Controlling signal transduction with synthetic ligands.
Dimerization and oligomerization are general biological control mechanisms contributing to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. Cell permeable, synthetic ligands were devised that can be used to control the intracellular oligomerization of specific proteins. To demonstrate their utility, these ligands were used to induce intracellular oligomerization of cell surface receptors that lacked their transmembrane and extracellular regions but contained intracellular signaling domains. Addition of these ligands to cells in culture resulted in signal transmission and specific target gene activation. Monomeric forms of the ligands blocked the pathway. This method of ligand-regulated activation and termination of signaling pathways has the potential to be applied wherever precise control of a signal transduction pathway is desired.
Spencer
D M
DM
Howard Hughes Medical Institute, Stanford University, CA 94305.
Wandless
T J
TJ
Schreiber
S L
SL
Crabtree
G R
GR
D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D003432:Cross-Linking Reagents; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D011108:Polymers; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D022021:Tacrolimus Binding Proteins; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D003432:Cross-Linking Reagents; C084260:FK 1012; D006360:Heat-Shock Proteins; D008024:Ligands; D008565:Membrane Proteins; D011108:Polymers; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C054979:antigen T cell receptor, zeta chain; D022021:Tacrolimus Binding Proteins; D016559:Tacrolimus