[HTML][HTML] PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR

H Zhang, N Bajraszewski, E Wu… - The Journal of …, 2007 - Am Soc Clin Investig
H Zhang, N Bajraszewski, E Wu, H Wang, AP Moseman, SL Dabora, JD Griffin
The Journal of clinical investigation, 2007Am Soc Clin Investig
The receptor tyrosine kinase/PI3K/Akt/mammalian target of rapamycin (RTK/PI3K/Akt/mTOR)
pathway is frequently altered in tumors. Inactivating mutations of either the TSC1 or the
TSC2 tumor-suppressor genes cause tuberous sclerosis complex (TSC), a benign tumor
syndrome in which there is both hyperactivation of mTOR and inhibition of RTK/PI3K/Akt
signaling, partially due to reduced PDGFR expression. We report here that activation of PI3K
or Akt, or deletion of phosphatase and tensin homolog (PTEN) in mouse embryonic …
The receptor tyrosine kinase/PI3K/Akt/mammalian target of rapamycin (RTK/PI3K/Akt/mTOR) pathway is frequently altered in tumors. Inactivating mutations of either the TSC1 or the TSC2 tumor-suppressor genes cause tuberous sclerosis complex (TSC), a benign tumor syndrome in which there is both hyperactivation of mTOR and inhibition of RTK/PI3K/Akt signaling, partially due to reduced PDGFR expression. We report here that activation of PI3K or Akt, or deletion of phosphatase and tensin homolog (PTEN) in mouse embryonic fibroblasts (MEFs) also suppresses PDGFR expression. This was a direct effect of mTOR activation, since rapamycin restored PDGFR expression and PDGF-sensitive Akt activation in Tsc1–/– and Tsc2–/– cells. Akt activation in response to EGF in Tsc2–/– cells was also reduced. Furthermore, Akt activation in response to each of EGF, IGF, and PMA was reduced in cells lacking both PDGFRα and PDGFRβ, implying a role for PDGFR in transmission of growth signals downstream of these stimuli. Consistent with the reduction in PI3K/Akt signaling, in a nude mouse model both Tsc1–/– and Tsc2–/– cells had reduced tumorigenic potential in comparison to control cells, which was enhanced by expression of either active Akt or PDGFRβ. In conclusion, PDGFR is a major target of negative feedback regulation in cells with activated mTOR, which limits the growth potential of TSC tumors.
The Journal of Clinical Investigation