Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
2002-4-1
pubmed:abstractText
Vav is a guanine nucleotide exchange factor for the Rho/Rac family predominantly expressed in hematopoietic cells and implicated in cell proliferation and cytoskeletal organization. The oncogenic tyrosine kinase Bcr-Abl has been shown to activate Rac-1, which is important for Bcr-Abl induced leukemogenesis. Previous studies by Matsuguchi et al. (Matsuguchi, T., Inhorn, R. C., Carlesso, N., Xu, G., Druker, B., and Griffin, J. D. (1995) EMBO J. 14, 257-265) describe enhanced phosphorylation of Vav in Bcr-Abl-expressing Mo7e cells yet fail to demonstrate association of the two proteins. Here, we report the identification of a direct complex between Vav and Bcr-Abl in yeast, in vitro and in vivo. Furthermore, we show tyrosine phosphorylation of Vav by Bcr-Abl. Mutational analysis revealed that the SH2 domain and the C-terminal SH3 domain as well as a tetraproline motif directly adjacent to the N-terminal SH3 domain of Vav are important for establishing this phosphotyrosine dependent interaction. Activation of Rac-1 by Bcr-Abl was abrogated by co-expression of the Vav C terminus encoding the SH3-SH2-SH3 domains as a dominant negative construct. Bcr-Abl transduced primary bone marrow from Vav knock-out mice showed reduced proliferation in a culture cell transformation assay compared with wild-type bone marrow. These results suggest, that Bcr-Abl utilizes Vav as a guanine nucleotide exchange factor to activate Rac-1 in a process that involves a folding mechanism of the Vav C terminus. Given the importance of Rac-1 activation for Bcr-Abl-mediated leukemogenesis, this mechanism may be crucial for the molecular pathogenesis of chronic myeloid leukemia and of importance for other signal transduction pathways leading to the activation of Rac-1.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins, http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary, http://linkedlifedata.com/resource/pubmed/chemical/Fusion Proteins, bcr-abl, http://linkedlifedata.com/resource/pubmed/chemical/Glutathione Transferase, http://linkedlifedata.com/resource/pubmed/chemical/Proline, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-vav, http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine, http://linkedlifedata.com/resource/pubmed/chemical/VAV1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Vav1 protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/rac1 GTP-Binding Protein
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
5
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
12437-45
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:11790798-3T3 Cells, pubmed-meshheading:11790798-Animals, pubmed-meshheading:11790798-Bone Marrow Cells, pubmed-meshheading:11790798-Cell Cycle Proteins, pubmed-meshheading:11790798-Cell Line, pubmed-meshheading:11790798-DNA, Complementary, pubmed-meshheading:11790798-Electrophoresis, Polyacrylamide Gel, pubmed-meshheading:11790798-Enzyme Activation, pubmed-meshheading:11790798-Fusion Proteins, bcr-abl, pubmed-meshheading:11790798-Genes, Dominant, pubmed-meshheading:11790798-Glutathione Transferase, pubmed-meshheading:11790798-Humans, pubmed-meshheading:11790798-Immunoblotting, pubmed-meshheading:11790798-Mice, pubmed-meshheading:11790798-Mice, Knockout, pubmed-meshheading:11790798-Phosphorylation, pubmed-meshheading:11790798-Plasmids, pubmed-meshheading:11790798-Precipitin Tests, pubmed-meshheading:11790798-Proline, pubmed-meshheading:11790798-Protein Binding, pubmed-meshheading:11790798-Protein Structure, Tertiary, pubmed-meshheading:11790798-Proto-Oncogene Proteins, pubmed-meshheading:11790798-Proto-Oncogene Proteins c-vav, pubmed-meshheading:11790798-Recombinant Fusion Proteins, pubmed-meshheading:11790798-Retroviridae, pubmed-meshheading:11790798-Signal Transduction, pubmed-meshheading:11790798-Temperature, pubmed-meshheading:11790798-Transfection, pubmed-meshheading:11790798-Two-Hybrid System Techniques, pubmed-meshheading:11790798-Tyrosine, pubmed-meshheading:11790798-rac1 GTP-Binding Protein, pubmed-meshheading:11790798-src Homology Domains
pubmed:year
2002
pubmed:articleTitle
Association of Bcr-Abl with the proto-oncogene Vav is implicated in activation of the Rac-1 pathway.
pubmed:affiliation
Department of Internal Medicine III, Laboratory of Leukemogenesis, Technical University of Munich, 81675, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't