title: Phosphorylation of Tyr245 in the open-inhibited state of Abelson kinase does not induce downstream signaling.
abstract: Binding of tyrosine kinase inhibitors such as imatinib was shown to induce a novel open-inhibited conformation of BCR-ABL, in which Tyr245 is exposed and prone to phosphorylation. To evaluate whether this leads to priming of the kinase in cellular systems, we probed activation of downstream signaling as a result of Tyr245 phosphorylation in a series of cellular washout experiments. While a spike in Tyr245 phosphorylation was observed both in overexpression and endogenous settings, no induction of downstream signaling was detected, showing that the priming hypothesis is not relevant for the therapeutic situation.
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Skora
authors.affiliation: Autoimmunity, Transplantation and Inflammatory Disease, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Kempf
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.affiliation: Autoimmunity, Transplantation and Inflammatory Disease, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: D'Orazio
authors.affiliation: Center for Proteomic Chemistry, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jahnke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism*
chemical_list: C513733:ABI1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D050799:STAT5 Transcription Factor; D014443:Tyrosine; D016044:Fusion Proteins, bcr-abl
keywords: Abelson kinase; GNF-5; chronic myelogenous leukemia; imatinib; kinase priming