Inhibition of the Activity of Src and Abl Tyrosine Protein Kinases by the Binding of the Wiskott−Aldrich Syndrome Protein
| Autor: | Roberta Schulte, Bartholomew M. Sefton |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Blotting
Western macromolecular substances Transfection SH2 domain Biochemistry Catalysis SH3 domain Receptor tyrosine kinase Cell Line src Homology Domains Humans Phosphorylation Proto-Oncogene Proteins c-abl Binding Sites Tyrosine-protein kinase CSK biology Wiskott–Aldrich syndrome protein Proteins Precipitin Tests Peptide Fragments Protein Structure Tertiary Wiskott-Aldrich Syndrome Cell biology src-Family Kinases Lymphocyte Specific Protein Tyrosine Kinase p56(lck) CDC37 Mitogen-activated protein kinase biology.protein Wiskott-Aldrich Syndrome Protein Protein Binding Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Biochemistry. 42:9424-9430 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi034519u |
| Popis: | The Wiscott-Aldrich syndrome protein, WASP, is an effector through which cdc42, a Rho family GTPase, regulates the actin cytoskeleton in hematopoietic cells. We have found that WASP binds readily to a number of tyrosine protein kinases including the Src kinases and the Abl kinase when the proteins are coexpressed during transient transfection. Binding inhibited the activity of each of these kinases strikingly, both in vitro and in vivo. Surprisingly, the binding was not due to an interaction between the proline-rich domain of WASP and the SH3 domain of these kinases. Rather, residues 83-93 in WASP were found to bind to the catalytic domains of the kinases. Binding did not decrease the affinity of Src kinases for either ATP or a peptide substrate noticeably. Rather, the V m a x of substrate phosphorylation was reduced by the binding of the peptide. This inhibition represents a novel form of regulation of protein kinase activity and suggests that that the isolation of small molecules that exploit this inhibitory mechanism may be possible. |
| Databáze: | OpenAIRE |
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