1. PTEN Tumor Suppressor Extraordinaire

2. Locus Very often mutated or missing in tumor cells
Eng, Human Mutation 22:183 (2003).

3. Structure Lipid & protein phosphatase Open/closed conformation
Vazquez et al, J. Bio. Chem. 276:48627 (2001).

4. Cellular Role Regulates homeostasis via: PI3K/Akt pathway
growth & apoptosis
FAK modulation
cell migration
Eng, Human Mutation 22:183 (2003).
Active-site amino acids of PTEN

5. Pathways PI3K/Akt pathway—PTEN is lipid phosphatase

6. Many Other Effects…

7. That PI3K/Akt pathway again is…

8. Nutrient Response through mTOR

9. FAK pathway—PTEN as a protein phosphatase

10. Biological Role Null homozygotes embryonic lethal
Heterozygotes incur greater cancer risk
Dysfunction is associated with human syndromes
Eng, Human Mutation 22:183 (2003).
Sansal & Sellers, J. Clinical Onc. 22(14):2954 (2004).

11. Cancer Role Tumor suppressor Often inactive in tumors
Dysfunction in tumors of many different tissues
Sansal & Sellers, J. Clinical Onc. 22(14):2954 (2004).

12. Loss of Functional PTEN
Loss of heterozygosity
Mutation
Promoter methylation
Sansal & Sellers, J. Clinical Onc. 22(14):2954 (2004).
Inappropriate subcellular compartmentalization
Eng, Human Mutation 22:183 (2003).

13. Tumorigenesis
Loss of the PTEN tumor suppressor contributes to loss in regulation of …
PI3K/Akt function
proliferation
apoptosis
cell size
nutrient response
glucose homeostasis
DNA damage response
FAK function
migration/metastasis
Sansal & Sellers, J. Clinical Onc. 22(14):2954 (2004).

14. Cowden Syndrome Frequency > 1/200,000
> 90% of diagnoses made before 20 years of age
80% of patients have germline PTEN mutations
Eng, Human Mutation 22:183 (2003).

15. Mucocutaneous lesions, thyroid abnormalities, fibrocystic disease
Mucocutaneous lesions, thyroid abnormalities, fibrocystic disease
Breast carcinoma (in up to 50% of cases), multiple early-onset uterine leiomyoma, macrocephaly
Sansal & Sellers, J. Clinical Onc. 22(14):2954 (2004).

16. Other PTEN-related syndromes
Bannayan-Zonana Syndrome
(elevated cancer risk)
Lhermitte-Duclos Disease
Proteus Syndrome
Proteus-Like Syndrome
Di Cristofano & Pandolfi, Cell 100(4):387 (2000).
Eng, Human Mutation 22:183 (2003).

17. http://health. discovery

18. Therapy Akt kinase inhibitors are in development
mTOR inhibitors, called rapamycin or rapamycin analogs, are in testing
“A cluster of leukemia-forming cells from a mouse lacking the Pten gene. Blood-forming stem cells and leukemia-initiating cells differ in their dependence on Pten, and this difference can be used to selectively kill the cancerous cells without harming normal stem cells.”
Sansal & Sellers, J. Clinical Onc. 22(14):2954 (2004).