title: Epithelial disruption of Gab1 perturbs surfactant homeostasis and predisposes mice to lung injuries.
abstract: GRB2-associated-binding protein 1 (Gab1) belongs to Gab adaptor family, which integrates multiple signals in response to the epithelial growth factors. Recent genetic studies identified genetic variants of human Gab1 gene as potential risk factors of asthmatic inflammation. However, the functions of Gab1 in lungs remain largely unknown. Alveolar type-II cells (AT-IIs) are responsible for surfactant homeostasis and essentially regulate lung inflammation following various injuries (3). In this study, in vitro knockdown of Gab1 was shown to decrease the surfactant proteins (SPs) levels in AT-IIs. We further examined in vivo Gab1 functions through alveolar epithelium-specific Gab1 knockout mice (Gab1Δ/Δ). In vivo Gab1 deficiency leads to a decrease in SP synthesis and the appearance of disorganized lamellar bodies. Histological analysis of the lung sections in Gab1Δ/Δmice shows no apparent pathological alterations or inflammation. However, Gab1Δ/Δmice demonstrate inflammatory responses during the LPS-induced acute lung injury. Similarly, in mice challenged with bleomycin, fibrotic lesions were found to be aggravated in Gab1Δ/ΔThese observations suggest that the abolishment of Gab1 in AT-IIs impairs SP homeostasis, predisposing mice to lung injuries. In addition, we observed that the production of surfactants in AT-IIs overexpressing Gab1 mutants, in which Shp2 phosphatase and PI3K kinase binding sites have been mutated (Gab1ΔShp2, Gab1ΔPI3K), has been considerably attenuated. Together, these findings provide the direct evidence about the roles of docking protein Gab1 in lungs, adding to our understanding of acute and interstitial lung diseases caused by the disruption of alveolar SP homeostasis.
authors: Department of Respiratory Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Kai
authors: K
authors: Wang
authors: Department of Pathology and Pathophysiology, and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
authors: Shenlu
authors: S
authors: Qin
authors: Department of Respiratory Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors: Zuyu
authors: Z
authors: Liang
authors: Department of Pathology and Pathophysiology, and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
authors: Yun
authors: Y
authors: Zhang
authors: Department of Pulmonary Diseases, Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; and.
authors: Yingchun
authors: Y
authors: Xu
authors: Department of Neonatal, Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors: An
authors: A
authors: Chen
authors: Department of Pathology and Pathophysiology, and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
authors: Xiaohong
authors: X
authors: Guo
authors: Department of Pathology and Pathophysiology, and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
authors: Hongqiang
authors: H
authors: Cheng
authors: Department of Pathology and Pathophysiology, and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
authors: Xue
authors: X
authors: Zhang
authors: Department of Pathology and Pathophysiology, and Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China; yke@zju.edu.cn.
authors: Yuehai
authors: Y
authors: Ke
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology; D048868:Adaptor Proteins, Signal Transducing; D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D000818:Animals; D001761:Bleomycin; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D006706:Homeostasis; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D037661:Pulmonary Surfactant-Associated Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001761:Bleomycin; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D037661:Pulmonary Surfactant-Associated Proteins; C490897:Gab1 protein, mouse
keywords: PI3K; SHP2; epithelial cells; lipopolysaccharide (LPS); lung injuries