The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine 
kinase (c-Abl) that has been implicated in processes of cell differentiation, 
cell division, cell adhesion and stress response. Alterations of ABL1 by 
chromosomal rearrangement or viral transduction can lead to malignant 
transformation. Activity of the c-Abl protein is negatively regulated by its SH3 
domain through an unknown mechanism, and deletion of the SH3 domain turns ABL1 
into an oncogene. We present evidence for an intramolecular inhibitory 
interaction of the SH3 domain with the catalytic domain and with the linker 
between the SH2 and catalytic domain (SH2-CD linker). Site-directed mutations in 
each of these three elements activate c-Abl. Mutations in the linker cause a 
conformational change of the molecule and increase binding of the SH3 domain to 
peptide ligands. Individual mutation of two charged residues in the SH3 and 
catalytic domain activates c-Abl, while inhibition is restored in the double 
reciprocal mutant. We propose that regulators of c-Abl will have opposite 
effects on its activity depending on their ability to favour or disrupt these 
intramolecular interactions.