JAK2 and JAK1 Constitutively Associate With an Interleukin-5 (IL-5) Receptor α and βc Subunit, Respectively, and Are Activated Upon IL-5 Stimulation

Ogata, Noboru; Kouro, Taku; Yamada, Atsuko; Koike, Masamichi; Hanai, Nobuo; Ishikawa, Takeru; Takatsu, Kiyoshi

doi:10.1182/blood.v91.7.2264

Cited by 89 publications

(19 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL‐5 activates at least three different signaling pathways, including the JAK2/STAT5, Btk, and Ras/ERK pathways. The JAK2 and JAK1 tyrosine kinases are constitutively associated with IL‐5RA and βc, respectively, and are activated by IL‐5 stimulation 28. According to the structural model of the IL‐5•IL‐5RA•βc octamer (4:2:2 ratio) [Fig.…”

Section: Discussionmentioning

confidence: 99%

“…IL‐5 stimulation induces rapid tyrosine phosphorylation of various cellular proteins, including βc, the SH2/SH3‐containing proteins Vav, HS1, Shc, and so forth . Btk, the Btk‐associated molecules, and the JAK1/JAK2, STAT1/STAT5, PI3K, and MAP kinases, activates downstream signaling molecules,24, 26–28 and leads to the maintenance of the survival and functions of B cells and eosinophils. The activation of JAK2 and STAT5 is essential for IL‐5‐dependent signal transduction 29–31.…”

Section: Introductionmentioning

confidence: 99%

“…The activation of JAK2 and STAT5 is essential for IL‐5‐dependent signal transduction 29–31. Especially, IL‐5 binding to IL‐5R activates the JAK kinases through the associations of IL‐5RA with JAK2 and of βc with JAK1, by means of their cytoplasmic domains 28. On the other hand, GM‐CSF binding to GM‐CSFR induces JAK2 activation via the formation of a unique dodecameric receptor complex 32.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural basis of interleukin‐5 dimer recognition by its α receptor

et al. 2012

Self Cite

View full text Add to dashboard Cite

Interleukin‐5 (IL‐5), a major hematopoietin, stimulates eosinophil proliferation, migration, and activation, which have been implicated in the pathogenesis of allergic inflammatory diseases, such as asthma. The specific IL‐5 receptor (IL‐5R) consists of the IL‐5 receptor α subunit (IL‐5RA) and the common receptor β subunit (βc). IL‐5 binding to IL‐5R on target cells induces rapid tyrosine phosphorylation and activation of various cellular proteins, including JAK1/JAK2 and STAT1/STAT5. Here, we report the crystal structure of dimeric IL‐5 in complex with the IL‐5RA extracellular domains. The structure revealed that IL‐5RA sandwiches the IL‐5 homodimer by three tandem domains, arranged in a “wrench‐like” architecture. This association mode was confirmed for human cells expressing IL‐5 and the full‐length IL‐5RA by applying expanded genetic code technology: protein photo‐cross‐linking experiments revealed that the two proteins interact with each other in vivo in the same manner as that in the crystal structure. Furthermore, a comparison with the previously reported, partial GM‐CSF•GM‐CSFRA•βc structure enabled us to propose complete structural models for the IL‐5 and GM‐CSF receptor complexes, and to identify the residues conferring the cytokine‐specificities of IL‐5RA and GM‐CSFRA.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Structural basis of interleukin‐5 dimer recognition by its α receptor

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…. These signal transduction pathways are catalysed by Janus kinases (JAK) , JAK/signal transducer and activator of transcription (STAT) , mitogen‐activated protein kinase (MAPK) , the extracellular signal‐regulated kinases (ERK1 and ERK2) , Lyn tyrosine kinase , phosphoinositide 3‐kinase and nuclear factor κB (NF‐κB) . IL‐5 can also induce JAK‐binding protein expression in eosinophils, which constitutes a negative feedback regulatory mechanism of IL‐5 signalling .…”

Section: Interleukin‐5/interleukin‐5r Interactionsmentioning

confidence: 99%

Molecular and clinical rationale for therapeutic targeting of interleukin‐5 and its receptor

Molfino¹,

Gossage²,

Kolbeck³

et al. 2011

Clin Experimental Allergy

190

138

View full text Add to dashboard Cite

Interleukin-5 is a Th2 homodimeric cytokine involved in the differentiation, maturation, migration, development, survival, trafficking and effector function of blood and local tissue eosinophils, in addition to basophils and mast cells. The IL-5 receptor (IL-5R) consists of an IL-5-specific α subunit that interacts in conformationally dynamic ways with the receptor's βc subunit, an aggregate of domains it shares with binding sites of IL-3 and granulocyte-macrophage colony-stimulating factor. IL-5 and IL-5R drive allergic and inflammatory immune responses characterizing numerous diseases, such as asthma, atopic dermatitis, chronic obstructive pulmonary disease, eosinophilic gastrointestinal diseases, hyper-eosinophilic syndrome, Churg-Strauss syndrome and eosinophilic nasal polyposis. Although corticosteroid therapy is the primary treatment for these diseases, a substantial number of patients exhibit incomplete responses and suffer side-effects. Two monoclonal antibodies have been designed to neutralize IL-5 (mepolizumab and reslizumab). Both antibodies have demonstrated the ability to reduce blood and tissue eosinophil counts. One additional monoclonal antibody, benralizumab (MEDI-563), has been developed to target IL-5R and attenuate eosinophilia through antibody-dependent cellular cytotoxicity. All three monoclonal antibodies are being clinically evaluated. Antisense oligonucleotide technology targeting the common βc IL-5R subunit is also being used therapeutically to inhibit IL-5-mediated effects (TPI ASM8). Small interfering RNA technology has also been used therapeutically to inhibit the expression of IL-5 in animal models. This review summarizes the structural interactions between IL-5 and IL-5R and the functional consequences of such interactions, and describes the pre-clinical and clinical evidence supporting IL-5R as a therapeutic target.

show abstract

“…Interleukin‐5 (IL‐5) is an important member of the IL‐2 superfamily, and mainly secreted by immune cells such as macrophages (Mø) and lymphocytes (especially the CD4 + T lymphocytes), but less secreted by smooth muscle cells and endothelial cells (Sewell et al, 1998; Deo et al, 2010; Takatsu, 2011; Park et al, 2017). IL‐5 binds to IL‐5 receptor (IL‐5R) on target cells, activates the Janus Kinase (JAK) 1/2 and signal transducer and activator of transcription 1/5 (STAT1/5) signaling pathway and initiates downstream signals (Takaki et al, 1994; Kouro et al, 1996; Ogata et al, 1998). Previous studies have indicated that IL‐5 participates in a variety of diseases by regulating immune effects and the inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Anti‐interleukin‐5‐neutralizing antibody attenuates caradiac injury and cadiac dysfunction by aggravating the inflammatory response in doxorubicin‐treated mice

Xian

Zhan

Yang

et al. 2020

Cell Biology International

View full text Add to dashboard Cite

Previous studies have demonstrated that interleukins (ILs) are closely associated with doxorubicin (DOX)-induced cardiac injury. IL-5 is an important member of the IL family, and this study was performed to investigate whether IL-5 affects DOX-induced cardiac injury and its underlying mechanisms. The cardiac IL-5 expression was first detected and the results showed that cardiac IL-5 levels were significantly lower in DOX-treated mice, and IL-5 was mainly derived from cardiac macrophage (Mø). In addition, some DOX-treated mice received an injection of anti-IL-5-neutralizing antibody (nAb), and we found that treatment with a mouse anti-IL-5 nAb significantly upregulated the levels of myocardial injury markers, aggravated cardiac dysfunction, increased M1 macrophage (Mø1) and decreased M2 macrophage (Mø2) differentiation, and promoted apoptotic marker expression. Furthermore, the effect of mouse IL-5 nAb on DOX-induced Mø differentiation and its role on mouse cardiomyocyte (MCM) cells apoptosis were detected in vitro, and the results exhibited that mouse IL-5 nAb promoted Mø1 differentiation but inhibited Mø2 differentiation in vitro and alleviated apoptosis in MCM cells. Our results found a mouse anti-IL-5 nAb-aggravated DOX-induced cardiac injury and dysfunction by alleviating the inflammatory response and myocardial cell apoptosis. (L. L.), and yingzhonglin@126.com (Y. L.) Abbreviations: ANOVA, analysis of variance; Arg-1, arginase-1; CK-MB, creatine kinase myocardial-bound; DOX, doxorubicin; ELISA, enzyme-linked immunosorbent assay; HE, hematoxylin and eosin; HR, heart rate; IFN-γ, interferon γ; ILs, interleukins; IL-5R, IL-5 receptors; iNOS, inducible nitric oxide synthase; JAK1/2, Janus Kinase 1/2; LDH, lactate dehydrogenase; LV, left ventricle; LVEF, left ventricle ejection fraction; LVEDP, left ventricular enddiastolic pressure; LVFS, left ventricle fractional shortening; LVSP, left ventricular systolic pressure; Mø, macrophage; MCMs, mouse cardiomyocytes; Mø1, M1 macrophage; Mø2, M2 macrophage; nAb, neutralizing antibody; PBS, phosphate-buffered saline; SDS, sodium dodecyl sulfate; STAT1/5, signal transducer and activator of transcription 1/5; SMCs, smooth muscle cells; SD, standard deviation; TNF-α, tumor necrosis factor α; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling; WT, wild-type; +dP/dt max, maximal slope of the systolic pressure increment; −dP/dt max, maximal slope of the diastolic pressure decrement

show abstract

JAK2 and JAK1 Constitutively Associate With an Interleukin-5 (IL-5) Receptor α and βc Subunit, Respectively, and Are Activated Upon IL-5 Stimulation

Cited by 89 publications

References 41 publications

Structural basis of interleukin‐5 dimer recognition by its α receptor

Structural basis of interleukin‐5 dimer recognition by its α receptor

Molecular and clinical rationale for therapeutic targeting of interleukin‐5 and its receptor

Anti‐interleukin‐5‐neutralizing antibody attenuates caradiac injury and cadiac dysfunction by aggravating the inflammatory response in doxorubicin‐treated mice

Contact Info

Product

Resources

About