Abstract
Bcr-Abl contributes prominently to the development of most chronic myeloid leukemias (CMLs). Prior work has identified the adapter protein CRKL as a major substrate of the Bcr-Abl tyrosine kinase. CRKL can also bind via its first SH3 domain [SH3(1)] to specific sequences in Bcr-Abl. Cell-penetrating peptides were developed that bind with high affinity and selectivity to the SH3(1) domain of CRKL. They disrupt Bcr-Abl-CRKL complexes and strongly reduce the proliferation of primary CML blast cells and cell lines established from Bcr-Abl-positive patients. Activation-specific antibodies against phosphorylated MAP kinase (MAPK) showed that MAPK activity is down-regulated in blast cells treated with the CRKLSH3(1) blocker peptides. We conclude that the Bcr-Abl-CRKL complexes are largely dependent on the CRKLSH3(1) domain, that the central mitogenic cascade is down-regulated as a consequence of the disruption of CRKLSH3(1) interactions, and that CRKL therefore contributes to the proliferation of CML blast cells.
Original language | English (US) |
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Pages (from-to) | 1529-1538 |
Number of pages | 10 |
Journal | FASEB Journal |
Volume | 14 |
Issue number | 11 |
DOIs | |
State | Published - 2000 |
Keywords
- Adapter protein
- Bcr-Abl
- CRKL
- MAP kinase (MAPK)
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics