sulis and Parson(2003) TRENDS in Cell Biology Vol.13:9

15. Simpson and Parsons (2001) Experimental Cell Research 264, 29-41
Cellular Role of PTEN
Cell Culture:
PTEN -/- mutants – showed a decreased sensitivity to apoptotic signals
These mutants could be rescued by reintroduction of PTEN
Mice Knockouts:
PTEN -/- mutant – LETHAL
PTEN -/+ mutants developed multiple tumors including endometrial, prostate, thyroid and colon
Simpson and Parsons (2001) Experimental Cell Research 264, 29-41