Molecular cell, 2003-07, Vol.12 (1), p.27-37
2003
Details
- Autor(en) / Beteiligte
- Titel
- Autoinhibition of Bcr-Abl through Its SH3 Domain
- Ist Teil von
- Molecular cell, 2003-07, Vol.12 (1), p.27-37
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2003
- Link zum Volltext
- Quelle
- Electronic Journals Library
- Beschreibungen/Notizen
- Bcr-Abl is a dysregulated tyrosine kinase whose mechanism of activation is unclear. Here, we demonstrate that, like c-Abl, Bcr-Abl is negatively regulated through its SH3 domain. Kinase activity, transformation, and leukemogenesis by Bcr-Abl are greatly impaired by mutations of the Bcr coiled-coil domain that disrupt oligomerization, but restored by an SH3 point mutation that blocks ligand binding or a complementary mutation at the intramolecular SH3 binding site defined in c-Abl. Phosphorylation of tyrosines in the activation loop of the catalytic domain and the linker between the SH2 and catalytic domains (SH2-CD linker) is dependent on oligomerization and required for leukemogenesis. These results suggest that Bcr-Abl has a monomeric, unphosphorylated state with the SH3 domain engaged intramolecularly to Pro1124 in the SH2-CD linker, the form that is sensitive to the inhibitor imatinib (STI-571). The sole function of the coiled-coil domain is to disrupt the autoinhibited conformation through oligomerization and intermolecular autophosphorylation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1097-2765eISSN: 1097-4164DOI: 10.1016/S1097-2765(03)00274-0Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7128750
- Format
- –
- Schlagworte
- 3T3 Cells, Abl gene, Alanine - genetics, Alanine - metabolism, Amino Acid Sequence - genetics, Animals, Bcl gene, Bcr gene, Binding Sites - genetics, Catalytic Domain - drug effects, Catalytic Domain - genetics, Cell Transformation, Neoplastic - genetics, Cell Transformation, Neoplastic - metabolism, Enzyme Inhibitors - pharmacology, Eukaryotic Cells - enzymology, Feedback, Physiological - drug effects, Feedback, Physiological - genetics, Fusion Proteins, bcr-abl, Humans, imatinib, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics, Mice, Mice, Inbred BALB C, Models, Molecular, Mutation - drug effects, Mutation - genetics, Phosphorylation - drug effects, Proline - genetics, Proline - metabolism, Protein Binding - drug effects, Protein Binding - genetics, Protein Structure, Tertiary - drug effects, Protein Structure, Tertiary - genetics, protein-tyrosine kinase, Protein-Tyrosine Kinases - antagonists & inhibitors, Protein-Tyrosine Kinases - genetics, Protein-Tyrosine Kinases - metabolism, SH3 domain, Tyrosine - metabolism