So they suggested that reduced NPRA signaling can activate MMP and is involved

A possible Ca2 dependent pathway from the PDGFR to mTORC1 involves ARN-509 ic50 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 PLC PLD inhibitor U73122 also suppressed S6 phosphorylation. It is possible that PLCγ 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 PLCγ deficient cells, PLD signaling is reduced and this may explain the observed reduction in S6 phosphorylation in PLCγ1 cells.

Analogous to Akt activation where both mTORC2 and PDK1 phosphorylation are required for full Akt activation, mTORC1 has been proposed to collaborate with PDK1 in S6 kinase activation. Erk1 2 MAP kinases are activated by most receptor tyrosine kinases and have been shown to regulate prolif eration AUY922 価格 as well as protein translation. mTOR is also involved in these processes, and there are reports impli cating a link between Erk1 2 and mTOR signaling. In particular, it has been shown that Erk1 2 can directly phosphorylate Raptor and as a consequence activate mTORC1. In addition, both Erk1 2 and the down stream p90 ribosomal S6 kinase can phosphorylate the TSC1 2 complex resulting in mTORC1 activation. To explore whether Erk1 2 is involved in PDGF BB induced mTOR signaling, we investigated the effect of the selective MEK1 2 inhibitor CI 1040 on Akt and S6 phosphorylation.

Inhibition of the Erk1 2 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 Erk1 2 phosphor ylation. Thus, signaling through Alvocidib CDK 阻害剤 the Erk1 2 pathway is not critical for mTORC2 activity, but is required for the initial rapid onset of mTORC1. The S6 phosphorylation observed after prolonged PDGF BB treatment was not dependent on Erk1 2 signaling. Furthermore, it has been proposed that inhibition of mTOR dependent signaling by rapamycin leads to an increased Erk1 2 activity and potentiation of PDGF induced Erk1 2 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 affected PDGF BB induced Erk1 2 phosphorylation. Signaling through mTOR has been reported to regulate both proliferation and migration. A commonly used inhibitor of mTOR is rapamycin. However, the two mTOR containing complexes, mTORC1 and mTORC2, have different sensitivities to rapamycin. mTORC1 is rapidly inhibited whereas mTORC2 requires prolonged rapamycin treatment, thus, short term treatment with rapamycin only inhibits mTORC1 whereas long term treatment also inhibit mTORC2. Treating cells for extended time periods with rapamycin abolished the mito genic effect of PDGF BB, suggesting that functional mTOR signaling is required for cell proliferation.