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The Role of Protein-Protein Interactions in Shaping MAP Kinase Kinase Identity

  • Author(s): Won, Angela P
  • Advisor(s): Lim, Wendell A
  • et al.

Eukaryotic cells process information through discrete signaling pathways that must maintain high signal fidelity to ensure proper response to environmental stimuli. Often, the signaling proteins in these pathways use shared interaction elements, both catalytic domains and protein-protein interactions. These elements help define network connectivity and guide information flow. Within the yeast Saccharomyces cerevisae, four distinct mitogen activated protein kinase kinases (MAPKKs) share closely related catalytic domains yet act in separate critical pathways. How have these four related kinases diverged to take on four distinct functional roles?

Within this thesis, I explore the relative contributions of modular interaction domains and motifs versus catalytic specificity in defining a kinases' identity. We probe kinase identity by asking whether we can use recruitment interactions to force other MAPKK catalytic domains to play the functional role of the mating MAPKK, Ste7. We find that two alternative MAPKK's, the osmoresponse MAPKK Pbs2 and the hypotonic response MAPKK Mkk2, can be forced to functionally replace the mating MAPKK Ste7, but only if the proper ensemble of recruitment interactions are overlaid on their catalytic domains. Further, we find that these alternative kinases do not exhibit cross-pathway activity and are restricted towards one identity. These results indicate recruitment interactions can play a dominant role in defining functional identity within a family, and is consistent with a model in which new kinase functions can arise through recombination of existing catalytic domains with new interaction modules. However, these recruitment interactions cannot be used in a "plug and play" method to alter any kinase's specificity. We find that addition of Ste7 recruitment interactions does not convert the identity of the hypotonic shock MAPKK, Mkk1. Further, subtle differences are observed in the temporal activity and level of flux of the converted alternative kinases. Altogether, these results indicate that although recruitment interactions can be utilized as a powerful tool to alter functional identity, evolution may have always insured pathway fidelity in some instances through the intrinsic contributions of kinase catalytic domains.

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