A new isoform of interleukin-3 receptor α with a novel differentiation activity and high affinity binding mode
Date
2009
Authors
Chen, Jinglong
Olsen, Jane
Ford, Sally
Mirza, Shamaruh
Walker, Andrew
Murphy, James M
Young, Ian
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American Society for Biochemistry and Molecular Biology Inc
Abstract
Interleukin-3 (IL-3) promotes both self-renewal and differentiation of early multipotential progenitors and is involved in inducible hematopoiesis in response to infections. Here we report new insights into these processes with the identification of a new isoform (SP2) of IL-3 receptor α (IL-3Rα), present in mouse and human hematopoietic cells, which lacks domain 1 of the full-length receptor (SP1). Binding assays with βIL-3 mutants showed that mouse SP2 uses a different high affinity binding mode to SP1, although both mouse and human SP2 and SP1 can stimulate IL-3-dependent growth. In IL-3-dependent differentiation models, human SP2 and SP1 gave differential effects on lineage commitment or self-renewal dependent on the cellular context, suggesting that different modes of ectodomain binding may modulate intracellular signaling. In a multipotential factor dependent cell-Paterson mix, the transcription factors C/EBPα and PU.1 and microRNAs miRNA-15a, -223, and -181a were up-regulated in cells undergoing SP2-supported differentiation compared with SP1-supported self-renewal. Similarly in M1 cells, SP2 promoted differentiation compared with SP1 and gave up-regulation of PU.1 and miRNA-155 and -223. These findings suggest that IL-3-promoted lineage commitment uses similar mechanisms to those of steady-state hematopoiesis. Both the SP1 and SP2 isoforms activated the Jak2/STAT5, Akt, and Erk1/2 signaling pathways in M1 cells, although the activation was more prolonged for the SP2 isoform.
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Keywords: Binding assays; Cellular contexts; Different modes; Differential effect; Ectodomain; Hematopoietic cell; High affinity binding; In-cell; Interleukin-3; Intracellular signaling; Isoform; Isoforms; MicroRNAs; Signaling pathways; Up-regulation; Binding energ
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Journal of Biological Chemistry
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Journal article
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2037-12-31
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