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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.

Author information

1
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.
2
David Geffen School of Medicine, Division of Rheumatology, University of California, Los Angeles CA 90095, USA.
3
Department of Laboratory Medicine, University of California, San Francisco CA 94143, USA.
4
Institute for Genomics and Proteomics; Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles CA 90095, USA.
5
California NanoSystems Institute, University of California, Los Angeles CA 90095, USA.
#
Contributed equally

Abstract

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.

PMID:
21447799
PMCID:
PMC4057100
DOI:
10.1126/scisignal.2001314
[Indexed for MEDLINE]
Free PMC Article

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