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https://hdl.handle.net/2440/61349
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Type: | Journal article |
Title: | Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common β-subunit |
Other Titles: | Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common beta-subunit |
Author: | Perugini, M. Brown, A. Salerno, D. Booker, G. Stojkoski, C. Hercus, T. Lopez, A. Hibbs, M. Gonda, T. D'Andrea, R. |
Citation: | Blood, 2010; 115(16):3346-3353 |
Publisher: | Amer Soc Hematology |
Issue Date: | 2010 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | Michelle Perugini, Anna L. Brown, Diana G. Salerno, Grant W. Booker, Cvetan Stojkoski, Timothy R. Hercus, Angel F. Lopez, Margaret L. Hibbs, Thomas J. Gonda, and Richard J. D'Andrea |
Abstract: | Granulocyte/macrophage colony-stimulating factor promotes growth, survival, differentiation, and activation of normal myeloid cells and plays an important role in myeloid leukemias. The GM-CSF receptor (GMR) shares a signaling subunit, βc, with interleukin-3 and interleukin-5 receptors and has recently been shown to induce activation of Janus kinase 2 (JAK2) and downstream signaling via formation of a unique dodecameric receptor complex. In this study we use 2 activated βc mutants that display distinct signaling capacity and have differential requirements for the GMR {alpha}-subunit (GMR-{alpha}) to dissect the signaling pathways associated with the GM-CSF response. The V449E transmembrane mutant selectively activates JAK2/signal transducer and activator of transcription 5 and extracellular signal-regulated kinase (ERK) pathways, resulting in a high level of sensitivity to JAK and ERK inhibitors, whereas the extracellular mutant (FI{Delta}) selectively activates the phosphoinositide 3-kinase/Akt and I{kappa}Kβ/nuclear factor{kappa}B pathways. We also demonstrate a novel and direct interaction between the SH3 domains of Lyn and Src with a conserved proline-rich motif in GMR-{alpha} and show a selective requirement for Src family kinases by the FI{Delta} mutant. We relate the nonoverlapping nature of signaling by the activated mutants to the structure of the unique GMR complex and propose alternative modes of receptor activation acting synergistically in the mature liganded receptor complex. |
Keywords: | Cell Line Animals Mice Receptors, Granulocyte-Macrophage Colony-Stimulating Factor Microscopy, Fluorescence Blotting, Western Flow Cytometry Immunoprecipitation Signal Transduction Enzyme Activation Mutation Leukemia, Myeloid, Acute |
Rights: | © 2010 by The American Society of Hematology |
DOI: | 10.1182/blood-2009-08-235846 |
Published version: | http://dx.doi.org/10.1182/blood-2009-08-235846 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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