Piers D. Nash, Ph.D.

Research Summary

Signal transduction is largely accomplished by regulated protein-protein interactions that are typically specified by modular protein interaction domains. In many cases, reversible post-translational modifications provide the means to regulate such interactions and act as a form of protein memory that is read out by interaction domains. We work on various problems relating to regulated protein-protein interactions in signal transduction.

1) Evolution of SH2 domains and the mechanisms that guide highlyselective interactions. SH2 domains and phosphotyrosine signaling appear at the junction of multicellularity in the pre-metazoans and expand rapidly as a key mechanism of signaling that appears to drive increasing complexity in the metazoan lineage. The 121 SH2 domains extant in humans explore a very small region of ligand sequence space in determining selectivity. Despite this, SH2 domains are highly selective for physiological peptide ligands. We have recently demonstrated that the basis for such selectivity is the ability of SH2 domains to read both motif and anti-motif sequences in a context-dependent manner.

2) Reversible ubiquitination is a post-translational modification that is involved in a wide array of cellular processes. We work on the deubiquitinating enzymes AMSH and USP8, and the role that these play in modulating EGFR and CXCR4 receptor sorting for recycling or degradation. USP8 and AMSH function broadly to regulate ESCRT components that utilize ubiquitin binding domains to recognize cargo and assemble into functional complexes. In 2010 we published three papers outlining some of the interactions that recruits AMSH and USP8 and their various roles in receptor trafficking.

Selected Papers

Liu, B.A., Jablonowski, K., Shah, E.E., Engelmann, B.W., Stergachis, A.B. Jones, R.B. and Nash, P.D. SH2 domains recognize contextual peptide sequence information to determine selectivity. Molecular and Cellular Proteomics 2010 9(11): 2391-2404. PMID: 20627867  Link

Berlin, I., Dise, R., Higginbotham, K.H., Sierra, M.I. and Nash, P.D. The deubiquitinating enzyme USP8 promotes trafficking and degradation of the chemokine receptor CXCR4 at the sorting endosome. The Journal of Biological Chemistry 2010 285(48):37895-37908. PMID: 20876529.  Link

Berlin, I., Schwartz, H., and Nash, P.D. Regulation of the epidermal growth factor receptor ubiquitination and trafficking by the USP8/STAM complex. The Journal of Biological Chemistry 2010 285(45): 34909-34921. PMID: 20736164 Link

Sierra, M., Wright, M.H. and Nash P.D. AMSH interacts with ESCRT-0 to regulate the stability and trafficking of CXCR4. The Journal of Biological Chemistry 2010 285(18):13990-4004. PMID: 20159979  Link

Liu, B.A., Jablonowski, K., Raina, M., Arcé, M., Pawson, T., and Nash, P.D. (2006) The Human and Mouse Complement of SH2 Domain Proteins – establishing the boundaries of phosphotyrosine signaling. Molecular Cell 22: 851-868.  Link

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

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

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.

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.