Research ArticleCancer

Global Phosphoproteomics Reveals Crosstalk Between Bcr-Abl and Negative Feedback Mechanisms Controlling Src Signaling

Sci. Signal.  29 Mar 2011:
Vol. 4, Issue 166, pp. ra18
DOI: 10.1126/scisignal.2001314

You are currently viewing the editor's summary.

View Full Text
As a service to the community, AAAS/Science has made this article free with registration.

When Negative Feedback Fails

Bcr-Abl is a fusion protein with tyrosine kinase activity that causes some forms of leukemia. Bcr-Abl activates Src family tyrosine kinases (SFKs), but resistance to drugs, such as dasatinib and imatinib, that target Bcr-Abl and SFKs limits their clinical usefulness. With global tyrosine phosphoproteomic analysis in a murine leukemia cell line model, Rubbi et al. identified several negative feedback mechanisms that limited SFK activity and showed that their effectiveness was blunted by Bcr-Abl. Sensitivity of human leukemia cell lines to imatinib correlated with the amount of negative feedback signaling to SFKs. By exploring the mechanisms by which Bcr-Abl overpowered the negative feedback, the authors identified potential therapeutic targets for treating leukemias resistant to Bcr-Abl and SFK inhibitors or that may be combined with these tyrosine kinase inhibitors to prevent the development of resistance.