Tyrosine phosphorylation of p62(dok) by p210(bcr-abl) inhibits RasGAP activity

Kashige, N., Carpino, N., Kobayashi, R. (February 2000) Tyrosine phosphorylation of p62(dok) by p210(bcr-abl) inhibits RasGAP activity. Proceedings of the National Academy of Sciences of the United States of America, 97 (5). pp. 2093-2098. ISSN 0027-8424

URL: http://www.ncbi.nlm.nih.gov/pubmed/10688886
DOI: 10.1073/pnas.040547997

Abstract

The t(9;22) chromosomal translocation is found in almost all patients with chronic myelogenous leukemia, The resultant Bcr-Abl fusion gene expresses a chimeric fusion protein p210(bcr-abl) with increased tyrosine kinase activity, Hematopoietic progenitors isolated from chronic myelogenous leukemia patients in the chronic phase contain constitutively tyrosine-phosphorylated p62(dok) protein, p62dok associates with the Ras GTPase-activating protein (RasGAP), but only when p62(dok) is tyrosine phosphorylated. Here we have investigated the interaction between p62(dok) and RasGAP and the consequences of p62(dok) tyrosine phosphorylation on the activity of RasGAP. We have found that p62(dok) is directly tyrosine phosphorylated by p210(bcr-abl), and the sites of phosphorylation are located in the C-terminal half of the p62(dok) molecule. We have identified five tyrosine residues that are involved in in vitro RasGAP binding and have found that tyrosine-phosphorylated p62(dok) inhibits RasGAP activity, Our results suggest that p210(bcr-abl) might lead to the activation of the Ras signaling pathway by inhibiting a key down-regulator of Ras signaling.

Item Type: Paper
Uncontrolled Keywords: chronic myelogenous leukemia Ras GTPASE-ACTIVATING PROTEIN CHRONIC MYELOGENOUS LEUKEMIA PLECKSTRIN HOMOLOGY DOMAIN SIGNAL-TRANSDUCTION DOCKING PROTEIN KINASE-ACTIVITY SH2 DOMAIN C-ABL GAP BINDING
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > GTPase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > G protein
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > G protein > Ras
CSHL Authors:
Communities: CSHL labs > Kobayashi lab
Depositing User: Matt Covey
Date: February 2000
Date Deposited: 28 Jan 2014 19:36
Last Modified: 28 Jan 2014 19:36
PMCID: PMC15759
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29458

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