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https://hdl.handle.net/2440/28111
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Type: | Journal article |
Title: | Peptide insertions in domain 4 of hbc, the shared signalling receptor subunit for GM-CSF, IL3 and IL5, induce ligand-independent activation |
Author: | Jones, K. Bagley, C. Butcher, C. Barry, S. Vadas, M. D'Andrea, R. |
Citation: | Cytokine, 2001; 14(6):303-315 |
Publisher: | Academic Press Ltd Elsevier Science Ltd |
Issue Date: | 2001 |
ISSN: | 1043-4666 1096-0023 |
Statement of Responsibility: | K. L. Jones, C. J. Bagley, C. Butcher, S. C. Barry, M. A. Vadas and R. J. D'Andrea |
Abstract: | A mutant form of the common beta-subunit of the GM-CSF, interleukin-3 (IL3) and IL5 receptors is activated by a 37 residue duplicated segment which includes the WSXWS motif and an adjacent, highly conserved, aliphatic/basic element. Haemopoietic expression of this mutant, hbeta(c)FIDelta, in mice leads to myeloproliferative disease. To examine the mechanism of activation of this mutant we targetted the two conserved motifs in each repeat for mutagenesis. Here we show that this mutant exhibits constitutive activity in BaF-B03 cells in the presence of mouse or human GM-CSF receptor alpha-subunit (GMRalpha) and this activity is disrupted by mutations of the conserved motifs in the first repeat. In the presence of these mutations the receptor reverts to an alternative conformation which retains responsiveness to human IL3 in a CTLL cell line co-expressing the human IL3 receptor alpha-subunit (hIL3Ralpha). Remarkably, the activated conformation is maintained in the presence of substitutions, deletions or replacement of the second repeat. This suggests that activation occurs due to insertion of extra sequence after the WSXWS motif and is not dependent on the length or specific sequence of the insertion. Thus hbeta(c) displays an ability to fold into functional receptor conformations given insertion of up to 37 residues in the membrane-proximal region. Constitutive activation most likely results from a specific conformational change which alters a dormant, inactive receptor complex, permitting functional association with GMRalpha and ligand-independent mitogenic signalling. |
Keywords: | Hematopoietic Stem Cells Cell Line Animals Humans Mice Peptides Interleukin-3 Receptors, Granulocyte-Macrophage Colony-Stimulating Factor Receptors, Interleukin-3 Receptors, Interleukin DNA, Complementary Ligands Mutagenesis, Site-Directed Signal Transduction Cell Division Mutagenesis Amino Acid Sequence Conserved Sequence Protein Structure, Tertiary Protein Binding Sequence Homology, Amino Acid Dose-Response Relationship, Drug Mutation Models, Molecular Molecular Sequence Data Receptors, Interleukin-5 |
Description: | Copyright © 2001 Academic Press. All rights reserved. |
DOI: | 10.1006/cyto.2001.0913 |
Published version: | http://dx.doi.org/10.1006/cyto.2001.0913 |
Appears in Collections: | Aurora harvest 2 Molecular and Biomedical Science publications |
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