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mTORC1 signaling can regulate growth factor activation of p44/42 mitogen-activated protein kinases through protein

Franklin C Harwood1, Lili Shu, Peter J Houghton

  • 1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 N. Lauderdale Street, Memphis, TN 38105, USA.

The Journal of Biological Chemistry
|December 7, 2007
PubMed

Insights

Mammalian target of rapamycin complex 1 (mTORC1) signaling regulates p44/42 mitogen-activated protein kinases (MAPKs) through protein phosphatase 2A (PP2A). This study reveals mTORC1

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Cancer research

Background:

  • The mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth and metabolism.
  • Mitogen-activated protein kinases (MAPKs), including p44/42, are crucial in cell proliferation and survival.
  • The interplay between mTORC1 and p44/42 MAPKs in cancer cell lines is not fully understood.

Purpose of the Study:

  • To investigate the role of mTORC1 signaling in the regulation of p44/42 MAPK activation.
  • To elucidate the molecular mechanisms by which mTORC1 influences p44/42 MAPK phosphorylation and activity.
  • To explore the involvement of phosphatases in the mTORC1-mediated regulation of p44/42 MAPKs.

Main Methods:

  • Utilized cancer cell lines (Rh1 cells) treated with rapamycin, IGF-I, and EGF.
  • Assessed phosphorylation status of p44/42 MAPKs and MEK1 using Western blotting.
  • Investigated the interaction and dissociation of protein phosphatase 2A (PP2A) catalytic subunit (PP2Ac) with p42.
  • Employed rapamycin-resistant mTOR expressing cells (Rh1mTORrr) to confirm mTORC1-dependent effects.
  • Manipulated amino acid availability to study its effect on p44/42 activation.

Main Results:

  • mTORC1 signaling, modulated by rapamycin and raptor down-regulation, is essential for IGF-I-stimulated p44/42 MAPK phosphorylation and kinase activity.
  • Rapamycin treatment affected the kinetics of p44/42 MAPK dephosphorylation and required higher concentrations to inhibit EGF-induced phosphorylation.
  • Involvement of protein phosphatase 2A (PP2A) was suggested by okadaic acid reversal of rapamycin's effect and observed PP2Ac dissociation from p42.
  • Amino acid deprivation mimicked rapamycin's effects on p44/42 activation, with rapamycin-specific effects abrogated in rapamycin-resistant mTOR cells.

Conclusions:

  • mTORC1 signaling complex plays a critical role in modulating p44/42 MAPK activation.
  • The regulation of p44/42 phosphorylation by mTORC1 involves protein phosphatases, particularly PP2A.
  • These findings suggest a model where mTORC1 influences p44/42 MAPK phosphorylation through PP2A regulation.

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