Piers Nash, Ph.D.

Research Summary

Protein-Protein Interactions, Self-Assembly and Complexity in Signal Transduction.

Signal Transduction

Reversible ubiquitination and regulation of signaling: Protein ubiquitination can have many outcomes depending on the length of the ubiquitin chain and the type of linkage. The 2004 Nobel Prize in Chemistry was awarded for the elucidation of the ubiutin-proteasome pathway in which proteins tagged with Lys-48-linked ubiquitin chains greater than 3 in length (polyubiquitination) are targeted to the proteasome for degradation. By contrast, short chains of Lys-63-linked ubiquitin act to coordinate the endocytic machinery and the internal trafficking of endocytic vesicles. We are interested ubiquitination as a regulated and reversible process that creates docking sites for a range of ubiquitin-binding proteins. We are currently studying the role of various ubiqutin linkages in regulating signaling events from activated cell surface receptors (the EGF-R and the T-cell receptor), and the role of specific deubiquitinating enzymes in modulating cellular signal transduction.

Systems Biology/Bioinformatics
The human and mouse complement of SH2 domains: The SH2 domain is a modular protein interaction domain that selectively binds to phosphorylated tyrosine containing sequences, and in doing so functions as the critical link between tyrosine kinases and downstream signaling. As such, SH2 domain containing proteins play key role in signaling cascades implicated in a wide range of human diseases, including cancers, diabetes, autoimmune diseases and a wide range of bacterial and viral pathogens. We have recently completed a bioinformatic analysis of the human and mouse complement of SH2 domains (Liu et al. 2006 Molecular Cell 22: 851-868). Using this approach we have identified a number of previously unknown SH2 domain proteins. We are utilizing a combination of chemical, biochemical, and cell biology techniques to determine the binding preference and cellular role of these novel proteins. In addition, we are examining the evolution and diversity of SH2 domain functional specificity using a variety of techniques, including analysis of intron-exon boundary structure, domains-assisted sequence comparison, structural and functional analysis.

Proteoscape®: With support from the Cancer Center, we are developing a large protein-centered relational database to act as both an investigational tool as well as an underlying support database for future biomedical informatics. The modular nature of proteins involved in signal transduction and cancer (see our review published in Science 2003) is allowing us to develop detailed approaches to bioinformatic analysis of a wide range of proteins involved in health and disease.  This serves as the support database for all of our bioinformatic efforts and underlies the SH2 domain resource website that have developed at sh2domain.org

Self-Assembly and Complexity
Ultrasensitivity: We are interested in how binding interactions that depend on a high-local concentration of low-affinity binding sites can act to set thresholds, integrate signals and create all-or-none responses on a single cell level. We have previously identified the requirement for multi-site phosphorylation of the CDK inhibitor Sic1 to allow a productive interaction with Cdc4 – an event that controls the initiation of DNA replication and the G1 to S-phase transition in the cell cycle (published in Nature, 2001). A project is available to study a variety of aspects of this fundamental problem using computational modeling, biophysical and biochemical techniques.