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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2011-2-17
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pubmed:abstractText |
Internal tandem duplication of FMS-like receptor tyrosine kinase 3 (FLT3/ITD) within its juxtamembrane domain is a frequent mutation in adult acute myeloid leukaemia (AML). This mutation causes constitutive activation of FLT3 and is associated with poor prognosis. The high relapse rate of FLT3/ITD-positive AML might be partly because of insufficient eradication of slow-cycling leukaemic stem cells in the bone marrow microenvironment. ?1 integrin mediates haematopoietic stem and progenitor cell homing along with their retention in the bone marrow and also inhibits haematopoietic proliferation and differentiation. Here, we demonstrate that inhibition of FLT3/ITD kinase activity by a FLT3 selective inhibitor named FI-700 decreases affinity of ?4?1 integrin to soluble VCAM-1. ?4?1 integrin deactivation by FI-700 is independent of Rap1, which is the critical regulator of integrin inside-out signalling. In addition, selective inhibition of FLT3/ITD induces Pyk2 dephosphorylation together with the inhibition of phosphatidylinositol-3-kinase (PI3K)/Akt pathway. Both wild-type and ITD-FLT3 proteins co-immunoprecipitated with ?1 integrin and Pyk2 indicating the signal crosstalk between FLT3, ?1 integrin and Pyk2. These results collectively indicated that the inhibition of FLT3 kinase might contribute not only to the induction of apoptosis, but also to the leukaemia cell detachment from the bone marrow microenvironment in the treatment of AML.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/FI-700,
http://linkedlifedata.com/resource/pubmed/chemical/FLT3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Focal Adhesion Kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Integrin alpha4beta1,
http://linkedlifedata.com/resource/pubmed/chemical/Multiprotein Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/TERF2IP protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Telomere-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Vascular Cell Adhesion Molecule-1,
http://linkedlifedata.com/resource/pubmed/chemical/fms-Like Tyrosine Kinase 3
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1600-0609
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pubmed:author |
pubmed-author:AbeAkihiroA,
pubmed-author:HamaguchiMichinariM,
pubmed-author:IwasakiToshihiroT,
pubmed-author:KaibuchiKozoK,
pubmed-author:KatsumiAkiraA,
pubmed-author:KiyoiHitoshiH,
pubmed-author:KobayashiMikiM,
pubmed-author:KohnoTakayukiT,
pubmed-author:KojimaTetsuhitoT,
pubmed-author:MatsushitaTadashiT,
pubmed-author:NaoeTomokiT,
pubmed-author:SengaTakeshiT,
pubmed-author:TanizakiRyoheiR
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pubmed:copyrightInfo |
© 2011 John Wiley & Sons A/S.
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pubmed:issnType |
Electronic
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pubmed:volume |
86
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
191-8
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pubmed:meshHeading |
pubmed-meshheading:21114537-Animals,
pubmed-meshheading:21114537-Cell Adhesion,
pubmed-meshheading:21114537-Cell Line, Tumor,
pubmed-meshheading:21114537-Coculture Techniques,
pubmed-meshheading:21114537-Focal Adhesion Kinase 2,
pubmed-meshheading:21114537-Gene Duplication,
pubmed-meshheading:21114537-Humans,
pubmed-meshheading:21114537-Integrin alpha4beta1,
pubmed-meshheading:21114537-Leukemia, Myeloid, Acute,
pubmed-meshheading:21114537-Mice,
pubmed-meshheading:21114537-Multiprotein Complexes,
pubmed-meshheading:21114537-Mutation,
pubmed-meshheading:21114537-Phosphorylation,
pubmed-meshheading:21114537-Pyridines,
pubmed-meshheading:21114537-Pyrimidines,
pubmed-meshheading:21114537-Signal Transduction,
pubmed-meshheading:21114537-Tandem Repeat Sequences,
pubmed-meshheading:21114537-Telomere-Binding Proteins,
pubmed-meshheading:21114537-Vascular Cell Adhesion Molecule-1,
pubmed-meshheading:21114537-fms-Like Tyrosine Kinase 3
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pubmed:year |
2011
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pubmed:articleTitle |
FLT3/?ITD regulates leukaemia cell adhesion through ?4?1 integrin and Pyk2 signalling.
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pubmed:affiliation |
Division of Transfusion Medicine and Cell Therapy, National Center for Geriatrics and Gerontology, 35 Gengo, Morioka-cho, Obu 474-8511, Japan. katsumi@ncgg.go.jp
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
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