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Pasteurella multocida toxin (PMT) activates mTOR and inhibits PP2A via Gαq/11/PLCβ/PKC
Author(s) -
Oubrahim Hammou,
Shi Yilan,
Chock P, Boon
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1038.4
Subject(s) - phosphorylation , ribosomal protein s6 , mtorc1 , protein phosphatase 2 , pi3k/akt/mtor pathway , protein kinase c , microbiology and biotechnology , phosphatase , p70 s6 kinase 1 , signal transduction , kinase , ribosomal s6 kinase , biology , chemistry , protein kinase b
PMT, a potent mitogen, activates several signaling pathways via deamidation of a conserved Gln residue in the α subunit of G‐proteins. However, its detailed mechanism is unknown. We show that PMT induces cell proliferation in serum‐starved Swiss 3T3 cells. Concomitantly PMT induces phosphorylation of ribosomal S6 kinase (S6K1) and its substrate, S6 protein (rpS6). The PMT mediated phosphorylation is inhibited by rapamycin and Torin1, two mTORC1 specific inhibitors. The mTOR activation occurs in MEF WT but not in Gα q/11 knockout cells, consistent with the notion that PMT‐induced mTORC1 activation proceeds via the deamidation of Gα q/11 leading to the activation of PLCβ to generate diacylglycerol (DAG) and inositol trisphosphate (IP 3 ), two activators of PKC pathway. PMT‐induced rpS6 phosphorylation is inhibited by PKC inhibitor, Gö 6976. The prolonged mTOR activation may involve inhibition of phosphatases. We show that PMT treatment leads to the phosphorylation of the protein phosphatase type 2 (PP2A) at Y307 and inactivates it. PMT‐mediated PP2A phosphorylation is inhibited by rapamycin and Gö 6976, and occurs in MEF WT but not in Gα q/11 knockout cells. Together, our findings reveal that PMT activates mTORC1 through Gα q/11 /PLCβ/PKC pathway leading, by an unknown mechanism, to phosphorylation/inhibition of PP2A. This research was supported by the Intramural Research Program of NHLBI, NIH.