PTENSignalingPathways

See online version for legend and references.550 Cell 133, May 2, 2008 2008 Elsevier Inc. DOI 10.1016/j.cell.2008.04.023 SnapShot: PTEN Signaling Pathways Arkaitz Carracedo, Leonardo Salmena, and Pier Paolo Pandolfi Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA 550.e1 Cell 133, May 2, 2008 2008 Elsevier Inc. DOI 10.1016/j.cell.2008.04.023 SnapShot: PTEN Signaling Pathways Arkaitz Carracedo, Leonardo Salmena, and Pier Paolo Pandolfi Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA The PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene encodes a plasma membrane lipid phosphatase that is recurrently lost in various human cancers. Heterozygous mutation of PTEN is causative for familial diseases including Cowden syndrome, which is characterized by multiple hamartomas, developmental defects, and increased cancer susceptibility. The major tumor-suppressive activity of PTEN is attributed to its ability to hydrolyze the 3 phosphate of phosphoinositides at the plasma membrane and thereby negatively regulate phosphoinositide 3-kinase (PI3K) signaling, a promoter of cell growth and survival. In mouse models, Pten is haploinsufficient for tumor suppression. Progressive reduction of Pten dose is also associated with more aggressive cancers in the mouse, leading to the notion that subtle variations in Pten levels could have critical conse- quences for tumor progression. Indeed, in addition to the loss of PTEN function through genetic alterations at the 10q23 locus, emerging lines of evidence demonstrate that PTEN is tightly regulated by transcriptional, posttranscriptional, and posttranslational mechanisms. Recent studies report that PTEN has tumor-suppressive functions from within the nucleus, including the regulation of chromosomal stability, the DNA repair response, and the cell cycle. Aberrant cytoplasmic localization of PTEN is associated with cancer progression, suggesting that the presence of PTEN in the nucleus is required for its tumor- suppressive activity. How PTEN gets in and out of the nucleus is still not completely understood. Nuclear pore-mediated import as well as the monoubiquitination of PTEN can modulate its subcellular compartmentalization, and germline mutations of residues that are ubiquitinated have been associated with the nuclear exclusion of PTEN in cancerous lesions. RefeRences Eng, C. (2003). PTEN: one gene, many syndromes. Hum. Mutat. 22, 183198. Engelman, J.A., Luo, J., and Cantley, L.C. (2006). The evolution of phosphatidylinositol 3 kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7, 606619. Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S.I., Puc, J., Miliaresis, C., Rodgers, L., McCombie, R., et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 19431947. Maehama, T., and Dixon, J.E. (1998). The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273, 1337513378. Radu, A., Neubauer, V., Akagi, T., Hanafusa, H., and Georgescu, M.-M. (2003). PTEN. Induces Cell Cycle Arrest by Decreasing the Level and Nuclear Localization of Cyclin D1. Mol. Cell. Biol. 23, 61396149. Shen, W.H., Balajee, A.S., Wang, J., Wu, H., Eng, C., Pandolfi, P.P., and Yin, Y. (2007). Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157170. Stambolic, V., Suzuki, A., de la Pompa, J.L., Brothers, G.M., Mirtsos, C., Sasaki, T., Ruland, J., Penninger, J.M., Siderovski, D.P., and Mak, T.W. (1998). Negative regulation of PKB/Akt dependent cell survival by the tumor suppressor PTEN. Cell 95, 2939. Steck, P.A., Pershouse, M.A., Jasser, S.A., Yung, W.K., Lin, H., Ligon, A.H., Langford, L.A., Baumgard, M.L., Hattier, T., Davis, T., et al. (1997). Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat. Genet. 15, 356362. Trotman, L.C., Wang, X., Alimonti, A., Chen, Z., Teruya-Feldstein, J., Yang, H., Pavletich, N.P., Carver, B.S., Cordon-Cardo, C., Erdjument-Bromage, H., et al. (2007). Ubiquit- ination regulates PTEN nuclear import and tumor suppression. Cell 128, 141