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Elucidation of protein interactions necessary for the maintenance of the BCR-ABL signaling complex
T. Gregor, MK. Bosakova, A. Nita, SP. Abraham, B. Fafilek, NH. Cernohorsky, J. Rynes, S. Foldynova-Trantirkova, D. Zackova, J. Mayer, L. Trantirek, P. Krejci,
Language English Country Switzerland
Document type Journal Article
Grant support
15-34405A
Agentura Pro Zdravotnický Výzkum České Republiky
CZ.02.1.01/0.0/0.0/16_019/0000729
European Regional Development Fund OP RDE
NLK
PubMed Central
from 1997
ProQuest Central
from 1997-01-01 to 1 year ago
Medline Complete (EBSCOhost)
from 2000-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 1997-01-01 to 1 year ago
- MeSH
- Adaptor Proteins, Signal Transducing metabolism MeSH
- Amino Acid Motifs MeSH
- Fusion Proteins, bcr-abl chemistry genetics metabolism MeSH
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism pathology MeSH
- Protein Array Analysis MeSH
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases metabolism MeSH
- Phosphorylation MeSH
- HEK293 Cells MeSH
- Protein Kinase Inhibitors pharmacology MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Pyrimidines pharmacology MeSH
- Signal Transduction * drug effects MeSH
- src Homology Domains MeSH
- Src Homology 2 Domain-Containing, Transforming Protein 1 metabolism MeSH
- Protein Binding drug effects MeSH
- Binding Sites MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Many patients with chronic myeloid leukemia in deep remission experience return of clinical disease after withdrawal of tyrosine kinase inhibitors (TKIs). This suggests signaling of inactive BCR-ABL, which allows the survival of cancer cells, and relapse. We show that TKI treatment inhibits catalytic activity of BCR-ABL, but does not dissolve BCR-ABL core signaling complex, consisting of CRKL, SHC1, GRB2, SOS1, cCBL, p85a-PI3K, STS1 and SHIP2. Peptide microarray and co-immunoprecipitation results demonstrate that CRKL binds to proline-rich regions located in C-terminal, intrinsically disordered region of BCR-ABL, that SHC1 requires pleckstrin homology, src homology and tyrosine kinase domains of BCR-ABL for binding, and that BCR-ABL sequence motif located in disordered region around phosphorylated tyrosine 177 mediates binding of three core complex members, i.e., GRB2, SOS1, and cCBL. Further, SHIP2 binds to the src homology and tyrosine kinase domains of BCR-ABL and its inositol phosphatase activity contributes to BCR-ABL-mediated phosphorylation of SHC1. Together, this study characterizes protein-protein interactions within the BCR-ABL core complex and determines the contribution of particular BCR-ABL domains to downstream signaling. Understanding the structure and dynamics of BCR-ABL interactome is critical for the development of drugs targeting integrity of the BCR-ABL core complex.
Central European Institute of Technology Masaryk University 62500 Brno Czech Republic
Department of Biology Faculty of Medicine Masaryk University 62500 Brno Czech Republic
References provided by Crossref.org
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- $a Gregor, Tomas $u Central European Institute of Technology, Masaryk University, 62500, Brno, Czech Republic. Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic. International Clinical Research Center, St. Anne's University Hospital, 65691, Brno, Czech Republic.
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- $a Many patients with chronic myeloid leukemia in deep remission experience return of clinical disease after withdrawal of tyrosine kinase inhibitors (TKIs). This suggests signaling of inactive BCR-ABL, which allows the survival of cancer cells, and relapse. We show that TKI treatment inhibits catalytic activity of BCR-ABL, but does not dissolve BCR-ABL core signaling complex, consisting of CRKL, SHC1, GRB2, SOS1, cCBL, p85a-PI3K, STS1 and SHIP2. Peptide microarray and co-immunoprecipitation results demonstrate that CRKL binds to proline-rich regions located in C-terminal, intrinsically disordered region of BCR-ABL, that SHC1 requires pleckstrin homology, src homology and tyrosine kinase domains of BCR-ABL for binding, and that BCR-ABL sequence motif located in disordered region around phosphorylated tyrosine 177 mediates binding of three core complex members, i.e., GRB2, SOS1, and cCBL. Further, SHIP2 binds to the src homology and tyrosine kinase domains of BCR-ABL and its inositol phosphatase activity contributes to BCR-ABL-mediated phosphorylation of SHC1. Together, this study characterizes protein-protein interactions within the BCR-ABL core complex and determines the contribution of particular BCR-ABL domains to downstream signaling. Understanding the structure and dynamics of BCR-ABL interactome is critical for the development of drugs targeting integrity of the BCR-ABL core complex.
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