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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,
Jazyk angličtina Země Švýcarsko
Typ dokumentu časopisecké články
Grantová podpora
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
od 1997
ProQuest Central
od 1997-01-01 do Před 1 rokem
Medline Complete (EBSCOhost)
od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest)
od 1997-01-01 do Před 1 rokem
- MeSH
- adaptorové proteiny signální transdukční metabolismus MeSH
- aminokyselinové motivy MeSH
- bcr-abl fúzní proteiny chemie genetika metabolismus MeSH
- chronická myeloidní leukemie metabolismus patologie MeSH
- čipová analýza proteinů MeSH
- fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy metabolismus MeSH
- fosforylace MeSH
- HEK293 buňky MeSH
- inhibitory proteinkinas farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- pyrimidiny farmakologie MeSH
- signální transdukce * účinky léků MeSH
- src homologní domény MeSH
- transformující protein 1 obsahující src homologní doménu 2 metabolismus MeSH
- vazba proteinů účinky léků MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články 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
Citace poskytuje 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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- $a Bosakova, Michaela Kunova $u 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. Institute of Animal Physiology and Genetics of the CAS, 60200, Brno, Czech Republic.
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