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RESEARCH PRODUCT

Multifaceted roles of GSK-3 and Wnt/beta-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention

Massimo LibraLucio CoccoMelchiorre CervelloJames A. MccubreyGiuseppe MontaltoAntonino B. D'assoroFred E. BertrandFerdinando NicolettiNicole Marie DavisLinda S. SteelmanRoberta MaestroStephen L. AbramsAlberto M. MartelliJörg Bäsecke

subject

MAPK/ERK pathwayCancer ResearchBeta-catenintherapy resistanceCarcinogenesisWnt ProteinReviewmacromolecular substancesAkt; GSK-3; leukemia stem cells; targeted therapy; therapy resistance; Wnt/b-cateninWNTGlycogen Synthase Kinase 3GSK-3PTENAnimalsHumansHematopoiesiProtein kinase BCarcinogenesiPI3K/AKT/mTOR pathwaybeta CateninWnt/β-cateninGSK-3LeukemiabiologyAnimalKinaseAktleukemia stem cellWnt signaling pathwayHematologyleukemia stem cellstargeted therapy3. Good healthHematopoiesisWnt ProteinsAnesthesiology and Pain MedicineOncologyCancer researchbiology.proteinWnt/b-cateninHuman

description

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. © 2014 Macmillan Publishers Limited.

yearjournalcountryeditionlanguage
2013-07-01
10.1038/leu.2013.184.http://hdl.handle.net/11585/261282