Piers D. Nash, Ph.D.

Research Summary

Modular Protein Interaction Domains in Cellular Communication

Malfunctions in cellular communication are the molecular basis of a wide variety of human diseases, including cancer. We are interested the underlying biochemical mechanisms through which specificity is generated during signal transduction, and the means by which signaling molecules may act in combination to generate complex biological responses. Our lab comes to this problem with a combination of biochemical, cell biology and bioinformatic approaches.

Modular Interaction Domains

Our interest in signal transduction centers on molecular interactions involving modular protein interaction domains such as SH2, SH3, WD40 and ubiquitin interacting domains. In the past decade a large number of such modular interaction domains have been described that together organize the localization, communication and functional activities of the proteins into which they are incorporated. The figure below illustrates a few such modular interaction domains. These interaction domains are typically independently folding subunits that are constructed such that their N and C termini are juxtaposed in space, while their ligand-binding site is located on the opposing surface. As a result, they are ideally configured for incorporation into a pre-existing polypeptide while retaining their binding properties. Interaction domains play a critical role in the selective activation of signaling pathways through their ability to recruit target proteins to activated receptors and thereby determine the specificity and kinetics of the assembly of signaling complexes.

The building blocks – modular interaction domains in signal transduction. Ref: Tony Pawson & Piers Nash (2003) Assembly of Cell Regulatory Systems Through Protein-Protein Interaction Domains. Science 300: 445-452.

Digital Switches at the Single Cell Level

An emergent theme in biology is how complex biological outcomes arise from simple events such as biomacromolecular interactions. Crucial cell fate decisions are controlled in a highly precise manner and the mechanisms by which this is achieved are key barriers to the initiation and progression of the oncogenic process. We study how specificity, affinity and complexity in protein-protein interactions in signal transduction and the cell cycle achieve complex biological outcomes. For instance, we have established that a binary protein-protein interaction set, regulated by reversible modifications such as phosphorylation, can produce an all-or-none control mechanism and set a threshold for the onset of DNA replication. In layman’s terms, this is what amounts to a biological digital switch. Ultrasensitive biological switches such as those that result from the interaction of Cdc4 with multiply phosphorylated Sic1, would be predicted to control key cellular events that require all-or-none decision states. Indeed, we have shown the existence just such a switch controlling the onset of DNA replication in yeast. Furthermore, such systems have other biochemical properties that allow for valuable biological effects, such as the ability to set thresholds in signal transduction cascades, and potentially allowing integration of multiple signals into a coherent and quantized output. From a therapeutic standpoint, the possibility of targeting molecular switches holds the promise of much greater precision than conventional inhibitors.

Selected Papers

Pawson T, Gish G, Nash P. (2001). SH2 domains, interaction modules and cellular wiring. Trends in Cell Biology 11(12): 504-511.

Nash P, Berry D, Liu S, Pawon T, McGlade J. (2002). A high affinity Arg-X-X-Lys SH3-binding motif confers specificity for the interaction between Gads and SLP-76 in T-cell signaling. Current Biology 12: 1336-1341.

Pawson T and Nash P. (2003). Modular protein interaction domains in cellular communication. Handbook of Cell Signaling. Volume 1. Chapter 67, pages 379-385.

Pawson T and Nash P. (2003). Assembly of cell regulatory systems through protein interaction domains. Science 300: 445-452.