Phosphorylation of Tyr245 in the open‐inhibited state of Abelson kinase does not induce downstream signaling

Abstract

Binding of tyrosine kinase inhibitors such as imatinib was shown to induce a novel open‐inhibited conformation of BCR‐ABL, in which Tyr245 is exposed and prone to phosphorylation. To evaluate whether this leads to priming of the kinase in cellular systems, we probed activation of downstream signaling as a result of Tyr245 phosphorylation in a series of cellular washout experiments. While a spike in Tyr245 phosphorylation was observed both in overexpression and endogenous settings, no induction of downstream signaling was detected, showing that the priming hypothesis is not relevant for the therapeutic situation.