The GM–CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling

Authors


Correspondence to:

Michael W. Parker

ACRF Rational Drug Discovery Centre and Biota Structural Biology Laboratory

St. Vincent's Institute of Medical Research

9 Princes Street

Fitzroy, Vic. 3065, Australia

Tel.: +613 928 82499

Fax: +613 941 62676

e-mail: mparker@svi.edu.au

Summary

Granulocyte–macrophage colony-stimulating factor (GM–CSF), interleukin-3 (IL-3), and IL-5 are members of a discrete family of cytokines that regulates the growth, differentiation, migration and effector function activities of many hematopoietic cells and immunocytes. These cytokines are involved in normal responses to infectious agents, bridging innate and adaptive immunity. However, in certain cases, the overexpression of these cytokines or their receptors can lead to excessive or aberrant initiation of signaling resulting in pathological conditions, with chronic inflammatory diseases and myeloid leukemias the most notable examples. Recent crystal structures of the GM–CSF receptor ternary complex and the IL-5 binary complex have revealed new paradigms of cytokine receptor activation. Together with a wealth of associated structure–function studies, they have significantly enhanced our understanding of how these receptors recognize cytokines and initiate signals across cell membranes. Importantly, these structures provide opportunities for structure-based approaches for the discovery of novel and disease-specific therapeutics. In addition, recent biochemical evidence has suggested that the GM–CSF/IL-3/IL-5 receptor family is capable of interacting productively with other membrane proteins at the cell surface. Such interactions may afford additional or unique biological activities and might be harnessed for selective modulation of the function of these receptors in disease.

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