Activation of c-Abl kinase activity and transformation by a chemical inducer of dimerization

c-Abl is a non-receptor tyrosine kinase that is activated in human leukemia s by the fusion of Bcr or Tel sequences to the Abl NH, terminus. Although B cr and Tel have little in common, both contain oligomerization domains. To determine whether oligomerization alone is sufficient to activate c-Abl, we have generated and characterized an Abl protein that can be activated sele ctively with the chemical inducer of dimerization, AP1510. Mutant Abl prote ins with one (c4F1) or two (c4F2) copies of the AP1510 binding motif (FKBP) transformed NIH 3T3 cells in a ligand-dependent manner with the c4F2 prote in 60-fold more potent than c4F1, Both chimeric proteins exhibited ligand-d ependent dimerization in vivo, suggesting that the increased transformation efficiency of the c4F2 mutant reflects more effective dimerization rather than formation of higher order oligomers. In the absence of ligand, c4F2-ex presssing fibroblasts morphologically reverted and arrested in G(1) In Ba/F 3 cells, the c4F2 chimera exhibited Ligand-dependent kinase activation, tra nsformation to interleukin S-independent growth, and relocalization of the fusion protein from nucleus to cytoplasm. These results demonstrate that di merization alone is sufficient to activate the Abl kinase and provide a met hod to regulate conditionally c-Abl activity that will be useful for studyi ng the normal physiological role of c-Abl and the mechanism of transformati on and leukemogenesis.