Modification of EWS/WT1 functional properties by phosphorylation

In many human cancers, tumor-specific chromosomal rearrangements are known to create chimeric products with the ability to transform cells. The EWS/WT 1 protein is such a fusion product resulting from a t(11;22) chromosomal tr anslocation in desmoplastic small round cell tumors, where 265 aa from the EWS amino terminus are fused to the DNA binding domain of the WT1 tumor sup pressor gene. Herein, we find that EWS/WT1 is phosphorylated in vivo on ser ine and tyrosine residues and that this affects DNA binding and homodimeriz ation. We also show that EWS/WT1 can interact with, and is a substrate for, modification on tyrosine residues by c-Abl. Tyrosine phosphorylation of EW S/WT1 by c-Abl negatively regulates its DNA binding properties. These resul ts indicate that the biological activity of EWS/WT1 is closely linked to it s phosphorylation status.