A-kinase anchoring proteins contribute to loss of E-cadherin and bronchial epithelial barrier by cigarette smokeOldenburger, A., Poppinga, W. J., Kos, F., de Bruin, H. G., Rijks, W. F., Heijink, H., Timens, W., Meurs, H., Maarsingh, H. & Schmidt, M., 15-Mar-2014, In : American Journal of Physiology - Cell Physiology. 306, 6, p. C585-C597 13 p.
Research output: Contribution to journal › Article › Academic › peer-review
Airway epithelium, which forms the first barrier towards environmental insults, is disturbed by cigarette smoking, a major risk factor for developing chronic obstructive pulmonary disease (COPD). A-kinase anchoring proteins (AKAP) maintain endothelial barrier function and coordinate subcellular localization of protein kinase A (PKA). However, the role of AKAPs in epithelial barrier function is unknown. We studied the role of AKAPs in regulating human bronchial epithelial (Hogg JC, Timens W. Annu Rev Pathol 4: 435-459, 2009; HBE) barrier. Cigarette smoke extract (CSE) reduced barrier function in 16HBE cells and the expression of the adhesion molecule E-cadherin specifically at the cell membrane. In addition, CSE reduced the protein expression of the AKAP family member AKAP9 at the cell membrane. The expression of AKAP5 and AKAP12 was unaffected by CSE. AKAP9 interacted and colocalized with E-cadherin at the cell membrane, suggesting that the reduction of both proteins may be related. Interestingly, disruption of AKAP-PKA interactions by st-Ht31 prevented the CSE-induced reduction of E-cadherin and AKAP9 protein expression and subsequent loss of barrier function. Silencing of AKAP9 reduced the functional epithelial barrier and prevented the ability of st-Ht31 to restore membrane localization of E-cadherin. Our data suggest the possibility of a specific role for AKAP9 in the maintenance of the epithelial barrier. E-cadherin, but not AKAP9, protein expression was reduced in lung tissue from COPD patients compared with controls. However, AKAP9 mRNA expression was decreased in primary bronchial epithelial cells from current smokers compared with non/ex-smokers. In conclusion, our results indicate that AKAP proteins, most likely AKAP9, maintain the bronchial epithelial barrier by regulating the E-cadherin expression at the cell membrane.
|Number of pages||13|
|Journal||American Journal of Physiology - Cell Physiology|
|Publication status||Published - 15-Mar-2014|
- A Kinase Anchor Proteins, Adult, Aged, Aged, 80 and over, Bronchi, Cadherins, Cell Cycle Proteins, Cell Line, Cell Membrane, Cytoskeletal Proteins, Female, Humans, Male, Middle Aged, Proto-Oncogene Proteins, Pulmonary Disease, Chronic Obstructive, RNA Interference, RNA, Small Interfering, Respiratory Mucosa, Smoke, Smoking, Tobacco