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

J. A. McCubrey, L. S. Steelman, F. E. Bertrand, N. M. Davis, S. L. Abrams, G. Montalto, A. B. D'Assoro, M. Libra, F. Nicoletti, R. Maestro, J. Basecke, L. Cocco, M. Cervello, A. M. Martelli

Research output: Contribution to journalReview article

145 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)15-33
Number of pages19
JournalLeukemia
Volume28
Issue number1
DOIs
StatePublished - 2014

Keywords

  • Akt
  • GSK-3
  • Wnt/b-catenin
  • leukemia stem cells
  • targeted therapy
  • therapy resistance

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    McCubrey, J. A., Steelman, L. S., Bertrand, F. E., Davis, N. M., Abrams, S. L., Montalto, G., D'Assoro, A. B., Libra, M., Nicoletti, F., Maestro, R., Basecke, J., Cocco, L., Cervello, M., & Martelli, A. M. (2014). Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: Opportunities for therapeutic intervention. Leukemia, 28(1), 15-33. https://doi.org/10.1038/leu.2013.184