Article

Site-Specific Serine Phosphorylation of the IL-3 Receptor Is Required for Hemopoietic Cell Survival

Department of Human Immunology, The Hanson Centre for Cancer Research, IMVS, Adelaide, South Australia, Australia.
Molecular Cell (Impact Factor: 14.46). 08/2000; 6(1):99-108. DOI: 10.1016/S1097-2765(05)00002-X
Source: PubMed

ABSTRACT In the hemopoietic compartment, IL-3, GM-CSF, and IL-5 receptors are major transducers of survival signals; however, the receptor-proximal events that determine this vital function have not been defined. We have found that IL-3 stimulation induces phosphorylation of Ser-585 of beta(c). This promotes the association of phospho-Ser-585 of beta(c) with 14-3-3 and the p85 subunit of PI 3-K. Mutation of Ser-585 specifically impairs the PI 3-K signaling pathway and reduces cell survival in response to IL-3. These results define a distinct IL-3 receptor-mediated survival pathway regulated by site-specific receptor serine phosphorylation and 14-3-3 binding and suggest that this novel mode of signaling may be utilized by disparate transmembrane receptors that have as a common theme the transduction of survival signals.

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    • "The activation of cell surface receptors like IL-3 and GM-CSF receptors ultimately regulates the Bcl-2 family of proteins to control whether a cell remains viable or commits to apoptosis (Chao et al. 1998; Vaux et al. 1988; Ekert et al. 2006). The observation that low concentrations of GM-CSF can maintain the viability of cytokine-dependent cells while not stimulating cell proliferation (Begley et al. 1986; Guthridge et al. 2000) suggests that it is possible for ligand– receptor binding to activate signaling pathways that regulate apoptosis, while not engaging those that drive proliferation and probably involves the phosphorylation of bc Ser585 (Guthridge et al. 2004, 2006). The flip side of survival signals transduced by GM-CSF and IL-3 is the initiation of apoptosis when these cytokine signals are lost. "
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    ABSTRACT: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pluripotent cytokine produced by many cells in the body, which regulates normal and malignant hemopoiesis as well as innate and adaptive immunity. GM-CSF assembles and activates its heterodimeric receptor complex on the surface of myeloid cells, initiating multiple signaling pathways that control key functions such as cell survival, cell proliferation, and functional activation. Understanding the molecular composition of these pathways, the interaction of the various components as well as the kinetics and dose-dependent mechanics of receptor activation provides valuable insights into the function of GM-CSF as well as the related cytokines, interleukin-3 and interleukin-5. This knowledge provides opportunities for the development of new therapies to block the action of these cytokines in hematological malignancy and chronic inflammation.
    Growth factors (Chur, Switzerland) 01/2012; 30(2):63-75. DOI:10.3109/08977194.2011.649919 · 3.09 Impact Factor
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    • "Our previous studies have shown that phosphorylation of Ser585 results in the binding of 14-3-3, while we and others have shown that phosphorylation of Tyr577 results in the binding of Shc (Durstin et al, 1996; Guthridge et al, 2000). One interpretation of the results in Figure 1 is that Ser585 and Tyr577 may regulate redundant signalling pathways and that it is only following mutation of both residues that a functional defect is revealed. "
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    ABSTRACT: Pleiotropism is a hallmark of cytokines and growth factors; yet, the underlying mechanisms are not clearly understood. We have identified a motif in the granulocyte macrophage-colony-stimulating factor receptor composed of a tyrosine and a serine residue that functions as a binary switch for the independent regulation of multiple biological activities. Signalling occurs either through Ser585 at lower cytokine concentrations, leading to cell survival only, or through Tyr577 at higher cytokine concentrations, leading to cell survival as well as proliferation, differentiation or functional activation. The phosphorylation of Ser585 and Tyr577 is mutually exclusive and occurs via a unidirectional mechanism that involves protein kinase A and tyrosine kinases, respectively, and is deregulated in at least some leukemias. We have identified similar Tyr/Ser motifs in other cell surface receptors, suggesting that such signalling switches may play important roles in generating specificity and pleiotropy in other biological systems.
    The EMBO Journal 03/2006; 25(3):479-89. DOI:10.1038/sj.emboj.7600948 · 10.75 Impact Factor
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    • "Mutation analysis of serine residues provides an answer to cell survival signals. Mutation analysis of serine residue at position 585 of the cytoplasmic domain βc subunit in response to GM-CSF was shown to recruit the adaptor protein 14-3-3ae and phosphatidyl inositol 3-OH kinase (Guthridge et al., 2000). This signal pathway is initially independent of the tyrosine phosphorylation pathway, i.e. phosphorylation of tyrosine residues will lead to the JAK-STAT pathway whereas serine phosphorylation will trigger activation PI-3 kinase and Akt (Guthridge et al., 2004). "
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    ABSTRACT: Stem cells that have totipotent, pluripotent and multipotent abilities can be divided into two main categories: embryonic stem cells and adult stem cells. Embryonic stem cells originate from the inner cell mass of the blastocyst stage during embryonic development whereas adult stem cells are derived from bone marrow. Stem cells have the ability to differentiate into mature cells or transdifferentiate into other tissues partly due to cellular signals triggered by the growth factors such as cytokines. Cytokines produce cellular signals through the cytoplasmic domain of their cognate receptor. Cytokine receptors have been categorised into several superfamilies followed by subfamilies partly due to structural similarities (extracellular and cytoplasmic domains) and combination of subunits. The ability of IL-3 to trigger differentiation not only to haemopoietic stem cells but also to liver stem cells might be a potential factor for transdifferentiation. IL-3, GM-CSF and IL-5 receptors are members of a common â subfamily because they share the same â subunit known as â common (âc). This review focuses on the â subfamily and in particular on their potential signalling pathways, i.e. proliferation, differentiation and survival that triggers at the cytoplasmic domain of both subunits (α subunits and âc) on the stem cells.
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