PTEN tumor suppressor

Freeman, D. J., et al., PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell, 2003, 3(2), 117-30. 

Ho, A., Wakeham, A, Itie, A., Khoo, W., Fukumoto, M., and Mak, T.W., 1998, High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. S 1169-1178. 

The great importance of PtdIns(3,4,5)P3 metabolism for growth regulation is illustrated by the observation that an enzyme of PtdIns(3,4,5)P3 metabolism has been identified as a tumor suppressor protein (Wu et al., 1998). PTEN tumor suppressor protein has lipid phosphatase activity that is specific for hydrolysis of PtdIns(3,4,5)P3. It is assumed that PTEN lipid phosphatase is a negative regulator of the Akt pathway by lowering the concentration of PtdIns(3,4,5)P3 and counteracting stimulation of Akt kinase. 

A selection of other tumor suppressor genes is summarized in Table 14.2. Interestingly, an enzyme of phosphatidyl-inositol metabolism has been also identified as a tumor suppressor. The PTEN tumor suppressor gene codes for a phospholipid phosphatase which specifically cleaves a phosphate from the second messenger phosphatidyl-inosi-tol-3,4,5-trisphosphate (PtdInsPj, see 6.6.2). and thus inactivates the messenger (review Maehama and Dixon, 1999). ... 

In a second way in which Akt kinase controls apoptosis, Akt kinase directly phosphorylates key regulators of apoptosis. The best-studied example of this type of control involves the Bad protein, which is a proapoptotic member of the Bcl-2 family. The Bad protein is phosphorylated by Akt kinase at Ser residues, and this modification promotes translocation of Bad to the cytosol, where it is found complexed with 14-3-3 proteins. By this mechanism, the pro-apoptotic effect of Bad can be inhibited. The effect on Bad is, however, not universal and is observed only in some cell types. Another pro-apoptotic substrate of Akt kinase is procaspase-9, which is inhibited upon phosphorylation by Akt. Dysregulation of the PI3-kinase/Akt kinase pathway, e. g., by inactivation of the PTEN tumor suppressor, has an anti-apoptotic effect and will favor tumor formation by preventing the death of cells that would be channeled to apoptosis under normal circumstances. 

The loss of function deletion/mutation in the phosphatase and tensin homolog (PTEN) tumor-suppressor loeus is found to occur in 30 0% of GBM patients [16, 17]. PTEN is a regulator of the pro-growth kinases, PI3K and AKT. Phosphorylation of these proteins can activate pro-growth/pro-survival... 

PTEN is a phosphatase, which is a product of a tumor suppressor gene. This phosphatase has an unusual broad specificity and can remove phosphate groups attached to serine, threonine, and tyrosine residues. It is believed that its ability to dephosphorylate phosphati-dylinositol (PI) 3,4,5-triphosphate, the product of PI-3 kinase, is responsible for its tumor suppressor effects. 

Maehama, T., and Dixon, J.E., 1998, The tumor suppressor, PTEN/MMACl,... 

Wu, Y., Dowbenko, D., Spencer, S., Laura, R., Lee, J., Gu Q., Lasky L.A. Interaction of the tumor suppressor PTEN/MMAC with a PDZ domain of MAGI3, a novel membrane-associated guanylate kinase 2000, J. Biol. Chem. 275 21477-21485... 

The PI3 kinase (PI3-K) is translocated to the membrane by interaction of the SH2 domain of its p85 subunit with phosphotyrosine residues of the activated receptor. There it converts PtdIns(3,4)P2.into PtdIns(3,4,5)P3 which binds to PH domains of various effector molecules and recruits them into the signaling chain. The effector molecules can stimulate cell division or can induce the programmed cell death. The tumor suppressor PTEN hydrolyses phosphates from PtdIns(3,4,5)P3 and thus inhibits the growth promoting effect of the PI3 kinase signaling. An important effector of PI3 kinase is the protein kinase Akt which is also termed protein kinase B (PKB). GF growth factor GFR growth factor receptor. 

Wu, X., Senechal, K., Neshat, M.S., Whang, YE. and Sawyers, C.L. The PTEN/MMACl tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway (1998) Proc Natl Acad Sd U S A 95, 15587-91... 

Rahdar, M., Inoue, T., Meyer, T., Zhang, J., Vazquez, F., and Devreotes, P. N. (2009). A phosphorylation-dependent intramolecular interaction regulates the membrane association and activity of the tumor suppressor PTEN. PNAS106, 480-485. 

Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG. 2002. Reversible inactivation of the tumor suppressor PTEN by H2Q2. J Biol Chem 277 20336-20342. 

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