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.
Agami
R
R
Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
Shaul
Y
Y
D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation / Q000235:genetics; D018816:Genes, cdc; D006367:HeLa Cells; D006801:Humans; D009698:Nucleoproteins / Q000378:metabolism; D016374:Oncogene Proteins v-abl / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation; D055232:Proline-Rich Protein Domains; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics*; D011994:Recombinant Proteins / Q000494:pharmacology; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D004268:DNA-Binding Proteins; D009698:Nucleoproteins; D016374:Oncogene Proteins v-abl; D010455:Peptides; D011991:Receptors, Virus; D011994:Recombinant Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl