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 selleck chemicals Inhibitors,Modulators,Libraries 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 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 Inhibitors,Modulators,Libraries 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 mTORC1. 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 affected PDGF Inhibitors,Modulators,Libraries BB induced Erk12 phosphorylation.

Inhibitors,Modulators,Libraries Signaling Inhibitors,Modulators,Libraries 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. In con trast, Rictor deficient cells showed a similar chemotactic response as control cells towards PDGF BB, indicating that mTORC2 is not involved in PDGF BB dependent cell migration. this is surprising selleck products since mTORC2 has been shown to regulate cell polarity and the dynamics of the actin cytoskeleton, although no alterations in the actin cytoskeleton were observed in Rictor null MEFs. Similarly, inhibition of mTORC1 and 2 in NIH3T3 cells did not influence the chemotactic properties of these cells.