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Sci. Signal., 29 March 2011
Vol. 4, Issue 166, p. ra18
[DOI: 10.1126/scisignal.2001314]

RESEARCH ARTICLES

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

Liudmilla Rubbi1,2,3,4*, Björn Titz1,2,3,4*, Lauren Brown1,2,3,4, Erica Galvan1,2,3,4, Evangelia Komisopoulou1,2,3,4, Sharon S. Chen1,2,3,4, Tracey Low1,2,3,4, Martik Tahmasian1,2,3,4, Brian Skaggs5, Markus Müschen6, Matteo Pellegrini7,8, and Thomas G. Graeber1,2,3,4,8{dagger}

1 Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
2 Institute for Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
3 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
4 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
5 Division of Rheumatology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
6 Department of Laboratory Medicine, University of California, San Francisco, CA 94143, USA.
7 Institute for Genomics and Proteomics; Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
8 California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA.

* These authors contributed equally to this work.

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.

{dagger} To whom correspondence should be addressed. E-mail: tgraeber{at}mednet.ucla.edu

Citation: L. Rubbi, B. Titz, L. Brown, E. Galvan, E. Komisopoulou, S. S. Chen, T. Low, M. Tahmasian, B. Skaggs, M. Müschen, M. Pellegrini, T. G. Graeber, Global Phosphoproteomics Reveals Crosstalk Between Bcr-Abl and Negative Feedback Mechanisms Controlling Src Signaling. Sci. Signal. 4, ra18 (2011).

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