Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips. Export

@article{citeulike:179816, abstract = {The TOR (target of rapamycin) proteins play important roles in nutrient signaling in eukaryotic cells. Rapamycin treatment induces a state reminiscent of the nutrient starvation response, often resulting in growth inhibition. Using a chemical genetic modifier screen, we identified two classes of small molecules, small-molecule inhibitors of rapamycin (SMIRs) and small-molecule enhancers of rapamycin (SMERs), that suppress and augment, respectively, rapamycin's effect in the yeast Saccharomyces cerevisiae. Probing proteome chips with biotinylated SMIRs revealed putative intracellular target proteins, including Tep1p, a homolog of the mammalian PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor, and Ybr077cp (Nir1p), a protein of previously unknown function that we show to be a component of the TOR signaling network. Both SMIR target proteins are associated with PI(3,4)P2, suggesting a mechanism of regulation of the TOR pathway involving phosphatidylinositides. Our results illustrate the combined use of chemical genetics and proteomics in biological discovery and map a path for creating useful therapeutics for treating human diseases involving the TOR pathway, such as diabetes and cancer.}, address = {Howard Hughes Medical Institute, Harvard Institute of Chemistry and Cell Biology, and Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. jinghuang@mednet.ucla.edu}, author = {Huang, J. and Zhu, H. and Haggarty, S. J. and Spring, D. R. and Hwang, H. and Jin, F. and Snyder, M. and Schreiber, S. L.}, citeulike-article-id = {179816}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0407117101}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/15539461}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=15539461}, day = {23}, doi = {10.1073/pnas.0407117101}, issn = {0027-8424}, journal = {Proc Natl Acad Sci U S A}, keywords = {chips, proteome}, month = {November}, number = {47}, pages = {16594--16599}, posted-at = {2008-01-21 21:14:44}, priority = {2}, title = {Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips.}, url = {http://dx.doi.org/10.1073/pnas.0407117101}, volume = {101}, year = {2004} }

TY - JOUR ID - citeulike:179816 L3 - citeulike-article-id:179816 N2 - The TOR (target of rapamycin) proteins play important roles in nutrient signaling in eukaryotic cells. Rapamycin treatment induces a state reminiscent of the nutrient starvation response, often resulting in growth inhibition. Using a chemical genetic modifier screen, we identified two classes of small molecules, small-molecule inhibitors of rapamycin (SMIRs) and small-molecule enhancers of rapamycin (SMERs), that suppress and augment, respectively, rapamycin's effect in the yeast Saccharomyces cerevisiae. Probing proteome chips with biotinylated SMIRs revealed putative intracellular target proteins, including Tep1p, a homolog of the mammalian PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor, and Ybr077cp (Nir1p), a protein of previously unknown function that we show to be a component of the TOR signaling network. Both SMIR target proteins are associated with PI(3,4)P2, suggesting a mechanism of regulation of the TOR pathway involving phosphatidylinositides. Our results illustrate the combined use of chemical genetics and proteomics in biological discovery and map a path for creating useful therapeutics for treating human diseases involving the TOR pathway, such as diabetes and cancer. IS - 47 JF - Proc Natl Acad Sci U S A SN - 0027-8424 AD - Howard Hughes Medical Institute, Harvard Institute of Chemistry and Cell Biology, and Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. jinghuang@mednet.ucla.edu EP - 16599 TI - Finding new components of the target of rapamycin (TOR) signaling network through chemical genetics and proteome chips. VL - 101 SP - 16594 KW - chips KW - proteome AU - Huang, J AU - Zhu, H AU - Haggarty, SJ AU - Spring, DR AU - Hwang, H AU - Jin, F AU - Snyder, M AU - Schreiber, SL PY - 2004/11/23/ UR - http://dx.doi.org/10.1073/pnas.0407117101 ER -