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Vol. 10, Issue 8, 2531-2546, August 1999
§ and
*Departments of Genetics, In complex with FKBP12, the immunosuppressant rapamycin binds to
and inhibits the yeast TOR1 and TOR2 proteins and the mammalian homologue mTOR/FRAP/RAFT1. The TOR proteins promote cell cycle progression in yeast and human cells by regulating translation and
polarization of the actin cytoskeleton. A C-terminal domain of the TOR
proteins shares identity with protein and lipid kinases, but only one
substrate (PHAS-I), and no regulators of the TOR-signaling cascade have been identified. We report here that yeast TOR1 has an
intrinsic protein kinase activity capable of phosphorylating PHAS-1, and this activity is abolished by an active site
mutation and inhibited by FKBP12-rapamycin or wortmannin. We find that an intact TOR1 kinase domain is essential for TOR1 functions in yeast.
Overexpression of a TOR1 kinase-inactive mutant, or of a central region
of the TOR proteins distinct from the FRB and kinase domains,
was toxic in yeast, and overexpression of wild-type TOR1 suppressed
this toxic effect. Expression of the TOR-toxic domain leads to a
G1 cell cycle arrest, consistent with an inhibition of TOR
function in translation. Overexpression of the PLC1
gene, which encodes the yeast phospholipase C homologue, suppressed growth inhibition by the TOR-toxic domains. In conclusion, our findings
identify a toxic effector domain of the TOR proteins that may interact
with substrates or regulators of the TOR kinase cascade and that shares
sequence identity with other PIK family members, including ATR,
Rad3, Mei-41, and ATM.
Pharmacology and Cancer
Biology, and §Medicine, the Howard Hughes
Medical Institute, Duke University Medical Center, Durham, North
Carolina 27710
Corresponding author. E-mail address:
carde004{at}mc.duke.edu.
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