The structural basis of the biological actions of the GM-CSF receptor

Nicola, NA; Smith, A; Robb, L; Metcalf, D; Begley, CG; Nossal; Lieschke; Melchers; Dexter; Burgess; Paul; Rajewsky

Author(s): Nicola, NA; Smith, A; Robb, L; Metcalf, D; Begley, CG; Nossal; Lieschke; Melchers; Dexter; Burgess; Paul; Rajewsky;
Journal Title: MOLECULAR BASIS OF CELLULAR DEFENCE MECHANISMS
Publication Type: S
Abstract: The receptor for granulocyte/macrophage colony-stimulating factor (GM-CSF) consists of a ligand-specific low-affinity binding chain (GM-CSFR alpha) and a second chain that is required for high-affinity binding and signal transduction. This second chain is shared by the ligand-specific alpha-chains for the interleukin 3 (IL-3) and IL-5 receptors and is therefore called beta common (beta(c)). In mice but not humans the IL-3 receptor can also use a closely related but IL-3-specific beta-chain (beta(IL-3)). In order to define the contributions of each each chain to receptor signalling we generated mice in which either beta(c) or beta(IL-3) expression was deleted. beta(IL-3) null mice were phenotypically normal but displayed a decreased responsiveness to IL-3 in vitro. beta(c) null mice, on the other hand, were unresponsive to GM-CSF or IL-5 but still responded to IL-3. These data demonstrated that GM-CSF and IL-5 receptors can use only one beta-chain for signalling (beta(c)) while IL-3 can effectively use either beta-chain. The hierarchical basis of receptor transmodulation was shown to result from this differential usage of beta-chains. To define the regions required for different types of cell signalling, we constructed human beta(c) mutants with successive cytoplasmic truncations. By the use of appropriate biological read-out systems we found that the cytoplasmic region of the receptor has a modular design with distinct domains required for cell proliferation, cell survival, differentiation and growth suppression. Appropriate targeting of these domains and the signalling pathways they initiate may provide highly specific cell therapies in the future.
Publisher: JOHN WILEY & SONS LTD
Keywords: COLONY-STIMULATING FACTOR; COMMON BETA-SUBUNIT; TYROSINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; IL-5 RECEPTORS; DEFICIENT MICE; INTERLEUKIN-5; INVOLVEMENT; TRANSPORT; PATHOLOGY
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Creation Date: 1997-01-01 12:00:00