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.