| Alternative modes of GM-CSF receptor activation revealed using activated mutants of the common beta-subunit. | |
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MedLine Citation:
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PMID: 20173116 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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, beta(c), 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 beta(c) 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 (FIDelta) selectively activates the phosphoinositide 3-kinase/Akt and IkappaKbeta/nuclear factorkappaB 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 FIDelta 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. |
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Authors:
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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; Richard J D'Andrea |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-02-19 |
Journal Detail:
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Title: Blood Volume: 115 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-23 Completed Date: 2010-05-20 Revised Date: 2011-07-28 |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 3346-53 Citation Subset: AIM; IM |
Affiliation:
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Division of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blotting, Western Cell Line Enzyme Activation / physiology* Flow Cytometry Immunoprecipitation Leukemia, Myeloid, Acute / metabolism Mice Microscopy, Fluorescence Mutation Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism* Signal Transduction / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL60657/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Granulocyte-Macrophage Colony-Stimulating Factor |
| Comments/Corrections | |
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