Cytoplasmic domains of the common beta -chain of the GM-CSF/IL-3/IL-5 receptors that are required for inducing differentiation or clonal suppression in myeloid leukaemic cell lines

Interleukin-5 (IL-5) regulates the production and function of B cells, eosinophils, and basophils. The IL-5 receptor (IL-5R) consists of two distinct membrane proteins, alpha and beta. The alpha chain (IL-5R alpha) is specific to IL-5. The beta chain is the common beta chain (beta c) of receptors for IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF). The cytoplasmic domains of both alpha and beta chains are essential for signal transduction. In this study, we generated cDNAs of IL-5R alpha having various mutations in their cytoplasmic domains and examined the function of these mutants by expressing them in IL-3-dependent FDC-P1 cells. The membrane-proximal proline-rich sequence of the cytoplasmic domain of IL-5R alpha, which is conserved among the alpha chains of IL-5R, IL-3R, and GM-CSF receptor (GM-CSFR), was found to be essential for the IL-5-induced proliferative response, expression of nuclear proto-oncogenes such as c-jun, c-fos, and c-myc, and tyrosine phosphorylation of cellular proteins including JAK2 protein-tyrosine kinase. In addition, analysis using chimeric receptors which consist of the extracellular domain of IL-5R alpha and the cytoplasmic domain of beta c suggested that dimerization of the cytoplasmic domain of beta c may be an important step in activating the IL-5R complex and transducing intracellular growth signals.

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Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation.

The EMBO Journal ◽

10.1002/j.1460-2075.1992.tb05437.x ◽

1992 ◽

Vol 11 (10) ◽

pp. 3541-3549 ◽

Cited By ~ 243

Author(s):

K. Sakamaki ◽

I. Miyajima ◽

T. Kitamura ◽

A. Miyajima

Keyword(s):

Signal Transduction ◽

Tyrosine Phosphorylation ◽

Beta Subunit ◽

Cytoplasmic Domains ◽

Gm Csf ◽

The Common

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Spatial and temporal expression of CCR3 and the common beta chain of the IL-3, IL-5 and GM-CSF receptor in the nasal epithelium and lymphoid tissues in a rat model of allergic rhinitis

Cytokine ◽

10.1016/j.cyto.2010.07.005 ◽

2010 ◽

Vol 52 (3) ◽

pp. 194-202 ◽

Cited By ~ 7

Author(s):

Marylène Fortin ◽

James G. Wagner ◽

Julie Brault ◽

Jack R. Harkema ◽

Paolo M. Renzi ◽

...

Keyword(s):

Allergic Rhinitis ◽

Rat Model ◽

Nasal Epithelium ◽

Lymphoid Tissues ◽

Beta Chain ◽

Temporal Expression ◽

Gm Csf ◽

The Common

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The induction and inhibition of differentiation in normal and leukaemic cells

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1990.0046 ◽

1990 ◽

Vol 327 (1239) ◽

pp. 99-109 ◽

Cited By ~ 8

Keyword(s):

Cell Lines ◽

Cellular Response ◽

Embryonic Stem ◽

Leukaemic Cell ◽

Leukaemia Inhibitory Factor ◽

Functional Activities ◽

Gm Csf ◽

Cellular Processes ◽

Leukaemic Cells ◽

Inhibition Of Differentiation

For granulocytic-macrophage progenitor populations and their progeny, five glycoproteins have been identified: GM-CSF, G-CSF, multi-CSF, M-CSF and IL-6 that can regulate their proliferative activity, maturation and functional activities. The same glycoproteins also have a capacity to induce irreversible differentiation commitment in normal bipotential granulocyte-macrophage progenitors and in some myeloid leukaemic cell lines, which suggests that common cellular processes exist in both situations. The leukaemia inhibitory factor (LIF) is a glycoprotein, with intriguing properties, which can either induce differentiation in some myeloid leukaemic cell lines or prevent differentiation in normal totipotential embryonic stem cells. The data from the LIF studies suggest a genetic mechanism controlling self-generation that is relatively simple and may be common to all cells. However, the actual cellular response observed appears to depend on the nature of the responding cell.

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The IL-3, IL-5, and GM-CSF common receptor beta chain mediates oncogenic activity of FLT3-ITD-positive AML

Leukemia ◽

10.1038/s41375-021-01462-4 ◽

2021 ◽

Author(s):

Anne Charlet ◽

Max Kappenstein ◽

Philip Keye ◽

Kathrin Kläsener ◽

Cornelia Endres ◽

...

Keyword(s):

Cell Lines ◽

Insertion Site ◽

Disease Onset ◽

Xenograft Model ◽

Beta Chain ◽

Oncogenic Signaling ◽

Gm Csf ◽

Common Receptor ◽

Receptor Beta

AbstractFLT3-ITD is the most predominant mutation in AML being expressed in about one-third of AML patients and is associated with a poor prognosis. Efforts to better understand FLT3-ITD downstream signaling to possibly improve therapy response are needed. We have previously described FLT3-ITD-dependent phosphorylation of CSF2RB, the common receptor beta chain of IL-3, IL-5, and GM-CSF, and therefore examined its significance for FLT3-ITD-dependent oncogenic signaling and transformation. We discovered that FLT3-ITD directly binds to CSF2RB in AML cell lines and blasts isolated from AML patients. A knockdown of CSF2RB in FLT3-ITD positive AML cell lines as well as in a xenograft model decreased STAT5 phosphorylation, attenuated cell proliferation, and sensitized to FLT3 inhibition. Bone marrow from CSF2RB-deficient mice transfected with FLT3-ITD displayed decreased colony formation capacity and delayed disease onset together with increased survival upon transplantation into lethally irradiated mice. FLT3-ITD-dependent CSF2RB phosphorylation required phosphorylation of the FLT3 juxtamembrane domain at tyrosines 589 or 591, whereas the ITD insertion site and sequence were of no relevance. Our results demonstrate that CSF2RB participates in FLT3-ITD-dependent oncogenic signaling and transformation in vitro and in vivo. Thus, CSF2RB constitutes a rational treatment target in FLT3-ITD-positive AML.

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