TEMPORAL AND SPATIAL CONTROL OF KINASE ACTIVITY IN VIVO

University Of California San Francisco, San Francisco CA

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Abstract

Protein kinases mediate signaling throughout the cell and are regulated in a temporal and spatially defined manner. Recently, a combined chemical and genetic strategy has been developed to selectively inactivate kinases of interest in vivo. Extending this technique with photosensitive kinase inhibitors offers a means to control the activity of a wide range of kinases. To achieve temporally controlled kinase inactivation, a series of photocleavably masked inhibitors will be synthesized, where irradiation reveals the active inhibitor. To achieve spatially and temporally controlled kinase activation, a series of photoreversible covalent inhibitors will be synthesized, where irradiation abolishes inhibition. The two groups of inhibitors will be tested for their ability to turn kinases "off" or "on" both in vitro and in vivo. Together these inhibitors will be used to address an outstanding question in kinase regulation and should provide new insights into the nature of cell signaling in vivo.