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Activation of the TAL1 (or SCL) gene, initially identified through its involvement by a recurrent chromosomal translocation, is the most frequent gain-of-function mutation recognized in T-cell acute lymphoblastic leukemia. The translational products of this gene contain the basic domain helix-loop-helix motif characteristic of a family of transcription factors that bind to a consensus nucleotide sequence termed the E-box. Previous work established that the TAL1 proteins are phosphorylated exclusively on serine and identified Ser122 as a substrate for the mitogen-activated protein kinase ERK-1. We provide evidence that an additional serine residue, Ser172, located in a conserved region proximal to the DNA binding domain and sharing homology with a similarly positioned sequence in the HLH oncoprotein LYL1, can be phosphorylated in vitro and in vivo by the catalytic subunit of cAMP-dependent protein kinase. Phosphorylation was found to alter TAL1 DNA binding activity in a target-dependent manner that was influenced by both the specific CANNTG E-box core motif and its flanking sequences. In contrast, the ability of TAL1 to interact with the E2A gene product E12 and its subcellular localization in transfected COS cells were unaffected by Ser172 phosphorylation. These results suggest this serine residue has a regulatory function and indicate a mechanism by which phosphorylation could affect DNA binding site discrimination.