A New Isoform of Interleukin-3 Receptor alpha with Novel Differentiation Activity and High Affinity Binding Mode
- Details
- Publication Year 2009-02-27,Volume 284,Issue #9,Page 5763-5773
- Journal Title
- JOURNAL OF BIOLOGICAL CHEMISTRY
- Publication Type
- Journal Article
- 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 alpha(IL-3R alpha), present in mouse and human hematopoietic cells, which lacks domain 1 of the full-length receptor (SP1). Binding assays with beta(IL-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/EBP alpha 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.
- Publisher
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- Keywords
- COLONY-STIMULATING FACTOR; HEMATOPOIETIC STEM-CELLS; ACUTE MYELOGENOUS LEUKEMIA; COMMON BETA-SUBUNIT; GM-CSF; SELF-RENEWAL; STRUCTURAL BASIS; MOUSE BASOPHIL; MAST-CELL; IN-VITRO
- Publisher's Version
- https://doi.org/10.1074/jbc.M808197200
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- Refer to copyright notice on published article.
Creation Date: 2009-02-27 12:00:00