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Re-Engineering in Vivo Signal Processing

Stephen A. Chapman, California Institute of Technology, 1200 E. California Blvd MC 210-41, Pasadena, CA 91125 and Anand R. Asthagiri, Chemical Engineering, California Institute of Technology, 1200 E. California Blvd MC 210-41, Pasadena, CA 91125.

Intracellular signaling pathways relay and integrate information sensed at the cell surface to targets internal to the cell, ultimately affecting a change in cell behavior. Because of its broad influence over numerous cell functions, the MAP kinase (MAPK) signaling module is a powerful target for re-engineering numerous stimulus-response relationships. A key element in the MAPK module is scaffold proteins. Scaffolds have been suspected of providing specificity to pathways that often use a common set of signaling proteins. Indeed, new input-output relationships may be derived by funneling MAPK signals through hybrid scaffolds. In this manner, a pheromone input may be rewired to produce a stress response, instead of the intended mating response (Park et. al., 2003). While scaffolds allow a qualitative rewiring of the MAPK circuit, it remains unclear how quantitative aspects of an input-output relationship may be tuned by redesigning the MAPK module. Recent work in our lab on yeast MAPK pathways reveals that the scaffold concentration is a potent variable by which signal output may be manipulated. Perturbation of scaffold concentration over a greater than 10-fold range resulted in a separation of the activation properties of two closely related MAPK's, Kss1 and Fus3. Further validation of our model will combine experiment with computation. Simulation of information flow through the MAPK signaling module will allow prediction of quantitative perturbations necessary to achieve control over cell behavior. In this way, features of the in vivo yeast response to extracellular cues may be altered in a tunable manner.