PTEN negatively regulates mTORC2 formation and signaling in grade IV glioma via Rictor hyperphosphorylation at Thr1135 and direct the mode of action of an mTORC1/2 inhibitor
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
View Archive Info| Field | Value | |
| Title |
PTEN negatively regulates mTORC2 formation and signaling
in grade IV glioma via Rictor hyperphosphorylation at
Thr1135 and direct the mode of action of an mTORC1/2
inhibitor
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| Creator |
Bhattacharya, K
Maiti, S Mandal, C |
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| Subject |
Cancer Biology and Inflammatory Disorder Division
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| Description |
To investigate the role of PTEN (phosphatase and tensin homolog) in mammalian target of rapamycin complex 2 (mTORC2)
signaling in glioblastoma multiforme (GBM), we found higher activation of mTORC2 in PTENmu cells, as evidenced by enhanced
phosphorylation of mTOR (Ser2481), AKT (Ser473) and glycogen synthase kinase 3 beta (GSK3β) (Ser9) as compared with PTENwt
cells. In addition, PTENwt cells upon PTEN depletion showed mTORC2 activation. The reduced mTORC2 signaling in PTENwt cells was
related to higher Rictor phosphorylation at Thr1135 residue. Phosphorylation of Rictor at Thr1135 inhibited its association with
mTORC and thus there was a reduction in mTORC2 complex formation. In addition, PTENwt cells expressing mutated Rictor in which
Thr1135 was substituted with alanine, showed enhanced mTORC2 formation and signaling. This enhanced mTORC2 signaling
promoted inactivation of GSK3β. Thus, we established the reciprocal activation of mTORC2 and GSK3β in GBM. To the best of our
knowledge, this is the first report describing role of PTEN in mTORC2 formation by promoting Rictor phosphorylation (Thr1135) in
GBM. Furthermore, the drug sensitivity of mTORC2 was evaluated. A newly identified carbazole alkaloid, mahanine, showed
cytotoxicity in both PTENmu and PTENwt cells. It inhibited both mTORC1/2 and AKT completely in PTENmu cells, whereas it inhibited
only mTORC1 in PTENwt cells. Cytotoxity and AKT-inhibitory activity of the mTORC1/2 inhibitor was increased either by depleting
PTEN or in combination with phosphatidylinositol 3 kinase inhibitors in PTENwt cells. In contrast, depletion of Rictor decreased the
cytotoxicity of the mTORC1/2 inhibitor in PTENmu cells. Thus, PTEN has an important role in mTORC2 formation and also influences
the effectiveness of an mTORC1/2 inhibitor in GBM.
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| Date |
2016
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2535/1/Oncogenesis_%2C.pdf
Bhattacharya, K and Maiti, S and Mandal, C (2016) PTEN negatively regulates mTORC2 formation and signaling in grade IV glioma via Rictor hyperphosphorylation at Thr1135 and direct the mode of action of an mTORC1/2 inhibitor. Oncogenesis, 5 (e227;). |
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| Relation |
http://dx.doi.org/10.1038/oncsis.2016.34
http://www.eprints.iicb.res.in/2535/ |
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