Reassessment of the Role of FKBP38 in the Rheb/mTORC1 Pathway

The small G-protein Rheb regulates cell growth via the mTORC1 complex by incompletely understood mechanisms. Recent studies document that Rheb activates mTORC1 via direct, GTP-dependent interaction with the peptidyl-prolyl-cis/trans-isomerase FKBP38, which is proposed to act as an inhibitor of mTORC1. We have conducted a comprehensive biochemical characterization of the Rheb/FKBP38 interaction. Using three different in vitro assays we did not detect an interaction between Rheb and FKBP38. Cell biological experiments illustrate that FKBP38 plays only a very minor, if any, role in mTORC1 activation. Our data document that FKBP38 is not the long-sought Rheb effector linking Rheb to mTORC1 activation.