title: Constitutive activation of Stat5 promotes its cytoplasmic localization and association with PI3-kinase in myeloid leukemias.
abstract: Persistent activation of Stat5 is frequently found in hematologic neoplasms. Studies conducted with constitutively active Stat5 mutants (Stat51*6 and cS5F) have shown that deregulated Stat5 activity promotes leukemogenesis. To investigate the oncogenic properties of these mutants, we used cS5F-expressing bone marrow cells which induce a multilineage leukemia when transplanted into recipient mice. Here, we show by immunocytochemistry that cS5F is localized mainly in the cytoplasmic compartment of leukemic cells, suggesting that the transforming nature of cS5F may be associated with a cytoplasmic function. In support of this hypothesis, we found that cS5F forms a complex with the p85 subunit of the phosphatidylinositol 3-kinase (PI3-K) and the scaffolding adapter Gab2 in leukemic bone marrow cells, resulting in the activation of Akt/PKB, a crucial downstream target of PI3-K. By using transducible TAT-Gab2 or TAT-Akt recombinant proteins, we were able to demonstrate that activation of the PI3-kinase/Akt pathway by cS5F molecules through Gab2 is essential for induction of cell growth. We also found that persistently phosphorylated Stat5 in primary cells from patients with myeloid leukemias has a cytoplasmic localization. These data suggest that oncogenic Stat5 proteins exert dual transforming capabilities not only as transcriptional activators but also as cytoplasmic signaling effectors.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (EMI 351), Amiens, France.
authors.forename: Noria
authors.initials: N
authors.lastname: Harir
authors.forename: Christian
authors.initials: C
authors.lastname: Pecquet
authors.forename: Marc
authors.initials: M
authors.lastname: Kerenyi
authors.forename: Karoline
authors.initials: K
authors.lastname: Sonneck
authors.forename: Boris
authors.initials: B
authors.lastname: Kovacic
authors.forename: Remy
authors.initials: R
authors.lastname: Nyga
authors.forename: Marie
authors.initials: M
authors.lastname: Brevet
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dhennin
authors.forename: Valerie
authors.initials: V
authors.lastname: Gouilleux-Gruart
authors.forename: Hartmut
authors.initials: H
authors.lastname: Beug
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.forename: Kaiss
authors.initials: K
authors.lastname: Lassoued
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.forename: Fabrice
authors.initials: F
authors.lastname: Gouilleux
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D003593:Cytoplasm / Q000737:chemistry; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D050799:STAT5 Transcription Factor; C490894:Gab2 protein, mouse