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Science. 2008 Mar 14;319(5869):1539-43. doi: 10.1126/science.1151153.

Using engineered scaffold interactions to reshape MAP kinase pathway signaling dynamics.

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Department of Cellular and Molecular Pharmacology, University of California at San Francisco, 600 16th Street, San Francisco, CA 94158, USA.


Scaffold proteins link signaling molecules into linear pathways by physically assembling them into complexes. Scaffolds may also have a higher-order role as signal-processing hubs, serving as the target of feedback loops that optimize signaling amplitude and timing. We demonstrate that the Ste5 scaffold protein can be used as a platform to systematically reshape output of the yeast mating MAP kinase pathway. We constructed synthetic positive- and negative-feedback loops by dynamically regulating recruitment of pathway modulators to an artificial binding site on Ste5. These engineered circuits yielded diverse behaviors: ultrasensitive dose response, accelerated or delayed response times, and tunable adaptation. Protein scaffolds provide a flexible platform for reprogramming cellular responses and could be exploited to engineer cells with novel therapeutic and biotechnological functions.

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