X-linked Inhibitor of Apoptosis Protein (XIAP) Regulates PTEN Ubiquitination, Content, and Compartmentalization

Apoptotic cell death plays a normal role in various physiological processes, and deregulated apoptosis is a hallmark of several diseases, including cancer. Cell fate is dictated by the balance between pro- and antiapoptotic factors. Akt is one of these antiapoptotic factors, which must be activated through phosphorylation. The phosphorylation of Akt has previously been shown to be promoted by X-linked inhibitor of apoptosis protein (XIAP), another antiapoptotic protein dictating the fate of normal and cancer cells. However, the underlying mechanisms are poorly understood. We have observed that XIAP associates with PTEN (phosphatase and tensin homolog deleted on chromosome ten), the best characterized negative regulator of Akt phosphorylation, in vitro and in vivo. XIAP knockdown reduces constitutive mono- and polyubiquitination of PTEN, increases PTEN protein levels, and prevents nuclear accumulation of PTEN. Overexpression of XIAP induces polyubiquitination of PTEN and proteasome-dependent decrease of PTEN protein levels. RNA interference experiments showed that XIAP-induced regulation of Akt phosphorylation is PTEN-dependent. Additional experiments confirmed that XIAP also regulates PTEN in vivo; primary mouse embryonic fibroblasts derived from XIAP−/− mice contain higher levels of PTEN protein, less mono- and polyubiquitinated PTEN, and less nuclear PTEN than primary mouse embryonic fibroblasts derived from XIAP+/+ mice. Finally, we found that XIAP can directly ubiquitinate PTEN in vitro. We thus propose that XIAP acts as an E3 ubiquitin ligase for PTEN and promotes Akt activity by regulating PTEN content and compartmentalization. Apoptotic cell death plays a normal role in various physiological processes, and deregulated apoptosis is a hallmark of several diseases, including cancer. Cell fate is dictated by the balance between pro- and antiapoptotic factors. Akt is one of these antiapoptotic factors, which must be activated through phosphorylation. The phosphorylation of Akt has previously been shown to be promoted by X-linked inhibitor of apoptosis protein (XIAP), another antiapoptotic protein dictating the fate of normal and cancer cells. However, the underlying mechanisms are poorly understood. We have observed that XIAP associates with PTEN (phosphatase and tensin homolog deleted on chromosome ten), the best characterized negative regulator of Akt phosphorylation, in vitro and in vivo. XIAP knockdown reduces constitutive mono- and polyubiquitination of PTEN, increases PTEN protein levels, and prevents nuclear accumulation of PTEN. Overexpression of XIAP induces polyubiquitination of PTEN and proteasome-dependent decrease of PTEN protein levels. RNA interference experiments showed that XIAP-induced regulation of Akt phosphorylation is PTEN-dependent. Additional experiments confirmed that XIAP also regulates PTEN in vivo; primary mouse embryonic fibroblasts derived from XIAP−/− mice contain higher levels of PTEN protein, less mono- and polyubiquitinated PTEN, and less nuclear PTEN than primary mouse embryonic fibroblasts derived from XIAP+/+ mice. Finally, we found that XIAP can directly ubiquitinate PTEN in vitro. We thus propose that XIAP acts as an E3 ubiquitin ligase for PTEN and promotes Akt activity by regulating PTEN content and compartmentalization. In normal and cancer cells, balance between survival and apoptosis is maintained by a complex network of proapoptotic and antiapoptotic factors. X-linked inhibitor of apoptosis protein (XIAP) 3The abbreviations used are: XIAPX-linked inhibitor of apoptosis proteinPTENphosphatase and tensin homolog deleted on chromosome tenMEFmouse embryonic fibroblastE1ubiquitin-activating enzymeE2ubiquitin-conjugating enzymeE3ubiquitin ligasePIphosphatidylinositolPIP2phosphatidylinositol 2-phosphatePIP3phosphatidylinositol 3-phosphateHAhemagglutininGAPDHglyceraldehyde-3-phosphate dehydrogenaseTGFtransforming growth factorP-Aktphosphorylated AktshRNAshort hairpin RNARNAiRNA interferenceWTwild typeKOknockout. 3The abbreviations used are: XIAPX-linked inhibitor of apoptosis proteinPTENphosphatase and tensin homolog deleted on chromosome tenMEFmouse embryonic fibroblastE1ubiquitin-activating enzymeE2ubiquitin-conjugating enzymeE3ubiquitin ligasePIphosphatidylinositolPIP2phosphatidylinositol 2-phosphatePIP3phosphatidylinositol 3-phosphateHAhemagglutininGAPDHglyceraldehyde-3-phosphate dehydrogenaseTGFtransforming growth factorP-Aktphosphorylated AktshRNAshort hairpin RNARNAiRNA interferenceWTwild typeKOknockout. and Akt are two antiapoptotic factors acting on distinct targets. Akt kinase inactivates various proapoptotic factors (1Cardone M.H. Roy N. Stennicke H.R. Salvesen G.S. Franke T.F. Stanbridge E. Frisch S. Reed J.C. Science. 1998; 282: 1318-1321Crossref PubMed Scopus (2726) Google Scholar), whereas XIAP binds and sterically inhibits caspases (2Deveraux Q.L. Takahashi R. Salvesen G.S. Reed J.C. Nature. 1997; 388: 300-304Crossref PubMed Scopus (1717) Google Scholar). XIAP protein contains a RING domain with E3 ubiquitin ligase activity (3Yang Y. Fang S. Jensen J.P. Weissman A.M. Ashwell J.D. Science. 2000; 288: 874-877Crossref PubMed Scopus (865) Google Scholar) and has been shown to ubiquitinate caspases to target them for proteasomal degradation (4Morizane Y. Honda R. Fukami K. Yasuda H. J. Biochem. 2005; 137: 125-132Crossref PubMed Scopus (125) Google Scholar, 5Suzuki Y. Nakabayashi Y. Takahashi R. Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 8662-8667Crossref PubMed Scopus (545) Google Scholar). XIAP is also thought to promote Akt activity; we have previously reported that overexpression of XIAP promotes Akt phosphorylation in normal and cancerous ovarian cells (6Asselin E. Wang Y. Tsang B.K. Endocrinology. 2001; 142: 2451-2457Crossref PubMed Scopus (58) Google Scholar, 7Asselin E. Mills G.B. Tsang B.K. Cancer Res. 2001; 61: 1862-1868PubMed Google Scholar). The mechanisms through which XIAP promotes Akt phosphorylation, however, have not been investigated. X-linked inhibitor of apoptosis protein phosphatase and tensin homolog deleted on chromosome ten mouse embryonic fibroblast ubiquitin-activating enzyme ubiquitin-conjugating enzyme ubiquitin ligase phosphatidylinositol phosphatidylinositol 2-phosphate phosphatidylinositol 3-phosphate hemagglutinin glyceraldehyde-3-phosphate dehydrogenase transforming growth factor phosphorylated Akt short hairpin RNA RNA interference wild type knockout. X-linked inhibitor of apoptosis protein phosphatase and tensin homolog deleted on chromosome ten mouse embryonic fibroblast ubiquitin-activating enzyme ubiquitin-conjugating enzyme ubiquitin ligase phosphatidylinositol phosphatidylinositol 2-phosphate phosphatidylinositol 3-phosphate hemagglutinin glyceraldehyde-3-phosphate dehydrogenase transforming growth factor phosphorylated Akt short hairpin RNA RNA interference wild type knockout. Akt phosphorylation is positively regulated by phosphatidylinositol (PI) 3-phosphate kinase, which converts phosphatidylinositol 2-phosphate (PIP2) into PIP3, allowing recruitment and phosphorylation of Akt by PDK1 (8Franke T.F. Yang S.I. Chan T.O. Datta K. Kazlauskas A. Morrison D.K. Kaplan D.R. Tsichlis P.N. Cell. 1995; 81: 727-736Abstract Full Text PDF PubMed Scopus (1826) Google Scholar). PIP3-induced Akt phosphorylation, however, is antagonized by PTEN (phosphatase and tensin homolog deleted on chromosome ten), which converts PIP3 into PIP2 (9Stambolic V. Suzuki A. de la Pompa J.L. Brothers G.M. Mirtsos C. Sasaki T. Ruland J. Penninger J.M. Siderovski D.P. Mak T.W. Cell. 1998; 95: 29-39Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar). PTEN content and activity are regulated transcriptionally (10Whang Y.E. Wu X. Suzuki H. Reiter R.E. Tran C. Vessella R.L. Said J.W. Isaacs W.B. Sawyers C.L. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 5246-5250Crossref PubMed Scopus (561) Google Scholar) and post-translationally (11Trotman 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. Tempst P. Chi S.G. Kim H.J. Misteli T. Jiang X. Pandolfi P.P. Cell. 2007; 128: 141-156Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar, 12Wu W. Wang X. Zhang W. Reed W. Samet J.M. Whang Y.E. Ghio A.J. J. Biol. Chem. 2003; 278: 28258-28263Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Similar to several other proteins, polyubiquitination of PTEN leads to proteasome-dependent degradation (12Wu W. Wang X. Zhang W. Reed W. Samet J.M. Whang Y.E. Ghio A.J. J. Biol. Chem. 2003; 278: 28258-28263Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Because XIAP has been shown to induce degradation of proapoptotic factors (4Morizane Y. Honda R. Fukami K. Yasuda H. J. Biochem. 2005; 137: 125-132Crossref PubMed Scopus (125) Google Scholar, 5Suzuki Y. Nakabayashi Y. Takahashi R. Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 8662-8667Crossref PubMed Scopus (545) Google Scholar), we hypothesized that XIAP promotes Akt phosphorylation by inducing PTEN degradation. Using in vitro and in vivo models, we have thus investigated whether XIAP regulates PTEN ubiquitination and content. Primary mouse embryonic fibroblasts (MEFs) derived from XIAP+/+ and XIAP−/− mice were kindly provided by Dr. Philip A. Barker (McGill University, Montreal, Quebec, Canada). Human embryonic kidney fibroblastic cells HEK-293-T were a generous gift from Dr. Lionel Berthoux (University of Quebec, Trois-Rivières, Quebec, Canada). Human breast adenocarcinoma cell line MCF-7 and human cervical carcinoma cell line HeLa were purchased from the ATCC. XIAP plasmid constructs were a kind gift from Dr. Robert G. Korneluk (University of Ottawa Eye Institute, Ottawa, Ontario, Canada). Cells were seeded in 6-well plates at the required density to reach ∼75% confluency after 24 h. On the day of transfection, shRNAs (XIAP shRNA (5′-GCCACGCAGTCTACAAATTCT-3′) or control (scrambled) shRNA or PTEN shRNA (5′-GCAGCTAAAGGAAGTGAATCT-3′) or control (scrambled) shRNA) (all shRNAs inserted into pGeneClip (SABiosciences, Frederick, MD)) or XIAP constructs (Myc6-XIAP (WT), Myc6-XIAP-H467A (E3 ligase inactive mutant), or empty pcDNA3.1 vector (13Arora V. Cheung H.H. Plenchette S. Micali O.C. Liston P. Korneluk R.G. J. Biol. Chem. 2007; 282: 26202-26209Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar)) were added to cells using a ratio of 3.6 μl of FuGENE:1.2 μg of DNA/well. Plates were incubated for 40 additional hours (total: 48 h) at 37 °C before cells were collected. Recombinant human XIAP (730 ng) (or deionized water as a control) and PTEN (200 ng) proteins were mixed in a 6-μl final volume and incubated on ice for 1 h. The remaining components for the ubiquitination reaction were then added: 50 mm Tris-HCl, pH 7.5, 5 mm MgCl2, 5 mm ATP, 2 μm ubiquitin aldehyde, 2 mm dithiothreitol, 15 mg of ubiquitin, 100 nm E1 enzyme, and 1 μm E2 enzyme (or deionized water as a control) (final reaction volume: 20 μl). Ubiquitination reaction was conducted for 1 h at 30 °C and stopped by adding 20 μl of 2× reducing sample buffer and by heating the samples for 5 min at 95 °C. Please see the supplemental materials for immunofluorescence, Western blot, and RT-PCR procedures. In accordance with a role for XIAP in promoting Akt activity, knockdown of XIAP using RNAi reduces the phosphorylation of Akt, as shown by a decrease of P-Akt levels when compared with total Akt levels (Fig. 1A). We have found that XIAP knockdown increased PTEN protein levels (Fig. 1A). Similar results were obtained using a small interfering RNA targeting a different sequence of XIAP (15Van Themsche C. Mathieu I. Parent S. Asselin E. J. Biol. Chem. 2007; 282: 4794-4802Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar) (supplemental Fig. S1A) and in other normal (HEK-293-T) or cancerous (HeLa) model cell lines (supplemental Fig. S1B). This indicates that XIAP down-regulates endogenous PTEN content, in various cell types. Akt phosphorylation is negatively regulated by PTEN (9Stambolic V. Suzuki A. de la Pompa J.L. Brothers G.M. Mirtsos C. Sasaki T. Ruland J. Penninger J.M. Siderovski D.P. Mak T.W. Cell. 1998; 95: 29-39Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar); in accordance, knockdown of PTEN using RNAi increases Akt phosphorylation (Fig. 1B). We found that RNAi-induced silencing of PTEN prevented XIAP knockdown from reducing Akt phosphorylation (Fig. 1B), indicating that regulation of PTEN content is necessary for XIAP to regulate Akt phosphorylation. We observed that overexpression of XIAP (Fig. 1C) or silencing of XIAP using RNAi (Fig. 1D) had no impact on PTEN transcript levels, indicating that XIAP does not regulate PTEN content at the transcriptional level. However, pretreating the cells with proteasome inhibitor MG-132 prevented a decrease of PTEN protein levels following overexpression of XIAP (Fig. 1E), indicating that XIAP negatively regulates PTEN content in a proteasome-dependent manner. Proteasomal degradation of PTEN protein is induced by its polyubiquitination (16Torres J. Pulido R. J. Biol. Chem. 2001; 276: 993-998Abstract Full Text Full Text PDF PubMed Scopus (527) Google Scholar); we have thus investigated whether XIAP induces polyubiquitination of PTEN. Immunoprecipitation of ubiquitinated proteins using anti-ubiquitin antibody, followed by Western blot analysis using an anti-PTEN antibody, allows the visualization of mono- and polyubiquitination of PTEN protein in a given condition (Fig. 1F). Monoubiquitination of unrelated protein Smad4 (as described in Ref. 17Dupont S. Mamidi A. Cordenonsi M. Montagner M. Zacchigna L. Adorno M. Martello G. Stinchfield M.J. Soligo S. Morsut L. Inui M. Moro S. Modena N. Argenton F. Newfeld S.J. Piccolo S. Cell. 2009; 136: 123-135Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar) was monitored as a control. Using this approach, we found that although knockdown of XIAP in resting cells did not alter monoubiquitination of Smad4 (Fig. 1G), it reduced both monoubiquitination and polyubiquitination of PTEN (Fig. 1G). This indicates that XIAP constitutively regulates mono- and polyubiquitination of PTEN in resting cells. Reciprocally, vector-induced delivery of XIAP did not modify monoubiquitination of Smad4 but markedly increased polyubiquitination of PTEN (Fig. 1H), consistent with a proteasome-dependent decrease of PTEN protein levels following overexpression of XIAP (Fig. 1E). Because monoubiquitination of PTEN induces its nuclear import (11Trotman 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. Tempst P. Chi S.G. Kim H.J. Misteli T. Jiang X. Pandolfi P.P. Cell. 2007; 128: 141-156Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar), we have investigated whether XIAP, which constitutively promotes monoubiquitination of PTEN (Fig. 1G), regulates subcellular localization of PTEN. We found that following XIAP knockdown, PTEN protein levels were increased in the cytosol but were decreased in the nucleus (Fig. 1I). These results indicate that XIAP constitutively promotes nuclear localization of PTEN. On the contrary, overexpression of XIAP decreased total PTEN content in both the cytosol and the nucleus, with no apparent change in PTEN localization (Fig. 1J). This result is consistent with the observation that overexpression of XIAP did not increase monoubiquitination of PTEN (Fig. 1H). Wang et al. (18Wang X. Trotman L.C. Koppie T. Alimonti A. Chen Z. Gao Z. Wang J. Erdjument-Bromage H. Tempst P. Cordon-Cardo C. Pandolfi P.P. Jiang X. Cell. 2007; 128: 129-139Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar) have shown that NEDD4.1 could act as an E3 ubiquitin ligase for PTEN. In our model cell lines, knockdown (supplemental Fig. S2A) or overexpression (supplemental Fig. S2B) of XIAP did not modify NEDD4 protein levels, and knockdown of NEDD4 before overexpression of XIAP did not prevent XIAP-induced reduction of PTEN protein levels (supplemental Fig. S2C). Altogether, these observations indicate that an E3 ligase different from NEDD4 mediates XIAP-induced ubiquitination of PTEN. XIAP protein harbors a RING domain with E3 ubiquitin ligase activity (3Yang Y. Fang S. Jensen J.P. Weissman A.M. Ashwell J.D. Science. 2000; 288: 874-877Crossref PubMed Scopus (865) Google Scholar) and has previously been shown to polyubiquitinate proapoptotic proteins to induce their proteasomal degradation (4Morizane Y. Honda R. Fukami K. Yasuda H. J. Biochem. 2005; 137: 125-132Crossref PubMed Scopus (125) Google Scholar, 5Suzuki Y. Nakabayashi Y. Takahashi R. Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 8662-8667Crossref PubMed Scopus (545) Google Scholar). We have thus investigated whether XIAP could act as an E3 ligase for PTEN. Supporting this idea, only wild-type XIAP protein and not E3 ligase-inactive mutant XIAP protein induced polyubiquitination of PTEN and reduction of PTEN levels (Fig. 1H), indicating that E3 ligase activity of XIAP is required for the induction of polyubiquitination and degradation of PTEN. We also found that PTEN co-immunoprecipitates with XIAP (Fig. 2A) and that XIAP co-immunoprecipitates with PTEN (Fig. 2B) in multiple cell types (supplemental Fig. S3), indicating that XIAP and PTEN proteins associate in resting cells. Moreover, ubiquitinated PTEN proteins co-immunoprecipitated with XIAP (Fig. 2A), even under highly stringent conditions where 2% SDS is added to the cell lysates before immunoprecipitation (19Gallagher E. Enzler T. Matsuzawa A. Anzelon-Mills A. Otero D. Holzer R. Janssen E. Gao M. Karin M. Nat. Immunol. 2007; 8: 57-63Crossref PubMed Scopus (84) Google Scholar) (supplemental Fig. S4). Contrary to XIAP, NEDD4 did not co-immunoprecipitate with PTEN (supplemental Fig. S5A) or with XIAP (supplemental Fig. S5B), that XIAP does not regulate PTEN ubiquitination by NEDD4 to a complex with PTEN. Finally, we have investigated whether XIAP could directly ubiquitinate PTEN, using in vitro ubiquitination PTEN protein that was used as a mono- and polyubiquitinated PTEN. In a XIAP and PTEN proteins were with the other reaction components for E2 ubiquitin-conjugating enzyme, which was in the control to of the ubiquitination of PTEN. The results showed increased levels of polyubiquitinated PTEN when E2 enzyme was (Fig. that XIAP can ubiquitinate PTEN in vitro. that E3 ligase activity that could have been with PTEN was not in the PTEN protein and for the ubiquitination of PTEN of we also conducted ubiquitination the ubiquitination of PTEN in the or in the of The results showed increased polyubiquitination of PTEN in the reaction where XIAP was (Fig. Altogether, these experiments indicate that XIAP can act as an E3 ubiquitin ligase for PTEN in vitro. We have used primary derived from XIAP mice or from control mice to whether XIAP also regulates PTEN protein in vivo. In primary derived from control XIAP+/+ PTEN co-immunoprecipitated with XIAP (Fig. and XIAP co-immunoprecipitated with PTEN (Fig. that PTEN and XIAP proteins also associate in vivo. PTEN proteins also co-immunoprecipitated with XIAP (Fig. even under highly stringent conditions (supplemental Fig. that XIAP can also ubiquitinate PTEN in vivo. PTEN levels were increased in primary XIAP−/− when compared with XIAP+/+ (Fig. a role for XIAP in negatively regulating PTEN content in vivo. In less polyubiquitinated PTEN was in XIAP−/− cells when compared with XIAP+/+ cells (Fig. that XIAP regulates PTEN ubiquitination in vivo. Finally, less PTEN was in XIAP−/− when compared with XIAP+/+ (Fig. In we found nuclear for PTEN in XIAP+/+ primary which was in XIAP−/− where PTEN to the (Fig. These results indicate that XIAP also regulates PTEN localization in vivo. We have previously reported that a in normal and cancerous XIAP and P-Akt levels in cancer cells (15Van Themsche C. Mathieu I. Parent S. Asselin E. J. Biol. Chem. 2007; 282: 4794-4802Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). we have investigated whether of XIAP by PTEN content, and localization in these cells. with less but ubiquitinated PTEN proteins co-immunoprecipitated with XIAP (supplemental Fig. In of XIAP was by a reduction of total PTEN content (supplemental Fig. XIAP knockdown prevented decrease of PTEN content (supplemental Fig. that of XIAP is for the decrease of PTEN levels following to of PTEN was observed in both the cytosol and the nucleus of cells (supplemental Fig. and analysis showed no between the subcellular localization of PTEN following to (supplemental Fig. This is consistent with our observation that overexpression of XIAP increases polyubiquitination of PTEN in vitro (Fig. and PTEN content but not its localization (Fig. and is that to a physiological Akt phosphorylation XIAP levels, was not with a of PTEN content (supplemental Fig. or of the levels of ubiquitinated PTEN with XIAP (supplemental Fig. Altogether, these results indicate that physiological that modify XIAP levels result in PTEN ubiquitination and content. The mechanisms and factors regulating PTEN ubiquitination only to be We have found that XIAP regulates PTEN content, and in and in vivo as it also in primary cells derived from mice. a role for XIAP in negatively regulating PTEN content in vitro and in vivo. of XIAP protein levels in cancer cells in to the is by an increase of PTEN content M. V. S. D. J. PubMed Scopus Google Scholar), and of mice to the PTEN protein levels in but markedly increases PTEN content in Y. L. Chan J. Z. Wang Y. J. PubMed Scopus Google Scholar). These that XIAP can regulate PTEN content in to and in with we that physiological can regulate is that only physiological XIAP levels impact Akt phosphorylation through the in the of induction of Akt phosphorylation in to which was not by increased XIAP levels, no of PTEN content were NEDD4.1 has been as an E3 ubiquitin for PTEN (18Wang X. Trotman L.C. Koppie T. Alimonti A. Chen Z. Gao Z. Wang J. Erdjument-Bromage H. Tempst P. Cordon-Cardo C. Pandolfi P.P. Jiang X. Cell. 2007; 128: 129-139Abstract Full Text Full Text PDF PubMed Scopus (552) Google Scholar); however, E3 for PTEN different from NEDD4 could PTEN ubiquitination has been reported to in the of in vitro and in vivo F. T. H. A. C. N. V. D. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). on our that XIAP associates with PTEN as as ubiquitinated PTEN proteins in vitro and in vivo and that XIAP can directly ubiquitinate PTEN in we propose that XIAP can act as an E3 ligase for PTEN. is that multiple E3 can act on PTEN, control of its activity, on We observed that although PTEN proteins co-immunoprecipitate with XIAP in resting cells and knockdown of XIAP both monoubiquitination and polyubiquitination of PTEN, overexpression of XIAP or to factors as only induces polyubiquitination of PTEN. is that XIAP mono- or PTEN on have that different ubiquitin could be for mono- and polyubiquitination of another which between the and the nucleus to PTEN S. Mamidi A. Cordenonsi M. Montagner M. Zacchigna L. Adorno M. Martello G. Stinchfield M.J. Soligo S. Morsut L. Inui M. Moro S. Modena N. Argenton F. Newfeld S.J. Piccolo S. Cell. 2009; 136: 123-135Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar). although we have that NEDD4 was not in XIAP-induced ubiquitination of PTEN, regulation of PTEN and is not the of In for mono- and polyubiquitination of PTEN can be in XIAP mice. Because and are increased in XIAP cells C. D. R.L. Cell PubMed Scopus Google Scholar) and these have been shown to act as E3 H. E. S. J.D. T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Google Scholar), or could be in mono- polyubiquitination PTEN. localization of PTEN has been shown to be in human including L. A. A. F. Teruya-Feldstein J. Pandolfi P.P. Nature. PubMed Scopus (392) Google Scholar). regulating PTEN XIAP could thus be one of the factors to of cancer. et al. C. D. R.L. Cell PubMed Scopus Google Scholar) observed no between XIAP and adenocarcinoma mouse mice for the and of this could be to a increase of and levels in XIAP cells C. D. R.L. Cell PubMed Scopus Google Scholar). did however, a in mice C. D. R.L. Cell PubMed Scopus Google Scholar), which is consistent with reduced nuclear localization of PTEN in the of The a role for XIAP in PTEN content and in promoting nuclear localization of PTEN. Because negative regulation of Akt phosphorylation only when PTEN to the C. Cancer Res. 2005; PubMed Scopus Google Scholar), the of XIAP to promote nuclear import of PTEN an additional through which XIAP promotes Akt the that are to PTEN and Akt in other than as Wang J. Wu H. C. Pandolfi P.P. Y. Cell. 2007; 128: Full Text Full Text PDF PubMed Scopus Google the of a role for XIAP in regulating the the of that can be to We K. and for with

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