title: Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2/STAT6 pathway.
abstract: Goblet cell hyperplasia (GCH) and mucous hypersecretion are common pathological features of chronic pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Despite numerous studies, the molecular basis for this condition remains elusive. Gab2 is a member of the Dos/Gab subfamily scaffolding molecules and plays important roles in regulating growth, differentiation, and inflammation. We found that an elevated level of Gab2 correlates with up-regulated mucus in airway epithelia from patients with lung cancer or COPD, suggesting the potential involvement of Gab2 in pathological lesions in lungs. Knockdown of Gab2 in human airway epithelial cells in vitro decreases IL-13-induced expression of mucin genes. To address the in vivo role of Gab2 in lungs, Gab2-knockout (Gab2(-/-)) mice were sensitized and challenged with ovalbumin (OVA). Further analysis of lungs in an OVA-induced allergy model suggested that GCH and mucus production are remarkably reduced in Gab2(-/-) mice. Mechanistically, Gab2 positively regulates IL-13-induced activation of TYK2/STAT6 by decreasing SOCS3-mediated degradation of TYK2. Together, we define a novel role for Gab2 in mediating mucin gene expression and GCH; these findings have important implications for the pathogenesis and therapy of airway inflammatory diseases.
authors.affiliation: Department of Pathology and Pathophysiology, Second Affiliated Hospital, Hangzhou, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Tao
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Cheng
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Ren
authors.initials: R
authors.lastname: Zhou
authors.forename: Qiangmin
authors.initials: Q
authors.lastname: Xie
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Ke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D020397:Goblet Cells / Q000473:pathology* / Q000502:physiology; D006801:Humans; D006965:Hyperplasia; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009077:Mucins / Q000235:genetics / Q000378:metabolism*; D009093:Mucus; D010047:Ovalbumin / Q000276:immunology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D053634:TYK2 Kinase / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; C490894:Gab2 protein, mouse; D018793:Interleukin-13; D009077:Mucins; D010750:Phosphoproteins; D050800:STAT6 Transcription Factor; D010047:Ovalbumin; D053634:TYK2 Kinase