TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin.
The rapamycin-sensitive signaling pathway is required to transduce specific mitogenic signals to the cell cycle machinery responsible for G1 progression. Genetic studies in yeast identified two related genes on this pathway, TOR1 and TOR2, thought to encode novel phosphatidylinositol kinases. We now show that an intact kinase domain is required for the G1 cell cycle functions of both proteins, for the ability of a mutation in a neighboring FKBP12-rapamycin-binding domain of the TOR1 protein to inhibit the growth of yeast cells when overexpressed, and for the essential function of the TOR2 protein. The G1 function of both TOR proteins is sensitive to rapamycin, but the essential function of TOR2 is not. Thus, FKBP12-rapamycin does not appear to inhibit the kinase activity of TOR proteins in a general way; instead, it may interfere selectively with TOR protein binding to or phosphorylation of G1 effectors.
Zheng
X F
XF
Howard Hughes Medical Institute Department of Chemistry, Harvard University Cambridge, Massachusetts 02138, USA.
Florentino
D
D
Chen
J
J
Crabtree
G R
GR
Schreiber
S L
SL
D000935:Antifungal Agents / Q000494:pharmacology*; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D004352:Drug Resistance, Microbial; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase / Q000502:physiology; D005800:Genes, Fungal; D006360:Heat-Shock Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation / Q000502:physiology; D011090:Polyenes / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D017384:Sequence Deletion / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D020123:Sirolimus; D022021:Tacrolimus Binding Proteins
D000935:Antifungal Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D006360:Heat-Shock Proteins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D029701:Saccharomyces cerevisiae Proteins; D020123:Sirolimus; D022021:Tacrolimus Binding Proteins; C083324:TOR1 protein, S cerevisiae; C081135:TOR2 protein, S cerevisiae