A conversation with mTOR pioneer David Sabatini
The master regulator mTOR has made its mark as the target of dozens of drugs and clinical candidates for diseases ranging from cancer to diabetes, but David Sabatini thinks its full therapeutic value won’t be realized until the molecule, which is involved in nearly every physiological process, can be modulated in a tissue-specific way.
Sabatini, who is a member of the Whitehead Institute for Biomedical Research, a professor of biology at Massachusetts Institute of Technology and an investigator at Howard Hughes Medical Institute, discovered mTOR as the target of rapamycin as a Ph.D. candidate at The Johns Hopkins University in the 1990s and has since been credited with the discovery of the two mTOR complexes, mTORC1 and mTORC2.
His focus is now on uncovering the signaling and sensing molecules in the mTOR pathway. Sabatini’s lab has identified components of the mTOR complexes and their regulators, including the Ras superfamily Rag GTPases and 23 other proteins involved in the molecule’s amino acid-sensing function (see “Modulating mTOR”).
Figure: Modulating mTOR
mTOR pioneer David Sabatini has spent the last two decades interrogating the target and identifying the proteins involved in its signaling. The two complexes that contain the mTOR kinase, mTORC1 and mTORC2, act as master regulators in the cell, coordinating a wide range of input signals to control cellular processes ranging from autophagy to proliferation.
mTOR was discovered as the target of the generic immunosuppressant rapamycin, which binds to FKBP12 to inhibit its activity.
mTORC1: This complex’s signaling network is initiated by activation of sensory molecules, including HIF1, which detects hypoxia, and p53, which detects DNA damage,