title: Rapid and efficient induction of an endogenous cell signaling event by subcellular targeting of a synthetic ligand.
abstract: It is now well-recognized that the spatial localization of proteins at the subcellular level is essential in regulating cell signaling. On the other hand, research efforts aimed at developing synthetic modulators of intracellular signaling processes have usually focused on the affinity and specificity of ligands to their target proteins, neglecting the localization of the molecules in cells. Here we show that it is feasible to rapidly and efficiently activate an endogenous signaling pathway by placing a synthetic ligand at a specific location within a cell. The agonist activity of the ligand is very weak when it is freely diffusing in the cytosol. This study highlights the importance of controlling the subcellular locations of ligand molecules in the design of new synthetic modulators (not only activators but also inhibitors) of endogenous biological events.
authors.affiliation: Department of Chemistry and Biotechnology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Hashiro
authors.forename: Shinya
authors.initials: S
authors.lastname: Tsukiji
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Nagamune
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002867:Chromones / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008024:Ligands; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D008024:Ligands; D009025:Morpholines; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017479:Receptors, Platelet-Derived Growth Factor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one