Molecular cloning and characterization of p56dok-2 defines a new family of RasGAP-binding proteins.

Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Chronic myelogenous leukemia (CML) is a disease characterized by the presence of p210(bcr-abl), a chimeric protein with tyrosine kinase activity. Substrates for p210(bcr-abl) are likely to be involved in the pathogenesis of CML. Here we describe the purification, cDNA cloning, and characterization of a 56-kDa tyrosine phosphorylated protein, p56(dok-2) (Dok-2), from p210(bcr-abl) expressing cells. The human dok-2 cDNA encodes a 412-amino acid protein with a predicted N-terminal pleckstrin homology domain as well as several other features of a signaling molecule, including 13 potential tyrosine phosphorylation sites, six PXXP motifs, and the ability to bind to p120(RasGAP). Dok-2 was shown to be 35% identical to p62(dok-1), a recently identified RasGAP binding protein from CML cells, and analysis of the expressed sequence tag data base revealed the presence of at least four additional proteins containing a Dok homology sequence motif. Dok mRNAs were primarily expressed in tissues of hematopoietic origin. These findings strongly suggest that a family of Dok-related proteins exists that bind to RasGAP and may mediate the effects of p210(bcr-abl) in CML.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, Cloning, Molecular, DNA, Complementary, DNA-Binding Proteins, Fusion Proteins, bcr-abl, GTPase-Activating Proteins, Hematopoietic Stem Cells, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mice, Molecular Sequence Data, Phosphoproteins, Phosphorylation, Protein Binding, Protein-Tyrosine Kinases, Proteins, RNA-Binding Proteins, Sequence Homology, Amino Acid, Signal Transduction, Tissue Distribution
J. Biol. Chem. Feb. 27, 1998; 273(9);4827-30 [PUBMED:9478921]
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