The kinase activity of c-Abl but not v-Abl is potentiated by direct interaction with RFXI, a protein that binds the enhancers of several viruses and cell-cycle regulated genes.

c-Abl, the non-receptor tyrosine kinase is associated with EP, a DNA element found in promoters/enhancers of different viruses and cell-cycle regulated genes. EP-DNA binds RFXI, a member of a novel family of DNA-binding proteins that is conserved through evolution and in yeast, it controls differentiation and exit from the mitotic cycle to G0. EP-associated proteins are preferentially tyrosine phosphorylated and the associated c-Abl has strong tyrosine kinase activity. Here we investigated the molecular mechanism underlying this c-Abl kinase activity. We show that RFXI and c-Abl are in direct interaction, in vitro and in cell extracts, through the RFXI proline rich (PxxP) motif and the c-Abl SH3 domain. Remarkably, this interaction significantly potentiates c-Abl but not v-Abl auto-kinase activity. Collectively, we describe a novel mechanism of c-Abl recruitment to a defined DNA-cis element with its concomitant kinase activation. We propose that this mechanism may act to regulate cell-cycle control genes.