title: Src regulates cigarette smoke-induced ceramide generation via neutral sphingomyelinase 2 in the airway epithelium.
abstract: We previously demonstrated that the neutral sphingomyelinase (nSMase) 2 is the sole sphingomyelinase activated during cigarette smoke (CS)-induced oxidative stress of human airway epithelial cells, leading to ceramide generation and subsequent apoptosis of affected cells. Since then, we reported that nSMase2 is a phosphoprotein, the degree of enzymatic activity and stability of which are dictated by its degree of phosphorylation. Simultaneously, the non-receptor tyrosine kinase and proto-oncogene Src has increasingly become a target of interest in both smoking-related lung injury, such as chronic obstructive pulmonary disease, and lung cancer. Within this context, we tested and now present Src as a regulator of ceramide generation via modulation of nSMase2 phosphorylation and activity during CS-induced oxidative stress. Specifically, we provide evidence that Src activity is necessary for both CS-induced ceramide accumulation in vivo (129/Sv mice) and in vitro (human airway epithelial cells) and for nSMase2 activity during CS-induced oxidative stress. Moreover, because nSMase2 is exclusively phosphorylated on serines, we show that this occurs through Src-dependent activation of the serine/threonine kinase p38 mitogen-activated protein kinase during oxidative stress. Finally, we provide evidence that Src and p38 mitogen-activated protein kinase activities are critical for regulating nSMase2 phosphorylation. This study provides insights into a molecular target involved in smoking-related lung injury, represented here as nSMase2, and its modulation by the oncogene Src.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care, School of Medicine, University of California, Davis, Davis, California.
authors.forename: Samuel
authors.initials: S
authors.lastname: Chung
authors.forename: Simon
authors.initials: S
authors.lastname: Vu
authors.forename: Simone
authors.initials: S
authors.lastname: Filosto
authors.forename: Tzipora
authors.initials: T
authors.lastname: Goldkorn
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002518:Ceramides / Q000096:biosynthesis*; D004789:Enzyme Activation; D004848:Epithelium / Q000201:enzymology; D006801:Humans; D008171:Lung Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D057507:Mice, 129 Strain; D018384:Oxidative Stress; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D000090063:Proto-Oncogene Mas; D020545:Respiratory Mucosa / Q000201:enzymology*; D012907:Smoking / Q000009:adverse effects*; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D002518:Ceramides; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019061:src-Family Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C491483:Smpd3 protein, mouse; D013108:Sphingomyelin Phosphodiesterase
keywords: Src; ceramide; neutral sphingomyelinase 2; sphingolipids