PTEN Tumor Suppressor Extraordinaire http://opm.phar.umich.edu/images/proteins/1d5r.gif

Locus Very often mutated or missing in tumor cells Eng, Human Mutation 22:183 (2003). http://www.uihealthcare.com/topics/medicaldepartments/cancercenter/juvenilepolyposis/images/pten.jpg

Structure Lipid & protein phosphatase Open/closed conformation Vazquez et al, J. Bio. Chem. 276:48627 (2001). http://www.bioscience.org/2002/v7/e/tsugawa/fig4.jpg http://www.mskcc.org/mskcc/_assets/content-image/29874.jpg

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 http://www.biochemistry.unimelb.edu.au/images/image010.jpg

Pathways PI3K/Akt pathway—PTEN is lipid phosphatase http://www.cellsignal.jp/technology/img_tech/RabbitPathway_05_2.jpg

Many Other Effects… http://www.piramed.com/misc_imgs/nrc_fig_600w_flat.gif

That PI3K/Akt pathway again is… http://www.cellsignal.jp/technology/img_tech/RabbitPathway_05_2.jpg

Nutrient Response through mTOR http://web.wi.mit.edu/sabatini/pub/images/mTOR_signaling_center.jpg

FAK pathway—PTEN as a protein phosphatase http://www.sigmaaldrich.com/img/assets/6460/pten_path.gif

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).

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

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).

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).

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). http://www.cumc.columbia.edu/news/frontiers/images/biof_040111.gif

Mucocutaneous lesions, thyroid abnormalities, fibrocystic disease http://www.nature.com/modpathol/journal/v18/n9/images/3800448f1.jpg 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).

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). http://health.discovery.com/convergence/elephantman/slideshow/gallery/ctscan_v_zoom.jpg Eng, Human Mutation 22:183 (2003).

http://health. discovery http://health.discovery.com/convergence/elephantman/slideshow/gallery/skull_h_zoom.jpg http://pics.centerblog.net/picture/blogpeople/b0cc7snf.jpg

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). http://www.umich.edu/~urecord/0506/Apr03_06/stem.shtml