Cell communication and signaling : CCS 2013,
PMID: 23311350
Razmara, Masoud; Heldin, Carl-Henrik; Lennartsson, Johan
Mammalian target of rapamycin (mTOR) can be found in two multi-protein complexes, i.e. mTORC1 (containing Raptor) and mTORC2 (containing Rictor). Here, we investigated the mechanisms by which mTORC1 and mTORC2 are activated and their downstream targets in response to platelet-derived growth factor (PDGF)-BB treatment. Inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited PDGF-BB activation of both mTORC1 and mTORC2. We found that in Rictor-null mouse embryonic fibroblasts, or after prolonged rapamycin treatment of NIH3T3 cells, PDGF-BB was not able to promote phosphorylation of Ser473 in the serine/threonine kinase Akt, whereas Thr308 phosphorylation was less affected, suggesting that Ser473 in Akt is phosphorylated in an mTORC2-dependent manner. This reduction in Akt phosphorylation did not influence the phosphorylation of the S6 protein, a well established protein downstream of mTORC1. Consistently, triciribine, an inhibitor of the Akt pathway, suppressed PDGF-BB-induced Akt phosphorylation without having any effect on S6 phosphorylation. Thus, mTORC2 does not appear to be upstream of mTORC1. We could also demonstrate that in Rictor-null cells the phosphorylation of phospholipase Cγ1 (PLCγ1) and protein kinase C (PKC) was impaired, and the PKCα protein levels strongly reduced. Furthermore, interfering with the PLCγ/Ca2+/PKC pathway inhibited PDGF-BB-induced Akt phosphorylation. In addition, PDGF-BB-induced activation of mTORC1, as measured by phosphorylation of the downstream S6 protein, was dependent on phospholipase D (PLD). It has been shown that Erk1/2 MAP-kinase directly phosphorylates and activates mTORC1; in partial agreement with this finding, we found that a Mek1/2 inhibitor delayed S6 phosphorylation in response to PDGF-BB, but it did not block it. Thus, whereas both mTORC1 and mTORC2 are activated in a PI3K-dependent manner, different additional signaling pathways are needed. mTORC1 is activated in a PLD-dependent manner and promotes phosphorylation of the S6 protein, whereas mTORC2, in concert with PLCγ signaling, promotes Akt phosphorylation.
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Text Mining Data
mTOR/Rictor → Akt: "
Platelet derived growth factor induced
Akt phosphorylation
requires mTOR/Rictor and phospholipase C-?1, whereas S6 phosphorylation depends on mTOR/Raptor and phospholipase D
"
Akt → mTOR/Rictor: "
Platelet derived growth factor induced Akt phosphorylation requires mTOR/Rictor and phospholipase C-?1, whereas S6 phosphorylation depends on mTOR/Raptor and phospholipase D
"
mTORC1 → phosphatidylinositol 3-kinase (PI3K): "
Inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited PDGF-BB activation of both mTORC1 and mTORC2
"
mTORC2 → phosphatidylinositol 3-kinase (PI3K): "
Inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited PDGF-BB activation of both mTORC1 and mTORC2
"
PDGF-BB → mTORC1: "
Inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited PDGF-BB activation of both mTORC1 and mTORC2
"
PDGF-BB → mTORC2: "
Inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited PDGF-BB activation of both mTORC1 and mTORC2
"
PDGF-BB → phosphatidylinositol 3-kinase (PI3K): "
Inhibition of phosphatidylinositol 3-kinase (PI3K) inhibited PDGF-BB activation of both mTORC1 and mTORC2
"
Akt → PDGF-BB: "
Consistently, triciribine, an inhibitor of the Akt pathway, suppressed PDGF-BB induced Akt phosphorylation without having any effect on S6 phosphorylation
"
Akt → PDGF-BB: "
Furthermore, interfering with the PLC?/Ca2+/PKC pathway inhibited PDGF-BB induced Akt phosphorylation
"
mTORC1 → phospholipase D ( PLD ): "
In addition, PDGF-BB induced activation of mTORC1 , as measured by phosphorylation of the downstream S6 protein, was dependent on phospholipase D ( PLD )
"
mTORC1 → PDGF-BB: "
In addition, PDGF-BB induced activation of mTORC1 , as measured by phosphorylation of the downstream S6 protein, was dependent on phospholipase D ( PLD )
"
mTORC2 — PI3K: "
Thus, whereas both mTORC1 and mTORC2 are activated in a PI3K dependent manner, different additional signaling pathways are needed
"
mTORC1 — PI3K: "
Thus, whereas both mTORC1 and mTORC2 are activated in a PI3K dependent manner, different additional signaling pathways are needed
"
Akt → mTORC2: "
mTORC1 is activated in a PLD dependent manner and promotes phosphorylation of the S6 protein, whereas mTORC2 , in concert with PLC? signaling, promotes Akt phosphorylation
"
mTORC1 — PLD: "
mTORC1 is activated in a PLD dependent manner and promotes phosphorylation of the S6 protein, whereas mTORC2, in concert with PLC? signaling, promotes Akt phosphorylation
"
Manually curated Databases
No curated data.