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Sci Signal. 2011 Mar 29;4(166):ra18. doi: 10.1126/scisignal.2001314.

Global phosphoproteomics reveals crosstalk between Bcr-Abl and negative feedback mechanisms controlling Src signaling.

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Crump Institute for Molecular Imaging; Institute for Molecular Medicine; Jonsson Comprehensive Cancer Center, California NanoSystems Institute, David Geffen School of Medicine, Department of Molecular & Medical Pharmacology, University of California, Los Angeles CA 90095, USA.
David Geffen School of Medicine, Division of Rheumatology, University of California, Los Angeles CA 90095, USA.
Department of Laboratory Medicine, University of California, San Francisco CA 94143, USA.
Institute for Genomics and Proteomics; Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles CA 90095, USA.
California NanoSystems Institute, University of California, Los Angeles CA 90095, USA.
Contributed equally


In subtypes and late stages of leukemias driven by the tyrosine kinase fusion protein Bcr-Abl, signaling by the Src family kinases (SFKs) critically contributes to the leukemic phenotype. We performed global tyrosine phosphoprofiling by quantitative mass spectrometry of Bcr-Abl-transformed cells in which the activities of the SFKs were perturbed to build a detailed context-dependent network of cancer signaling. Perturbation of the SFKs Lyn and Hck with genetics or inhibitors revealed Bcr-Abl downstream phosphorylation events either mediated by or independent of SFKs. We identified multiple negative feedback mechanisms within the network of signaling events affected by Bcr-Abl and SFKs and found that Bcr-Abl attenuated these inhibitory mechanisms. The C-terminal Src kinase (Csk)-binding protein Pag1 (also known as Cbp) and the tyrosine phosphatase Ptpn18 both mediated negative feedback to SFKs. We observed Bcr-Abl-mediated phosphorylation of the phosphatase Shp2 (Ptpn11), and this may contribute to the suppression of these negative feedback mechanisms to promote Bcr-Abl-activated SFK signaling. Csk and a kinase-deficient Csk mutant both produced similar globally repressive signaling consequences, suggesting a critical role for the adaptor protein function of Csk in its inhibition of Bcr-Abl and SFK signaling. The identified Bcr-Abl-activated SFK regulatory mechanisms are candidates for dysregulation during leukemia progression and acquisition of SFK-mediated drug resistance.

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