A mammalian protein targeted by G1-arresting rapamycin-receptor complex.
The structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways. FKBP12-rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma, liver and T cells as well as in yeast, and interferes with mitogenic signalling pathways that are involved in G1 progression, namely with activation of the protein p70S6k (refs 5, 11-13) and cyclin-dependent kinases. Here we isolate a mammalian FKBP-rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly, these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases.
Brown
E J
EJ
Department of Chemistry, Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138.
Albers
M W
MW
Shin
T B
TB
Ichikawa
K
K
Keith
C T
CT
Lane
W S
WS
Schreiber
S L
SL
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D018797:Cell Cycle Proteins; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary; D005656:Fungal Proteins / Q000235:genetics; D016193:G1 Phase / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D020104:Immunophilins; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D011090:Polyenes / Q000378:metabolism* / Q000494:pharmacology; D011506:Proteins / Q000032:analysis* / Q000737:chemistry / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D022021:Tacrolimus Binding Proteins
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D005656:Fungal Proteins; D006360:Heat-Shock Proteins; D020104:Immunophilins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D011506:Proteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D022021:Tacrolimus Binding Proteins; C546842:MTOR protein, human; C083324:TOR1 protein, S cerevisiae; C081135:TOR2 protein, S cerevisiae