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Expression of carboxyl-terminal mutants in PTEN-deficient glioblastoma cells permitted the anchorage-independent growth of the cells that otherwise was suppressed by wild-type PTEN. The stability of these mutants in cells was reduced because of rapid degradation. Although the carboxyl-terminal region contains regulatory PEST sequences and a PDZ-binding motif, these specific elements were dispensable for the tumor-suppressor function. The study of carboxyl-terminal point mutations affecting the stability of PTEN revealed that these were located in strongly predicted \u03b2-strands. Surprisingly, the phosphatase activity of these mutants was affected in correlation with the degree of disruption of these structural elements. We conclude that the carboxyl-terminal region is essential for regulating PTEN stability and enzymatic activity and that mutations in this region are responsible for the reversion of the tumor-suppressor phenotype. We also propose that the molecular conformational changes induced by these mutations constitute the mechanism for PTEN inactivation.<\/jats:p>","DOI":"10.1073\/pnas.96.18.10182","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:35:07Z","timestamp":1027679707000},"page":"10182-10187","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":268,"title":["The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region"],"prefix":"10.1073","volume":"96","author":[{"given":"Maria-Magdalena","family":"Georgescu","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Oncology, The Rockefeller University, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin H.","family":"Kirsch","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, The Rockefeller University, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Akagi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, The Rockefeller University, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Shishido","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, The Rockefeller University, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidesaburo","family":"Hanafusa","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Oncology, The Rockefeller University, New York, NY 10021"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1999,8,31]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0497-356"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.275.5308.1943"},{"key":"e_1_3_3_3_2","first-page":"4187","volume":"57","author":"Rasheed B K","year":"1997","unstructured":"B K Rasheed, T T Stenzel, R E McLendon, R Parsons, A H Friedman, H S Friedman, D D Bigner, S H Bigner Cancer Res 57, 4187\u20134190 (1997).","journal-title":"Cancer Res"},{"key":"e_1_3_3_4_2","first-page":"4183","volume":"57","author":"Wang S I","year":"1997","unstructured":"S I Wang, J Puc, J Li, J N Bruce, P Cairns, D Sidransky, R Parsons Cancer Res 57, 4183\u20134186 (1997).","journal-title":"Cancer Res"},{"key":"e_1_3_3_5_2","first-page":"3935","volume":"57","author":"Tashiro H","year":"1997","unstructured":"H Tashiro, M S Blazes, R Wu, K R Cho, S Bose, S I Wang, J Li, R Parsons, L H Ellenson Cancer Res 57, 3935\u20133940 (1997).","journal-title":"Cancer Res"},{"key":"e_1_3_3_6_2","first-page":"4997","volume":"57","author":"Cairns P","year":"1997","unstructured":"P Cairns, K Okami, S Halachmi, N Halachmi, M Esteller, J G Herman, J Jen, W B Isaacs, G S Bova, D Sidransky Cancer Res 57, 4997\u20135000 (1997).","journal-title":"Cancer Res"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1201956"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0597-64"},{"key":"e_1_3_3_9_2","first-page":"2124","volume":"57","author":"Li D M","year":"1997","unstructured":"D M Li, H Sun Cancer Res 57, 2124\u20132129 (1997).","journal-title":"Cancer Res"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.22.13375"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81780-8"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(07)00493-9"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.23.13513"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.23.12479"},{"key":"e_1_3_3_15_2","first-page":"2331","volume":"58","author":"Cheney I W","year":"1998","unstructured":"I W Cheney, D E Johnson, M T Vaillancourt, J Avanzini, A Morimoto, G W Demers, K N Wills, P W Shabram, J B Bolen, S V Tavtigian, et al. 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