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Letters to Nature

Nature 373, 536-539 (9 February 1995) | doi:10.1038/373536a0; Accepted 20 December 1994

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

Zhou Songyang*†, Kermit L. Carraway , III*, Michael J. Eck‡, Stephen C. Harrison†, Ricardo A. Feldman§, Moosa Mohammadi*, Joseph Schlessinger§, Stevan R. Hubbard, Darrin P. Smithstar, Charis Engstar**, Marla J. Lorenzostar, Bruce A. J. Ponderstar, Bruce J. Mayer‡†† & Lewis C. Cantley*‡‡

  1. *Division of Signal Transduction, Department of Medicine, Beth Israel Hospital and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02215, USA
  2. †Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
  3. ‡Howard Hughes Medical Institute and Laboratory of Molecular Medicine, Children's Hospital, Boston, Massachusetts 02115, USA
  4. §Department of Microbiology and Immunology, University of Maryland School of Medicine, and Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, USA
  5. parallelDepartment of Pharmacology, New York University Medical Center, New York, New York 10016, USA
  6. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA
  7. starCRC Human Cancer Genetics Research Group, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK
  8. **Department of Medicine, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
  9. ‡‡Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
  10. ‡‡To whom correspondence should be addressed.
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HOW do distinct protein-tyrosine kinases activate specific downstream 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.