title: Depletion of Pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 by Bcr-Abl promotes chronic myelogenous leukemia cell proliferation through continuous phosphorylation of Akt isoforms.
abstract: The constitutive activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway commonly occurs in cancers and is a crucial event in tumorigenesis. Chronic myelogenous leukemia (CML) is characterized by a reciprocal chromosomal translocation (9;22) that generates the Bcr-Abl fusion gene. The PI3K/Akt pathway is activated by Bcr-Abl chimera protein and mediates the leukemogenesis in CML. However, the mechanism by which Bcr-Abl activates the PI3K/Akt pathway is not completely understood. In the present study, we found that pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1 and PHLPP2) were depleted in CML cells. We investigated the interaction between PHLPPs and Bcr-Abl in CML cell lines and Bcr-Abl+ progenitor cells from CML patients. The Abl kinase inhibitors and depletion of Bcr-Abl induced the expression of PHLPP1 and PHLPP2, which dephosphorylated Ser-473 on Akt1, -2, and -3, resulting in inhibited proliferation of CML cells. The reduction of PHLPP1 and PHLPP2 expression by short interfering RNA in CML cells weakened the Abl kinase inhibitor-mediated inhibition of proliferation. In colony-forming unit-granulocyte, erythroid, macrophage, megakaryocyte; colony-forming unit-granulocyte, macrophage; and burst-forming unit-erythroid, treatment with the Abl kinase inhibitors and depletion of Bcr-Abl induced PHLPP1 and PHLPP2 expression and inhibited colony formation of Bcr-Abl+ progenitor cells, whereas depletion of PHLPP1 and PHLPP2 weakened the inhibition of colony formation activity by the Abl kinase inhibitors in Bcr-Abl+ progenitor cells. Thus, Bcr-Abl represses the expression of PHLPP1 and PHLPP2 and continuously activates Akt1, -2, and -3 via phosphorylation on Ser-473, resulting in the proliferation of CML cells.
authors.affiliation: Department of Internal Medicine III, Hamamatsu, Shizuoka 431-3192, Japan; Cancer Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Hirano
authors.affiliation: Department of Internal Medicine III, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Satoki
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Internal Medicine III, Hamamatsu, Shizuoka 431-3192, Japan; Cancer Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yokota
authors.affiliation: Department of Internal Medicine III, Hamamatsu, Shizuoka 431-3192, Japan; Cancer Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ono
authors.affiliation: Department of Internal Medicine III, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Shigeno
authors.affiliation: Division of Hematology, Hamamatsu Medical Center, 328 Tomitsuka, Naka-ku, Hamamatsu, Shizuoka 432-8580, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujisawa
authors.affiliation: Department of Internal Medicine III, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Shinjo
authors.affiliation: Department of Internal Medicine III, Hamamatsu, Shizuoka 431-3192, Japan; Cancer Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ohnishi
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D009687:Nuclear Proteins; D020033:Protein Isoforms; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; D051057:Proto-Oncogene Proteins c-akt; C400601:PHLPP1 protein, human; C541572:PHLPP2 protein, human; D010749:Phosphoprotein Phosphatases