Piers Nash, Ph.D.

Primary:

Assistant Professor, Ben May Institute for Cancer Research

Secondary:

Committee on Cancer Biology
Committee on Cell Physiology
Cancer Research Center
Education:
Degree Year Institution Area
BSc
1992
University of Guelph
Chemistry/Biochemistry
PhD
1999
University of Alberta
Biochemistry
Postdoc
1999-2003
Mount Sinai Hospital/University of Toronto
Signal Transduction


Phone: (773) 702-6852 /  Fax: (773) 702-4672
E-Mail: pdnash@uchicago.edu
Address: CIS W432

Web page:
 http://ben-may.bsd.uchicago.edu/bmi2/faculty/nash.htm
http://nashlab.uchicago.edu/

Research Summary

Protein-protein interactions, 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 SH2-ome: 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 an initial bioinformatic analysis of the human and mouse complement of SH2 domains (manuscript in preparation).  In doing so, we 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.  We are also conducting an evolutionary analysis of SH2 domains 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.

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.

Selected Publications

Pawson, T. and Nash, P.  Protein-protein interactions define specificity in signal transduction. Genes and Development, 14(9):1027-1047, 2000.

Nash, P., Tang, X., Orlicky, S., Chen, Q., Gertler, F.B., Mendenhall, M.D., Sicheri, F., Pawson, T. and Tyers, M. Multi-site phosphorylation of a CDK inhibitor sets a threshold for the onset of DNA replication. Nature, 414:514-521, 2001.

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

Nash, P., Berry, D., Liu, S., Pawon, T., McGlade, J. 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, 2002.

This article was the focus of the following reviews and comments:

  • Ferrell, J. E. Jr.  Six steps to destruction. Nature, 414, 498-499, 2001.
  • Tromans, A. Highlights of the Week: Switching on S-Phase. Nature Reviews Molecular Cell Biology, 2:873, 2001.
  • Deshaies, R.J. and Ferrell, J. E. Jr.  Multisite Phosphorylation and the Countdown to S Phase. Cell, 107:819-822, 2002.
  • Harper, J. W.  A phosphorylation-driven ubiquitination switch for cell-cycle control. Trends in Cell Biology, 12(3):104-107, 2002.

Pawson, T., Raina, M. and Nash, P. Interaction domains: From simple binding events to complex cellular behaviour. FEBS Letters, 513:2-10, 2002.

This was the focus of the following review:

  • Gough, N.R., Adler, E.A., & Ray, L. B., Cellular Regulation through Protein Interaction Domains. An Editorial Guide appearing in Science magazines. Signal Transduction Knowledge Environment (STKE) Vol. 2003, Issue 179, 22 April 2003.
Pawson, T. and Nash, P. Assembly of cell regulatory systems through protein interaction domains. Science, 300:445-452, 2003.

Liu, Q., Nash, P., Berry, D., Pawson, T., McGlade, J., Li, S. (2003) Structural Basis for Specific Binding of the Gads SH3 domain to an RXXK Motif-containing Slp-76 Peptide: A Novel Mode of Peptide Recognition. Molecular Cell, 11:471-481, 2003.

Bladt, F., Aippersbach, E., Gelkop, S., Strasser, G. A., Nash, P., Tafuri, A., Gertler, F., Pawson, T. The murine Nck SH2/SH3 adaptors regulate mesoderm-derived embryonic structures in vivo and the cellular actin network. Molecular and Cellular Biology, 23(13):4586-4597, 2003.

Pawson, T., and Nash, P. Modular protein interaction domains in cellular communication. "Handbook of Cell Signaling" Chapter 67, Volume 1, 2003.

Tong, J., Elowe, S., Nash, P. and Pawson, T.  Manipulation of EphB2 regulatory motifs and SH2 binding sites switches MAP kinase signaling and biological activity. Journal of Biological Chemistry, 278:6111-6119, 2003.

This was the focus of the following review:

  • Gough, N.R., Adler, E.A., & Ray, L. B., Cellular Regulation through Protein Interaction Domains. An Editorial Guide appearing in Science magazines. Signal Transduction Knowledge Environment (STKE) Vol. 2003, Issue 179, 22 April 2003.
Pawson, T. and Nash, P. Assembly of cell regulatory systems through protein interaction domains. Science, 300:445-452., 2003.

Liu, Q., Nash, P., Berry, D., Pawson, T., McGlade, J. and Li, S. (2003) Structural Basis for Specific Binding of the Gads SH3 domain to an RXXK Motif-containing Slp-76 Peptide: A Novel Mode of Peptide Recognition. Molecular Cell, 11:471-481, 2003.

Bladt, F., Aippersbach, E., Gelkop, S., Strasser, G. A., Nash, P., Tafuri, A., Gertler, F. and Pawson, T. The murine Nck SH2/SH3 adaptors regulate mesoderm-derived embryonic structures in vivo and the cellular actin network. Molecular and Cellular Biology, 23(13):4586-4597, 2003.

Pawson, T., and Nash, P. Modular protein interaction domains in cellular communication. "Handbook of Cell Signaling" Chapter 67, Volume 1, 2003.

Pawson, T., Gish, G.D., and Nash, P. The SH2 domain: a prototype for protei interaction domains. In: "Modular Protein Domains" ed. Cesareni, G. et al. Chapter 1, pages 5-36, Wiley VCH Press, 2004.

Updated 10/18/05.