The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyro
sine kinase (c-Abl) that has been implicated in processes of cell diff
erentiation, cell division, cell adhesion and stress response(1-4). Al
terations of ABL1 by chromosomal rearrangement or viral transduction c
an lead to malignant transformation(5,6). Activity of the c-Abl protei
n is negatively regulated by its SH3 domain through an unknown mechani
sm, and deletion of the SH3 domain turns ABL1 into an oncogene(7-10).
We present evidence for an intramolecular inhibitory interaction of th
e 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 c
ause a conformational change of the molecule and increase binding of t
he SH3 domain to peptide ligands. Individual mutation of two charged r
esidues in the SH3 and catalytic domain activates c-Abl, while inhibit
ion is restored in the double reciprocal mutant. We propose that regul
ators of c-Abl will have opposite effects on its activity depending on
their ability to favour or disrupt these intramolecular interactions.