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

Hongbing Zhang1, Natalia Bajraszewski, Erxi Wu

  • 1Department of Physiology, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China. hbzhang2006@gmail.com

The Journal of Clinical Investigation
|February 10, 2007
PubMed

Insights

Tuberous sclerosis complex (TSC) involves mTOR hyperactivation, which suppresses platelet-derived growth factor receptor (PDGFR) expression. This feedback loop limits tumor growth in TSC by inhibiting growth signaling pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The receptor tyrosine kinase/PI3K/Akt/mammalian target of rapamycin (RTK/PI3K/Akt/mTOR) pathway is frequently dysregulated in various cancers.
  • Tuberous sclerosis complex (TSC) arises from inactivating mutations in TSC1 or TSC2 tumor-suppressor genes, leading to mTOR hyperactivation and impaired RTK/PI3K/Akt signaling.
  • Reduced platelet-derived growth factor receptor (PDGFR) expression is observed in TSC, contributing to signaling inhibition.

Purpose of the Study:

  • To investigate the regulatory relationship between mTOR activation and PDGFR expression.
  • To elucidate the role of PDGFR in mediating growth signals downstream of RTK/PI3K/Akt pathway.
  • To assess the impact of PDGFR on the tumorigenic potential of TSC-associated cells.

Main Methods:

  • Utilized mouse embryonic fibroblasts (MEFs) with genetic alterations in the PI3K/Akt/mTOR pathway (e.g., Tsc1/2 knockout, PTEN deletion).
  • Assessed PDGFR expression levels following activation of PI3K, Akt, or mTOR inhibition with rapamycin.
  • Evaluated Akt activation in response to various growth factors (EGF, IGF) and in cells with altered PDGFR expression.
  • Determined tumorigenic potential of Tsc1/2-deficient cells in a nude mouse model, with and without modifications in Akt or PDGFRbeta expression.

Main Results:

  • mTOR activation, induced by PI3K/Akt activation or PTEN deletion, directly suppressed PDGFR expression.
  • Rapamycin treatment restored PDGFR expression and PDGF-sensitive Akt activation in Tsc1/2-deficient cells.
  • PDGFR signaling appears crucial for transmitting growth signals downstream of EGF, IGF, and PMA.
  • Tsc1/2-deficient cells exhibited reduced tumorigenic potential, which was increased by expressing active Akt or PDGFRbeta.

Conclusions:

  • Platelet-derived growth factor receptor (PDGFR) acts as a key negative feedback target of mTOR.
  • This feedback mechanism limits the growth potential of tumors associated with tuberous sclerosis complex (TSC) by attenuating growth factor signaling.
  • Targeting this feedback loop could offer therapeutic strategies for TSC-related tumors.

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