title: Differential signaling networks of Bcr-Abl p210 and p190 kinases in leukemia cells defined by functional proteomics.
abstract: The two major isoforms of the oncogenic Bcr-Abl tyrosine kinase, p210 and p190, are expressed upon the Philadelphia chromosome translocation. p210 is the hallmark of chronic myelogenous leukemia, whereas p190 occurs in the majority of B-cell acute lymphoblastic leukemia. Differences in protein interactions and activated signaling pathways that may be associated with the different diseases driven by p210 and p190 are unknown. We have performed a quantitative comparative proteomics study of p210 and p190. Strong differences in the interactome and tyrosine phosphoproteome were found and validated. Whereas the AP2 adaptor complex that regulates clathrin-mediated endocytosis interacts preferentially with p190, the phosphatase Sts1 is enriched with p210. Stronger activation of the Stat5 transcription factor and the Erk1/2 kinases is observed with p210, whereas Lyn kinase is activated by p190. Our findings provide a more coherent understanding of Bcr-Abl signaling, mechanisms of leukemic transformation, resulting disease pathobiology and responses to kinase inhibitors.
authors.affiliation: ISREC Foundation Chair in Translational Oncology, Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Reckel
authors.affiliation: Proteomics Core Facility, School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Hamelin
authors.affiliation: ISREC Foundation Chair in Translational Oncology, Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Georgeon
authors.affiliation: Proteomics Core Facility, School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Armand
authors.affiliation: Proteomics Core Facility, School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Q
authors.initials: Q
authors.lastname: Jolliet
authors.affiliation: Proteomics Core Facility, School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Chiappe
authors.affiliation: Proteomics Core Facility, School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Moniatte
authors.affiliation: ISREC Foundation Chair in Translational Oncology, Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: O
authors.initials: O
authors.lastname: Hantschel
mesh_terms: D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D007938:Leukemia / Q000201:enzymology*; D010766:Phosphorylation; D040901:Proteomics / Q000379:methods*; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D050799:STAT5 Transcription Factor; D016044:Fusion Proteins, bcr-abl