title: PAK-dependent STAT5 serine phosphorylation is required for BCR-ABL-induced leukemogenesis.
abstract: The transcription factor STAT5 (signal transducer and activator of transcription 5) is frequently activated in hematological malignancies and represents an essential signaling node downstream of the BCR-ABL oncogene. STAT5 can be phosphorylated at three positions, on a tyrosine and on the two serines S725 and S779. We have investigated the importance of STAT5 serine phosphorylation for BCR-ABL-induced leukemogenesis. In cultured bone marrow cells, expression of a STAT5 mutant lacking the S725 and S779 phosphorylation sites (STAT5(SASA)) prohibits transformation and induces apoptosis. Accordingly, STAT5(SASA) BCR-ABL(+) cells display a strongly reduced leukemic potential in vivo, predominantly caused by loss of S779 phosphorylation that prevents the nuclear translocation of STAT5. Three distinct lines of evidence indicate that S779 is phosphorylated by group I p21-activated kinase (PAK). We show further that PAK-dependent serine phosphorylation of STAT5 is unaffected by BCR-ABL tyrosine kinase inhibitor treatment. Interfering with STAT5 phosphorylation could thus be a novel therapeutic approach to target BCR-ABL-induced malignancies.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Berger
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Hoelbl-Kovacic
authors.affiliation: GICC CNRS UMR 7292, Université François Rabelais, Tours, France.
authors.forename: J
authors.initials: J
authors.lastname: Bourgeais
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Hoefling
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Warsch
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Grundschober
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: I Z
authors.initials: IZ
authors.lastname: Uras
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: I
authors.initials: I
authors.lastname: Menzl
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: E M
authors.initials: EM
authors.lastname: Putz
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Hoermann
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), Office of Technology Transfer T010, Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schuster
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Fajmann
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Leitner
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Kubicek
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: GICC CNRS UMR 7292, Université François Rabelais, Tours, France.
authors.forename: F
authors.initials: F
authors.lastname: Gouilleux
authors.affiliation: Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Vienna, Austria.
authors.forename: V
authors.initials: V
authors.lastname: Sexl
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D017931:DNA Primers; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D007938:Leukemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D050799:STAT5 Transcription Factor; D012694:Serine; D016044:Fusion Proteins, bcr-abl; D054462:p21-Activated Kinases