Scaffolding protein Gab1 regulates myeloid dendritic cell migration in allergic asthma

Zhang, Yun; Xu, Yun; Liu, Shuwan; Guo, Xiaohong; Cen, Dong; Li, Heyuan; Li, Kaijun; Zeng, Chunlai; Lu, Linrong; Zhou, Yi; Shen, Huahao; Cheng, Hongqiang; Zhang, Xue; Ke, Yuehai

doi:10.1038/cr.2016.124

Cited by 19 publications

(18 citation statements)

References 65 publications

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“…GRASP encodes GRP1 (general receptor for phosphoinositides-1)-associated scaffold protein and has been shown to be highly expressed in the brain with lower levels of expression in the lung, heart, embryo, kidney and ovary 39 . Although little is known about the function of this gene or its potential role in asthma, scaffold proteins have been implicated in asthma signalling pathways 40 41 .…”

Section: Discussionmentioning

confidence: 99%

Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma

et al. 2015

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Common variants at many loci have been robustly associated with asthma but explain little of the overall genetic risk. Here we investigate the role of rare (<1%) and low frequency (1–5%) variants using the Illumina HumanExome BeadChip array in 4,794 asthma cases, 4,707 non-asthmatic controls, and 590 case-parent trios representing European Americans, African Americans/African Caribbeans, and Latinos. Our study reveals one low frequency missense mutation in the GRASP gene that is associated with asthma in the Latino sample (P=4.31×10−6; OR=1.25; MAF=1.21%) and two genes harboring functional variants that are associated with asthma in a gene-based analysis: GSDMB at the 17q12-21 asthma locus in the Latino and combined samples (P=7.81×10−8 and 4.09×10−8, respectively) and MTHFR in the African ancestry sample (P=1.72×10−6). Our results suggest that associations with rare and low frequency variants are ethnic specific and not likely to explain a significant proportion of the “missing heritability” of asthma.

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Section: Discussionmentioning

confidence: 99%

Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma

et al. 2015

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“…The noninvasive lung function examination was performed by EMKA‐WBP measurement system as described 17 . Briefly, mice were placed into a WBP and then were atomized with 10 µl methacholine (Sigma–Aldrich, St. Louis, MO, USA) at concentrations of 0, 3.125, 6.25, 12.5, 25, and 50 mg/ml, respectively.…”

Section: Methodsmentioning

confidence: 99%

Frontline Science: Two flavonoid compounds attenuate allergic asthma by regulating epithelial barrier via G protein-coupled estrogen receptor: Probing a possible target for allergic inflammation

Yuan

Chen

et al. 2020

Journal of Leukocyte Biology

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Allergic asthma is a common chronic lung inflammatory disease and seriously influences public health. We aim to investigate the effects of formononetin (FMN) and calycosin (CAL), 2 flavonoids in Radix Astragali, on allergic asthma and elucidate possible therapeutic targets. A house dust mite (HDM)‐induced allergic asthma mouse model and TNF‐α and Poly(I:C) co‐stimulated human bronchial epithelial cell line (16HBE) were performed respectively in vivo and in vitro. The role of G protein‐coupled estrogen receptor (GPER) was explored by its agonist, antagonist, or GPER small interfering RNA (siGPER). E‐cadherin, occludin, and GPER were detected by western blotting, immunohistochemistry, or immunofluorescence. The epithelial barrier integrity was assessed by trans‐epithelial electric resistance (TEER). Cytokines were examined by enzyme‐linked immunosorbent assay (ELISA). The results showed that flavonoids attenuated pulmonary inflammation and hyperresponsiveness in asthmatic mice. These flavonoids significantly inhibited thymic stromal lymphopoietin (TSLP), increased occludin and restored E‐cadherin in vivo and in vitro. The effects of flavonoids on occludin and TSLP were not interfered by ICI182780 (estrogen receptor antagonist), while blocked by G15 (GPER antagonist). Furthermore, compared with PPT (ERα agonist) and DPN (ERβ agonist), G1 (GPER agonist) significantly inhibited TSLP, up‐regulated occludin, and restored E‐cadherin. siGPER and TEER assays suggested that GPER was pivotal for the flavonoids on the epithelial barrier integrity. Finally, G1 attenuated allergic lung inflammation, which could be abolished by G15. Our data demonstrated that 2 flavonoids in Radix Astragali could alleviate allergic asthma by protecting epithelial integrity via regulating GPER, and activating GPER might be a possible therapeutic strategy against allergic inflammation.

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“…Gab1 flox/flox mice (41) were crossed with LysM cre/ϩ mice to generate conditional Gab1 KO mice (Gab1 MyKO ). Gab2 Ϫ/Ϫ mice were bred with Gab2 ϩ/Ϫ mice to generate Gab2 KO animals (65).…”

Section: Micementioning

confidence: 99%

“…However, contrary to Gab1, Gab2 depletion surprisingly results in the increased activation of AKT (39,40). We previously reported that Gab1 enhances allergic asthma by promoting dendritic cell migration (41), whereas Gab2 is involved in asthma by positively regulating goblet cell hyperplasia and mucus secretion in the airway epithelium (42).…”

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confidence: 96%

Increased levels of Gab1 and Gab2 adaptor proteins skew interleukin-4 (IL-4) signaling toward M2 macrophage-driven pulmonary fibrosis in mice

Guo

et al. 2017

Journal of Biological Chemistry

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M2-polarized macrophages, also known as alternatively activated macrophages, have long been associated with pulmonary fibrosis; however, the mechanism has not been fully defined. Gab1 and Gab2 proteins belong to the Gab family of adaptors and are integral components of the signal specificity in response to various extracellular stimuli. In this report, we found that levels of both Gab1 and Gab2 were elevated in M2-polarized macrophages isolated from bleomycin-induced fibrotic lungs. Gab1/2 deficiency in bone marrow-derived macrophages abrogated IL-4-mediated M2 polarization. Furthermore, conditional removal of (Gab1) and germ line knock-out of (Gab2) in macrophages prevented a bias toward the M2 phenotype and attenuated bleomycin-induced fibrotic lung remodeling. In support of these observations, Gab1/2 were involved in responses predominated by IL-4 signaling, an essential determinant for macrophage M2 polarization. Further investigation revealed that both Gab1 and -2 are recruited to the IL-4 receptor, synergistically enhancing downstream signal amplification but conferring IL-4 signal preference. Mechanistically, the loss of Gab1 attenuated AKT activation, whereas the absence of Gab2 suppressed STAT6 activation in response to IL-4 stimulation, both of which are commonly attributed to M2-driven pulmonary fibrosis in mice. Taken together, these observations define a non-redundant role of Gab docking proteins in M2 polarization, adding critical insights into the pathogenesis of idiopathic pulmonary fibrosis.

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Scaffolding protein Gab1 regulates myeloid dendritic cell migration in allergic asthma

Cited by 19 publications

References 65 publications

Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma

Ethnic-specific associations of rare and low-frequency DNA sequence variants with asthma

Frontline Science: Two flavonoid compounds attenuate allergic asthma by regulating epithelial barrier via G protein-coupled estrogen receptor: Probing a possible target for allergic inflammation

Increased levels of Gab1 and Gab2 adaptor proteins skew interleukin-4 (IL-4) signaling toward M2 macrophage-driven pulmonary fibrosis in mice

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