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Function and Signal Transduction Mediated by the Interleukin 3 Receptor System in Hematopoiesis

Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan

Key Words. IL-3 • Cytokine receptor • Common ß subunit • JAK-STAT pathway • Ras • Colony-stimulating factor

Dr. Takahiko Hara, Institute of Molecular and Cellular Biosciences (IMCB), The University of Tokyo, 1-1-1 Yayoi Bunkyo-ku, Tokyo 113, Japan.

Interleukin 3 (IL-3) promotes development of hematopoietic cells through activation of the IL-3 receptor (IL-3R) complex consisting of and ß subunits. The subunit binds IL-3 with low affinity and forms a high-affinity receptor with the common ß subunit (ß_C). The ß_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 subunits provide the specificity to cytokines and ß_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 ß_C and triggers the signaling events. The membrane proximal region of ß_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 ß_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.

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