Function and signal transduction mediated by the interleukin 3 receptor system in hematopoiesis.
Interleukin 3 (IL-3) promotes development of hematopoietic cells through activation of the IL-3 receptor (IL-3R) complex consisting of alpha and beta subunits. The alpha subunit binds IL-3 with low affinity and forms a high-affinity receptor with the common beta subunit (beta c). The beta c subunit does not bind any cytokine by itself but is involved in the formation of high-affinity functional receptors for IL-5 and GM-CSF. As the alpha subunits provide the specificity to cytokines and beta c plays a major role in signal transduction, IL-3, GM-CSF and IL-5 exhibit similar functions when they act on the same cells. Surprisingly, no apparent hematological defect other than a reduced number of eosinophils was found in knock-out mice lacking an entire function of IL-3, GM-CSF and IL-5; this indicates a remarkable functional overlap with other cytokine systems for hematopoiesis. Binding of the cytokines to the receptor induces activation of the JAK2 tyrosine kinase that associates with beta c and triggers the signaling events. The membrane proximal region of beta c is responsible for activation of JAK2 and STAT5, as well as for induction of c-myc. The signals induced by this region are required for cell-cycle progression and DNA synthesis. Activation of the Ras pathway requires the distal region of beta c and is involved in the suppression of apoptosis. Proliferation of hematopoietic cells requires signals for both DNA synthesis and anti-apoptosis. In this review, we describe the recent findings of the function and signal transduction mediated by the IL-3R system.
Hara
T
T
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Miyajima
A
A
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D011905:Genes, ras; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006410:Hematopoiesis; D006801:Humans; D015848:Interleukin-5 / Q000502:physiology; D053614:Janus Kinase 2; D051379:Mice; D008894:Milk Proteins; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016185:Receptors, Interleukin-3 / Q000502:physiology*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D015848:Interleukin-5; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D016185:Receptors, Interleukin-3; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2