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Michael LaubHow are regulatory molecules arranged and orchestrated into systems, so that cells can process information, make decisions, and control their physiology or behavior? What are the design principles underlying these systems, and what are the constraints that limit their function? To address these fundamental questions, my lab studies the genetic circuitry controlling cell-cycle progression and cellular asymmetry in the bacterium Caulobacter crescentus. Progression through the Caulobacter cell cycle is governed by a complex regulatory network that integrates both internal and environmental cues. Although many of the major cell-cycle regulators in Caulobacter are known, it remains a major challenge to identify the complete network underlying cell-cycle oscillations and cellular asymmetry. Caulobacter is a powerful model for studying regulation, as cells are easily synchronized, cell-cycle progression can be tracked by monitoring a series of morphological transitions, and a complete suite of genetic tools is available. We are currently focused on understanding cell-cycle regulation by two-component signal transduction systems, one of the major classes of signaling molecules in prokaryotes. These systems comprise sensor histidine kinases and their response regulator substrates, which execute changes in cellular physiology when phosphorylated. The Caulobacter genome encodes 64 histidine kinases and 42 response regulators, at least 10 of which have been found to be involved in cell-cycle progression, in previous genetic screens. We are using a variety of systems-level approaches to map the connectivity of these signaling proteins, and to understand how this wiring enables cell-cycle control. We are also working to understand how cells maintain the specificity of signaling systems. Given the highly related sequence and structure of the two-component signaling proteins in Caulobacter, how do cells maintain the insulation of different pathways, avoiding harmful cross-talk? How are signals integrated? How do new connections arise? We use computational and experimental approaches to answer these questions and to understand, at the molecular level, the basis for specificity in signal transduction systems. Contact |
