PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR
Hongbing Zhang, … , James D. Griffin, David J. Kwiatkowski
Hongbing Zhang, … , James D. Griffin, David J. Kwiatkowski
Published March 1, 2007
Citation Information: J Clin Invest. 2007;117(3):730-738. https://doi.org/10.1172/JCI28984.
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Research Article Oncology

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

Abstract

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.

Authors

Hongbing Zhang, Natalia Bajraszewski, Erxi Wu, Hongwei Wang, Annie P. Moseman, Sandra L. Dabora, James D. Griffin, David J. Kwiatkowski

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Figure 5

Akt activation by EGF, IGF, and PMA is reduced in cells lacking PDGFR.

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Akt activation by EGF, IGF, and PMA is reduced in cells lacking PDGFR. (...
(A–C) Immunoblots of cell lysates. Each set of 3 lanes in A consists of lysates from PDGFRα/β double-null, Pdgfra–/–, and Pdgfrb–/– MEFs. All cells were serum starved for 48 hours and then stimulated with 50 ng/ml PDGFbb, 50 ng/ml EGF, 50 ng/ml IGF, or 10% serum for 10 minutes; or 200 nM PMA for 30 minutes. p-Akt levels were markedly reduced in PDGFRα/β double-null cells in response to all stimuli. (D) Immunoblots of WT or Egfr–/– MEFs. Cells were serum starved for 24 hours and stimulated with 50 ng/ml EGF (E), 50 ng/ml TGF-α (T), 50 ng/ml PDGF (P), 50 ng/ml IGF (I), or 0.2 nM insulin (In) for 10 minutes. Note that phosphorylation of Akt, S6, and ERK in response to PDGF, IGF, and insulin was similar in Egfr–/– and control MEFs.