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Molecular and Cellular Biology, November 2006, p. 8461-8474, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01491-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Screening for PTB Domain Binding Partners and Ligand Specificity Using Proteome-Derived NPXY Peptide Arrays{triangledown} ,{dagger}

Matthew J. Smith,1,2 W. Rod Hardy,1,2 James M. Murphy,1 Nina Jones,1 and Tony Pawson1,2*

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5,1 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Canada2

Received 10 August 2006/ Returned for modification 21 August 2006/ Accepted 31 August 2006

Modular interaction domains that recognize peptide motifs in target proteins can impart selectivity in signaling pathways. Phosphotyrosine binding (PTB) domains are components of cytoplasmic docking proteins that bind cell surface receptors through NPXY motifs. We have employed a library of human proteome-derived NXXY sequences to explore PTB domain specificity and function. SPOTS peptide arrays were used to create a comprehensive matrix of receptor motifs that were probed with a set of 10 diverse PTB domains. This approach confirmed that individual PTB domains have selective and distinct recognition properties and provided a means to explore over 2,500 potential PTB domain-NXXY interactions. The results correlated well with previously known associations between full-length proteins and predicted novel interactions, as well as consensus binding data for specific PTB domains. Using the Ret, MuSK, and ErbB2 receptor tyrosine kinases, we show that interactions of these receptors with PTB domains predicted to bind by the NXXY arrays do occur in cells. Proteome-based peptide arrays can therefore identify networks of receptor interactions with scaffold proteins that may be physiologically relevant.

* Corresponding author. Mailing address: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5. Phone: (416) 586-8262. Fax: (416) 586-8869. E-mail: pawson{at}mshri.on.ca.

{triangledown} Published ahead of print on 18 September 2006.

{dagger} Supplemental data for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2006, p. 8461-8474, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.01491-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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