Phosphorylation of transglutaminase 2 (TG2) at serine-216 plays a role in TG2 mediated activation of nuclear factor-kappa B and in the downregulation of PTEN

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dc.contributor.authorWang, Yi
dc.contributor.authorAnde, Sudharsana R
dc.contributor.authorMishra, Suresh
dc.date.accessioned2012-11-07T20:05:53Z
dc.date.available2012-11-07T20:05:53Z
dc.date.issued2012-07-03
dc.date.updated2012-11-07T20:05:54Z
dc.description.abstractAbstract Background Transglutaminase 2 (TG2) and its phosphorylation have been consistently found to be upregulated in a number of cancer cell types. At the molecular level, TG2 has been associated with the activation of nuclear factor-kappa B (NF-κB), protein kinase B (PKB/Akt) and in the downregulation of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). However, the underlying mechanism involved is not known. We have reported that protein kinase A (PKA) induced phosphorylation of TG2 at serine-216 (Ser216) regulates TG2 function and facilitates protein-protein interaction. However, the role of TG2 phosphorylation in the modulation of NF-κB, Akt and PTEN is not explored. Methods In this study we have investigated the effect of TG2 phosphorylation on NF-κB, Akt and PTEN using embryonic fibroblasts derived from TG2 null mice (MEF tg2-/- ) overexpressing native TG2 or mutant-TG2 (m-TG2) lacking Ser216 phosphorylation site with and without dibutyryl cyclic-AMP (db-cAMP) stimulation. Functional consequences on cell cycle and cell motility were determined by fluorescence activated cell sorting (FACS) analysis and cell migration assay respectively. Results PKA activation in TG2 overexpressing MEF tg2-/- cells resulted in an increased activation of NF-κB and Akt phosphorylation in comparison to empty vector transfected control cells as determined by the reporter-gene assay and immunoblot analysis respectively. These effects were not observed in MEF tg2-/- cells overexpressing m-TG2. Similarly, a significant downregulation of PTEN at both, the mRNA and protein levels were found in cells overexpressing TG2 in comparison to empty vector control and m-TG2 transfected cells. Furthermore, Akt activation correlated with the simultaneous activation of NF-κB and a decrease in PTEN suggesting that the facilitatory effect of TG2 on Akt activation occurs in a PTEN-dependent manner. Similar results were found with MCF-7 and T-47D breast cancer cells overexpressing TG2 and m-TG2 further supporting the role of TG2 phosphorylation in NF-κB activation and in the downregulation of PTEN. Conclusions Collectively, these data suggest that phosphorylation of TG2 at Ser216 plays a role in TG2 mediated activation of NF-κB, Akt and in the downregulation of PTEN. Blocking TG2 phosphorylation may provide a novel strategy to attenuate NF-κB activation and downregulation of PTEN in TG2 overexpressing cancers.
dc.description.versionPeer Reviewed
dc.identifier.citationBMC Cancer. 2012 Jul 03;12(1):277
dc.identifier.doihttp://dx.doi.org/10.1186/1471-2407-12-277
dc.identifier.urihttp://hdl.handle.net/1993/11120
dc.language.rfc3066en
dc.rightsopen accessen_US
dc.rights.holderYi Wang et al.; licensee BioMed Central Ltd.
dc.titlePhosphorylation of transglutaminase 2 (TG2) at serine-216 plays a role in TG2 mediated activation of nuclear factor-kappa B and in the downregulation of PTEN
dc.typeJournal Article
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