Molecular Cloning and Characterization of p56dok-2Defines a New Family of RasGAP-binding Proteins

Antonio Di Cristofano, Nick Carpino, Nicolas Dunant, Gayle Friedland, Ryuji Kobayashi, Annabel Strife, David Wisniewski, Bayard Clarkson, Pier Paolo Pandolfi, Marilyn D. Resh
1998 Journal of Biological Chemistry  
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 412amino acid protein with a predicted N-terminal pleckstrin homology
more » ... omain 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. Human chronic myelogenous leukemia (CML) 1 is a myelo-proliferative disease (reviewed in Ref. 1) characterized by the presence of a chromosomal translocation known as the Philadelphia chromosome. Cells from CML patients contain a t(9;22) translocation in which the 5Ј exons of the bcr (breakpoint cluster) gene on chromosome 22 are fused to the c-abl protooncogene on chromosome 9 (2). The most common fusion generates the chimeric protein p210 bcr-abl responsible for CML.
doi:10.1074/jbc.273.9.4827 pmid:9478921 fatcat:yedq4ir77ratxnoga2lgvpji4u