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Sphingosine-1-phosphate induced mTOR-activation is mediated by the E3-ubiquitin ligase PAM

Christian Maeurer1, Sabrina Holland, Sandra Pierre

  • 1Pharmazentrum Frankfurt, ZAFES, Institute of Clinical Pharmacology, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.

Cellular Signalling
|November 13, 2008
PubMed

Insights

Sphingosine-1-phosphate (S1P) activates the mTOR pathway through Protein Associated with Myc (PAM), a novel regulator. PAM facilitates Rheb

Area of Science:

  • Cellular signaling pathways
  • Cancer biology
  • Molecular mechanisms

Background:

  • Sphingosine-1-phosphate (S1P) and mammalian target of rapamycin (mTOR) pathways regulate critical cellular processes.
  • These pathways are key targets for cancer therapeutic development.
  • The precise mechanisms linking S1P and mTOR signaling remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms connecting sphingosine-1-phosphate (S1P) and mammalian target of rapamycin (mTOR) pathways.
  • To identify novel regulators involved in S1P-mediated mTOR activation.
  • To investigate the role of Protein Associated with Myc (PAM) in this signaling cross-talk.

Main Methods:

  • Treatment of cancer cell lines and primary cells with S1P.
  • Assessment of mTOR pathway activation (p70S6K, 4EBP1 phosphorylation).
  • Investigation of the role of Protein Associated with Myc (PAM) using genetic deletion and manipulation of intracellular concentrations.
  • Analysis of Rheb guanine nucleotide exchange activity.

Main Results:

  • S1P treatment robustly activated mTOR in various cancer cells and primary cells.
  • PAM mediated S1P-induced mTOR activation, independent of ERK, Akt, and PI3-kinase.
  • Increased PAM levels enhanced S1P- and insulin-induced mTOR activation, while PAM deletion diminished it.
  • PAM was found to facilitate the GDP/GTP-exchange of Rheb, a known mTOR activator.

Conclusions:

  • Protein Associated with Myc (PAM) is identified as a novel regulator of the mTOR pathway.
  • PAM acts as a crucial mediator in S1P-induced mTOR activation.
  • PAM may function as a guanine exchange factor (GEF) for Rheb, directly activating mTOR signaling.

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