Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common β-subunit

Perugini, M., Brown, A. L., Salerno, D. G., Booker, G. W., Stojkoski, C., Hercus, T. R., Lopez, A. F., Hibbs, M. L., Gonda, T. J. and D'Andrea, R. J. (2010) Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common β-subunit. Blood, 115 16: 3346-3353. doi:10.1182/blood-2009-08-235846

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Author Perugini, M.
Brown, A. L.
Salerno, D. G.
Booker, G. W.
Stojkoski, C.
Hercus, T. R.
Lopez, A. F.
Hibbs, M. L.
Gonda, T. J.
D'Andrea, R. J.
Title Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common β-subunit
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2010-04-22
Sub-type Article (original research)
DOI 10.1182/blood-2009-08-235846
Open Access Status File (Author Post-print)
Volume 115
Issue 16
Start page 3346
End page 3353
Total pages 8
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Collection year 2011
Language eng
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 α-subunit (GMR-α) 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 (FIΔ) selectively activates the phosphoinositide 3-kinase/Akt and IκKβ/nuclear factorκB 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-α and show a selective requirement for Src family kinases by the FIΔ 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.
Keyword Granulocyte-macrophage colony-stimulating factor
I kappa B
Immunoprecipitation
Signal transduction
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
UQ Diamantina Institute - Open Access Collection
UQ Diamantina Institute Publications
 
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Created: Sun, 09 May 2010, 00:05:49 EST