Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Amino Acid Sequence
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Cloning, Molecular
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DNA, Complementary / genetics
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DNA-Binding Proteins*
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Fusion Proteins, bcr-abl / metabolism*
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GTPase-Activating Proteins
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Hematopoietic Stem Cells / chemistry
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / etiology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Mice
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Molecular Sequence Data
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Phosphoproteins / genetics
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Phosphoproteins / isolation & purification
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Phosphoproteins / metabolism*
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Phosphorylation
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Protein Binding
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Protein-Tyrosine Kinases / metabolism*
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Proteins / metabolism*
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RNA-Binding Proteins*
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Sequence Homology, Amino Acid
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Signal Transduction
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Tissue Distribution
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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DNA, Complementary
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DNA-Binding Proteins
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DOK1 protein, human
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DOK2 protein, human
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Dok1 protein, mouse
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Dok2 protein, mouse
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GAP-associated protein p62
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GTPase-Activating Proteins
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Phosphoproteins
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Proteins
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RNA-Binding Proteins
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl
Associated data
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GENBANK/AF034970
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GENBANK/AF035117