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Src regulates cigarette smoke-induced ceramide generation via neutral sphingomyelinase 2 in the airway epithelium.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Chung, Samuel C. K. Vu, Simon Filosto, Simone Goldkorn, Tzipora |
| Copyright Year | 2015 |
| 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. |
| Starting Page | 1 |
| Ending Page | 188 |
| Page Count | 188 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://cloudfront.escholarship.org/dist/prd/content/qt0r59z25w/qt0r59z25w.pdf |
| PubMed reference number | 25347576v1 |
| Alternate Webpage(s) | https://doi.org/10.1165/rcmb.2014-0122OC |
| DOI | 10.1165/rcmb.2014-0122OC |
| Journal | American journal of respiratory cell and molecular biology |
| Volume Number | 52 |
| Issue Number | 6 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Calpain Carcinoma of lung Ceramides Chronic Obstructive Airway Disease Cigarette smoke (substance) Epithelium Lung Diseases, Obstructive Lung Injury Lung diseases MARK2 gene Mitogen-Activated Protein Kinases Mitogens Oncogenes Oxidative Stress Phosphoproteins Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Proto-Oncogenes Receptor Protein-Tyrosine Kinases SPHINGOMYELINASE Threonine |
| Content Type | Text |
| Resource Type | Article |
