Deletion of the Src Homology 3 Domain and C-terminal Proline-rich Sequences in Bcr-Abl Prevents Abl Interactor 2 Degradation and Spontaneous Cell Migration and Impairs Leukemogenesis
| Autor: | Ian K. McNiece, William Schroeder, Patrick J. Kerzic, Zonghan Dai |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Male
endocrine system Proline ABL Interactor 2 Fusion Proteins bcr-abl Mutagenesis (molecular biology technique) Mice Transgenic macromolecular substances Biology Transfection Biochemistry SH3 domain Cell Line src Homology Domains Mice Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Tumor Cells Cultured medicine Animals Humans Amino Acid Sequence Interactor Ubiquitins neoplasms Molecular Biology Adaptor Proteins Signal Transducing Bone Marrow Transplantation Sequence Deletion Homeodomain Proteins ABL Chemotaxis Signal transducing adaptor protein Cell Biology medicine.disease Fusion protein Peptide Fragments Recombinant Proteins Fibronectins Cell biology Mice Inbred C57BL Retroviridae Mice Inbred DBA Mutagenesis Chronic myelogenous leukemia |
| Zdroj: | Journal of Biological Chemistry. 276:28954-28960 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m101170200 |
| Popis: | The hematopoietic cells from patients with Bcr-Abl-positive chronic myelogenous leukemia exhibit multiple abnormalities of cytoskeletal function. The molecular events leading to these abnormalities are not fully understood. Previously we showed that Bcr-Abl elicits ubiquitin-dependent degradation of Abl interactor proteins. Because recent studies have suggested a role of Abl interactor proteins in the pathway that regulates cytoskeletal function, we investigated whether mutations in Bcr-Abl that interfere with the signaling to Abl interactor proteins affect its leukemogenic activity. We report here that the Src homology 3 domain and C-terminal proline-rich sequences of Bcr-Abl are required for its binding to Abl interactor 2 as well as for the induction of Abl interactor 2 degradation. Although the deletion of these regions did not affect the ability of the mutant Bcr-Abl to transform hematopoietic cells to growth factor independence, it abrogated its ability to stimulate spontaneous cell migration on fibronectin-coated surfaces. Furthermore, the mutant Bcr-Abl, defective in binding to Abl interactor 2 and inducing its degradation, failed to induce chronic myelogenous leukemia-like disease in mouse. These results are consistent with a role of Abl interactor proteins in the regulation of cytoskeletal function as well as in the pathogenesis of Bcr-Abl-induced leukemogenesis. |
| Databáze: | OpenAIRE |
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