The Structure of the GM-CSF Receptor Complex Reveals a Distinct Mode of Cytokine Receptor Activation

Hansen, Guido; Hercus, Timothy R.; McClure, Barbara J.; Stomski, Frank C.; Dottore, Mara; Powell, Jason A.; Ramshaw, Hayley S.; Woodcock, Joanna M.; Xu, Yibin; Guthridge, Mark A.; McKinstry, William J.; Lopez, Angel F.; Parker, Michael W.

doi:10.1016/j.cell.2008.05.053

Cited by 278 publications

(328 citation statements)

References 53 publications

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“…3A depicts a model of the ternary complex, based on our ternary complex crystal structure (26), of a partially refined crystal structure of the GM-CSF:GMR-α binary complex and the crystal structure of the homologous IL-5 receptor alpha subunit (27). To visualize how anti-GM-CSF mAbs could interfere with the bioactivity of GM-CSF and its formation of a signaling complex with the GM-CSF receptor, we used Pisa (Version 1.37; www.ebi.…”

Section: Resultsmentioning

confidence: 99%

“…S2A). Each mAb when bound to GM-CSF could sterically interfere with the formation of the dodecamer signaling complex (26) (Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

“…3 is based partly on the crystal structure of the published ternary GM-CSF: receptor complex (Protein Data Bank ID code 3CXE). However, the GMR-α extracellular region in this complex was incomplete, with only the extracellular domain 3 (D3) of GMR-α well defined (26). Thus, extracellular domains 1 [N-terminal domain (NTD)] and 2 (D2) of GMR-α were modeled based on a partially refined crystal structure of the GM-CSF:GMR-α binary complex and the crystal structure of the homologous IL-5 receptor α subunit (27).…”

Section: Inhibition Of Cd11b Expression Level On Neutrophils Stimulatmentioning

confidence: 99%

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Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The origin of pathogenic autoantibodies remains unknown. Idiopathic pulmonary alveolar proteinosis is caused by autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). We generated 19 monoclonal autoantibodies against GM-CSF from six patients with idiopathic pulmonary alveolar proteinosis. The autoantibodies used multiple V genes, excluding preferred V-gene use as an etiology, and targeted at least four nonoverlapping epitopes on GM-CSF, suggesting that GM-CSF is driving the autoantibodies and not a B-cell epitope on a pathogen cross-reacting with GM-CSF. The number of somatic mutations in the autoantibodies suggests that the memory B cells have been helped by T cells and re-entered germinal centers. All autoantibodies neutralized GM-CSF bioactivity, with general correlations to affinity and off-rate. The binding of certain autoantibodies was changed by point mutations in GM-CSF that reduced binding to the GM-CSF receptor. Those monoclonal autoantibodies that potently neutralize GM-CSF may be useful in treating inflammatory disease, such as rheumatoid arthritis and multiple sclerosis, cancer, and pain.

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Section: Resultsmentioning

confidence: 99%

“…S2A). Each mAb when bound to GM-CSF could sterically interfere with the formation of the dodecamer signaling complex (26) (Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

Section: Inhibition Of Cd11b Expression Level On Neutrophils Stimulatmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Wang

Thomson

Allan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The GM-CSF receptor is composed of an a subunit and a common b subunit shared by IL-3Rs and IL-5Rs (17). After stimulation of GM-CSF receptors, signaling pathways are activated through the formation of a unique dodecameric receptor complex (18,19). The transcription factors STAT5 and IFN regulatory factor 4 (IRF4) (20,21) are essential for GM-CSF-mediated signaling pathways, and MAPK and AKT are also activated by GM-CSF (17).…”

Section: Endritic Cells (Dcs) Play a Central Role In Instructing T mentioning

confidence: 99%

Critical Role of AZI2 in GM-CSF–Induced Dendritic Cell Differentiation

Fukasaka

Ori

Kawagoe

et al. 2013

The Journal of Immunology

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TNFR-associated factor family member–associated NF-κB activator (TANK)–binding kinase 1 (TBK1) is critical for the activation of IFN regulatory factor 3 and type I IFN production upon virus infection. A set of TBK1-binding proteins, 5-azacytidine–induced gene 2 (AZI2; also known as NAP1), TANK, and TBK1-binding protein 1 (TBKBP1), have also been implicated in the production of type I IFNs. Among them, TANK was found to be dispensable for the responses against virus infection. However, physiological roles of AZI2 and TBKBP1 have yet to be clarified. In this study, we found that none of these TBK1-binding proteins is critical for type I IFN production in mice. In contrast, AZI2, but not TBKBP1, is critical for the differentiation of conventional dendritic cells (cDCs) from bone marrow cells in response to GM-CSF. AZI2 controls GM-CSF–induced cell cycling of bone marrow cells via TBK1. GM-CSF–derived DCs from AZI2-deficient mice show severe defects in cytokine production and T cell activation both in vitro and in vivo. Reciprocally, overexpression of AZI2 results in efficient generation of cDCs, and the cells show enhanced T cell activation in response to Ag stimulation. Taken together, AZI2 expression is critical for the generation of cDCs by GM-CSF and can potentially be used to increase the efficiency of immunization by cDCs.

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“…In turn, JAK-2 phosphorylates tyrosine residues on ßc and initiates several signalling cascades. The solution of the structure of the GM-CSF receptor has provided insights into the activation of the receptor by ligand binding [37]. The GM-CSF receptor consists of a hexameric complex of the four domains of a common ß chain and the two domains of a GM-CSF receptor chain.…”

Section: Receptor Activationmentioning

confidence: 99%

Critical Evaluation of Antiepileptic Drugs in Epileptic Pregnant Women - Hungarian Experiences

Ekert¹,

Jabbour²

2011

Open Cell Signal J

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It has long been known that many cell types are dependent on specific cytokines that signal proliferation, regulate differentiation and suppress apoptosis. A detailed picture of the structure of several cytokine receptors has added to our understanding of the molecular mechanism of receptor activation. An explosion of knowledge of apoptosis pathways and the ways in which the Bcl-2 family of proteins function has deepened the understanding of the effector arm of the programmed cell death pathway. The challenge is to uncover the molecular links between these two pathways. In this article, we will try to examine what is known of the intersections between cytokine signalling pathways and apoptosis pathways, with particular reference to receptor signalling by the haematopoietic cytokines Interleukin-3 (IL-3) and Granulocyte-Macrophage-Colony Stimulating Factor (GM-CSF).

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The Structure of the GM-CSF Receptor Complex Reveals a Distinct Mode of Cytokine Receptor Activation

Cited by 278 publications

References 53 publications

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

Critical Role of AZI2 in GM-CSF–Induced Dendritic Cell Differentiation

Critical Evaluation of Antiepileptic Drugs in Epileptic Pregnant Women - Hungarian Experiences

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