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Serine/threonine phosphorylation in cytokine signal transduction

Leukemia volume 14, pages 9–21 (2000)Cite this article

Abstract

Over the past decade, the involvement of tyrosine kinases in signal transduction pathways evoked by cytokines has been intensively investigated. Only relatively recently have the roles of serine/threonine kinases in cytokine-induced signal transduction and anti-apoptotic pathways been examined. Cytokine receptors without intrinsic kinase activity such as interleukin-3 (IL-3), granulocyte–macrophage colony-stimulating factor (GM-CSF) and the interferons were thought to transmit their regulatory signals primarily by the receptor-associated Jak family of tyrosine kinases. This family of tyrosine kinases activates STAT transcription factors, which subsequently transduced their signals into the nucleus to modulate gene expression. Cytokine receptors with intrinsic tyrosine kinase activity such as c-Kit were initially thought to transduce their signals independently of serine/threonine kinase cascades. Recently, both of these types of receptor signaling pathways have been shown to interact with serine/threonine kinase pathways as maximal activation of these tyrosine kinase regulated cascades involve serine/threonine phosphorylation modulated by, for example MAP kinases. A common intermediate pathway initiating from cytokine receptors is the Ras/Raf/MEK/ERK (MAPK) cascade, which can result in the phosphorylation and activation of additional downstream kinases and transcription factors such as p90Rsk, CREB, Elk and Egr-1. Serine/threonine phosphorylation is also involved in the regulation of the apoptosis-controlling Bcl-2 protein, as certain phosphorylation events induced by cytokines such as IL-3 are anti-apoptotic, whereas other phosphorylation events triggered by chemotherapeutic drugs such as Paclitaxel are associated with cell death. Serine/threonine phosphorylation is implicated in the etiology of certain human cancers as constitutive serine phosphorylation of STATs 1 and 3 is observed in chronic lymphocytic leukemia and can be inhibited by the chemotherapeutic drug fludarabine. Serine/threonine phosphorylation also plays a role in the etiology of immunodeficiencies. Activated STAT5 proteins are detected in reduced levels in lymphocytes recovered from HIV-infected individuals and immunocompromised mice. Serine/threonine phosphorylation may be an important target of certain chemotherapeutic drugs which recognize the activated proteins. This meeting report and mini-review will discuss the interactions of serine/threonine kinases with signal transduction and apoptotic molecules and how some of these pathways can be controlled by chemotherapeutic drugs.

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Acknowledgements

The meeting was organized by Dr Allan Mufson and occurred 30 and 31 March at the Georgetown Holiday Inn, Washington, DC, USA. JAM was supported in part by a grant from the National Institute of Health (R01 CA51025). We sincerely thank Ms Catherine Spruill for the outstanding artwork.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, East Carolina University School of Medicine, Greenville, NC, USA

    JA McCubrey

  2. Member Leo Jenkins Cancer Center, East Carolina University, USA

    JA McCubrey

  3. Sealy Center for Oncology/Hematology, UT Medical Branch at Galveston, Galveston, TX, USA

    W Stratford May

  4. Dept of Medicine, University of British Columbia and VH&HSC, Jack Bell Research Centre, Vancouver, BC, Canada

    V Duronio

  5. Cancer Immunology and Hematology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    A Mufson

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  1. JA McCubrey
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  4. A Mufson
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McCubrey, J., May, W., Duronio, V. et al. Serine/threonine phosphorylation in cytokine signal transduction. Leukemia 14, 9–21 (2000). https://doi.org/10.1038/sj.leu.2401657

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