-
Something wrong with this record ?
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
Grant support
NV15-34405A
MZ0
CEP Register
Digital library NLK
Full text - Article
Source
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
- Protein Binding drug effects MeSH
- Binding Sites MeSH
- Check Tag
- Humans 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
Gregor Tomas Central European Institute of Technology Masaryk University 62500 Brno Czech Republic
Institute of Animal Physiology and Genetics of the CAS 60200 Brno Czech Republic
Institute of Organic Chemistry and Biochemistry of the CAS 16610 Prague Czech Republic
International Clinical Research Center St Anne's University Hospital 65691 Brno Czech Republic
ternational Clinical Research Center St Anne's University Hospital 65691 Brno Czech Republic
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc20018630
- 003
- CZ-PrNML
- 005
- 20201119085038.0
- 007
- ta
- 008
- 201116s2020 sz f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1007/s00018-019-03397-7 $2 doi
- 035 __
- $a (PubMed)31820037
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a sz
- 100 1_
- $a Gregor, Tomáš $u Gregor, Tomas. Central European Institute of Technology, Masaryk University, 62500, Brno, Czech Republic ; Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic ; nternational Clinical Research Center, St. Anne's University Hospital, 65691, Brno, Czech Republic
- 245 10
- $a Elucidation of protein interactions necessary for the maintenance of the BCR-ABL signaling complex / $c 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
- 520 9_
- $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.
- 536 __
- $c Grant Information: No: 15-34405A<ovid:br/>Organization: *Agentura Pro Zdravotnicky Vyzkum Ceske Republiky*<ovid:br/>
- 536 __
- $c Grant Information: No: CZ.02.1.01/0.0/0.0/16_019/0000729<ovid:br/>Organization: *European Regional Development Fund OP RDE*
- 650 02
- $a adaptorové proteiny signální transdukční $x metabolismus $7 D048868
- 650 02
- $a aminokyselinové motivy $7 D020816
- 650 02
- $a vazebná místa $7 D001665
- 650 02
- $a nádorové buněčné linie $7 D045744
- 650 02
- $a bcr-abl fúzní proteiny $x chemie $x genetika $x metabolismus $7 D016044
- 650 02
- $a HEK293 buňky $7 D057809
- 650 02
- $a lidé $7 D006801
- 650 02
- $a chronická myeloidní leukemie $x metabolismus $x patologie $7 D015464
- 650 02
- $a fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy $x metabolismus $7 D000072183
- 650 02
- $a fosforylace $7 D010766
- 650 02
- $a čipová analýza proteinů $7 D040081
- 650 02
- $a vazba proteinů $x účinky léků $7 D011485
- 650 02
- $a inhibitory proteinkinas $x farmakologie $7 D047428
- 650 02
- $a pyrimidiny $x farmakologie $7 D011743
- 650 02
- $a signální transdukce $x účinky léků $7 D015398
- 650 02
- $a Src Homology 2 Domain-Containing, Transforming Protein 1 $x me [Metabolism]
- 650 02
- $a src Homology Domains
- 700 1_
- $a Kunová Bosaková, Michaela $u Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic ; nternational 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
- 700 1_
- $a Nita, Alexandru $u Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic ; Institute of Organic Chemistry and Biochemistry of the CAS, 16610, Prague, Czech Republic
- 700 1_
- $a Abraham, Sara P $u Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic.
- 700 1_
- $a Fafílek, Bohumil $7 xx0126442 $u Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic ; nternational 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
- 700 1_
- $a Cernohorsky, Nicole H. $u Department of Biology, Faculty of Medicine, Masaryk University, 62500, Brno, Czech Republic.
- 700 1_
- $a Rynes ,Jan $u Central European Institute of Technology, Masaryk University, 62500, Brno, Czech Republic
- 700 1_
- $a Trantírková, Silvie $7 xx0107098 $u Central European Institute of Technology, Masaryk University, 62500, Brno, Czech Republic
- 700 1_
- $a Žáčková, Daniela $7 xx0074334 $u Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital, 62500, Brno, Czech Republic
- 700 1_
- $a Mayer, Jiří, $d 1960- $7 nlk20000083651 $u Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital, 62500, Brno, Czech Republic
- 700 1_
- $a Trantírek, Lukáš $7 xx0129019 $u Central European Institute of Technology, Masaryk University, 62500, Brno, Czech Republic
- 700 1_
- $a Krejčí, Pavel $7 xx0007657 $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.
- 773 0_
- $t Cellular and molecular life sciences $g Roč. 77, č. 19 (2020), s. 3885-3903 $p Cell Mol Life Sci $x 1420-682X $w MED00001078
- 773 0_
- $p Cell Mol Life Sci $g 77(19):3885-3903, 2020 Oct
- 910 __
- $a ABA008 $y p $z 0
- 990 __
- $a 20201116105847 $b ABA008
- 991 __
- $a 20201119085035 $b ABA008
- 999 __
- $a ok $b bmc $g 1583284 $s 1108828
- BAS __
- $a 3
- BMC __
- $a 2020 $b 77 $c 19 $d 3885-3903 $x MED00001078 $i 1420-682X $m Cellular and molecular life sciences
- GRA __
- $a NV15-34405A $p MZ0
- LZP __
- $a 2020-lp
