This is consistent with a study in Drosophila showing that Akt ph

This is consistent with a study in Drosophila showing that Akt phosphorylation of TSC2 is not required for mTOR activation, but in contrast to studies inhibitor bulk on insulin signaling, where it was shown that Akt phosphorylation of TSC2 is necessary for mTORC1 activation. We observed inhibition of S6 phosphorylation after treatment with Ca2 chelators. A possible Ca2 dependent pathway from the PDGFR to mTORC1 involves PLD. PLD degrades phosphatidylcholine into choline and phosphati dic acid. Phosphatidic acid have been shown to bind to mTOR and activate mTORC1. Treatment of cells with the PLD inhibitor 1 butanol suppressed the PDGF BB induced S6 phosphorylation, without affecting Akt phos phorylation. As expected, the PLCPLD inhibitor U73122 also suppressed S6 phosphorylation.

It is possible Inhibitors,Modulators,Libraries that PLC�� contributes to PLD activation by causing increased Ca2 levels, since PLD requires Ca2 for its activity. In support of this notion, it has been reported that in PLC�� deficient cells, PLD signaling is reduced and this may explain the observed reduction in S6 phosphorylation in PLC��1 cells. Analogous to Akt activation where both mTORC2 and PDK1 phosphorylation Inhibitors,Modulators,Libraries are required for full Akt activation, mTORC1 has been proposed to collaborate with PDK1 in S6 kinase activation. Erk12 MAP kinases are activated by most receptor tyrosine kinases and have been shown to regulate prolif eration as well as protein translation. mTOR is also involved in these processes, and there are reports impli cating a link between Erk12 and mTOR signaling.

In particular, it has been shown that Erk12 can directly phosphorylate Raptor and as a consequence activate mTORC1. In addition, both Erk12 and the down stream p90 ribosomal S6 kinase can phosphorylate the TSC12 complex resulting in mTORC1 Inhibitors,Modulators,Libraries activation. To explore whether Erk12 is involved in PDGF BB induced mTOR signaling, we investigated the effect of the selective MEK12 inhibitor CI 1040 on Akt and S6 phosphorylation. Inhibition of the Erk12 pathway did not influence the PDGF BB induced phosphorylation of Akt, however, it delayed the onset of S6 phosphorylation. Conversely, interfering with mTOR signaling did not sig nificantly affect the PDGF BB induced Erk12 phosphor ylation. Thus, signaling through the Erk12 pathway is not critical for mTORC2 activity, but is required for the initial rapid onset of Inhibitors,Modulators,Libraries mTORC1.

Inhibitors,Modulators,Libraries The S6 phosphorylation observed after prolonged PDGF BB treatment was not dependent on Erk12 signaling. Furthermore, it has been proposed that inhibition of mTOR dependent signaling by rapamycin leads to an increased Erk12 activity and potentiation of PDGF induced Erk12 phosphorylation. In contrast to these findings, we observed that nei ther interfering with mTOR signaling using Rictor null cells, short or long term treatment of NIH3T3 cells with rapamycin and PLD inhibition, nor Ca2 chelation sellckchem affected PDGF BB induced Erk12 phosphorylation.

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