title: Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention.
abstract: Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/β-catenin, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), Notch and others. Moreover, we will discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. In summary, GSK-3 is a crucial regulatory kinase interacting with multiple pathways to control various physiological processes, as well as leukemia stem cells, leukemia progression and therapeutic resistance. GSK-3 and Wnt are clearly intriguing therapeutic targets.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Steelman
authors.affiliation: Department of Oncology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: F E
authors.initials: FE
authors.lastname: Bertrand
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Davis
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Abrams
authors.affiliation: Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Montalto
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: D'Assoro
authors.affiliation: Department of Bio-Medical Sciences, University of Catania, Catania, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Libra
authors.affiliation: Department of Bio-Medical Sciences, University of Catania, Catania, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Experimental Oncology 1, CRO IRCCS, National Cancer Institute, Aviano, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Maestro
authors.affiliation: 1] Department of Medicine, University of Göttingen, Göttingen, Germany [2] Sanct-Josef-Hospital Cloppenburg, Department of Hematology and Oncology, Cloppenburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Basecke
authors.affiliation: Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Cocco
authors.affiliation: Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare 'Alberto Monroy', Palermo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cervello
authors.affiliation: 1] Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy [2] Institute of Molecular Genetics, National Research Council-IOR, Bologna, Italy.
authors.forename: A M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006410:Hematopoiesis; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3