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Rheb GTPase controls apoptosis by regulating interaction of FKBP38 with Bcl-2 and Bcl-XL

Dongzhu Ma1, Xiaochun Bai, Huafei Zou

  • 1Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

The Journal of Biological Chemistry
|January 6, 2010
PubMed

Insights

The oncogenic Rheb protein regulates apoptosis by controlling FKBP38

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • FKBP38 inhibits the mammalian target of rapamycin (mTOR).
  • Rheb, an oncogenic GTPase, antagonizes FKBP38's mTOR inhibition.
  • FKBP38 binds anti-apoptotic proteins Bcl-2 and Bcl-X(L), recruiting them to mitochondria.

Purpose of the Study:

  • To investigate if Rheb controls apoptosis by modulating FKBP38 interactions with Bcl-2 and Bcl-X(L).

Main Methods:

  • In vitro binding assays to assess Rheb-dependent FKBP38-Bcl-2 interactions.
  • Cell culture experiments to observe Rheb's control over FKBP38 interactions under varying nutrient and growth factor conditions.
  • Analysis of the association between Bcl-X(L) and Bak in response to Rheb activity.

Main Results:

  • Rheb regulates the interaction between FKBP38 and Bcl-2 in a GTP-dependent manner in vitro.
  • Rheb controls FKBP38 interactions with Bcl-2 in response to amino acid and growth factor availability in cultured cells.
  • Rheb-dependent release of Bcl-X(L) from FKBP38 promotes Bcl-X(L) association with the pro-apoptotic protein Bak.

Conclusions:

  • Rheb modulates apoptosis by regulating the interaction of FKBP38 with anti-apoptotic proteins Bcl-2 and Bcl-X(L).
  • Increased Rheb activity enhances cellular resistance to apoptosis.
  • This study reveals a novel pathway for growth factor and amino acid control of apoptosis via Rheb-FKBP38-Bcl-xL signaling.

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