Catalytic specificity of protein-tyrosine kinases is critical for selective signalling

Zhou Songyang, Kermit L Carraway, Michael J. Eck, Stephen C. Harrison, Ricardo A. Feldman, Moosa Mohammadi, Joseph Schlessinger, Stevan R. Hubbard, Darrin P. Smith, Charis Eng, Marla J. Lorenzo, Bruce A J Ponder, Bruce J. Mayer, Lewis C. Cantley

Research output: Contribution to journalArticle

819 Scopus citations

Abstract

How do distinct protein-tyrosine kinases activate specific down-stream events? Src-homology-2 (SH2) domains on tyrosine kinases or targets of tyrosine kinases recognize phosphotyrosine in a specific sequence context and thereby provide some specificity1-3. The role of the catalytic site of tyrosine kinases in determining target specificity has not been fully investigated. Here we use a degenerate peptide library to show that each of nine tyrosine kinases investigated has a unique optimal peptide substrate. We find that the cytosolic tyrosine kinases preferentially phosphorylate peptides recognized by their own SH2 domains or closely related SH2 domains (group I; ref. 3), whereas receptor tyrosine kinases preferentially phosphorylate peptides recognized by subsets of group III SH2 domains3. The importance of these findings for human disease is underscored by our observation that a point mutation in the RET receptor-type tyrosine kinase, which causes multiple endocrine neoplasia type 2B, results in a shift in peptide substrate specificity.

Original languageEnglish (US)
Pages (from-to)536-539
Number of pages4
JournalNature
Volume373
Issue number6514
StatePublished - Feb 9 1995
Externally publishedYes

ASJC Scopus subject areas

  • General

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    Songyang, Z., Carraway, K. L., Eck, M. J., Harrison, S. C., Feldman, R. A., Mohammadi, M., Schlessinger, J., Hubbard, S. R., Smith, D. P., Eng, C., Lorenzo, M. J., Ponder, B. A. J., Mayer, B. J., & Cantley, L. C. (1995). Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature, 373(6514), 536-539.