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| Item Type: | Article | ||||
|---|---|---|---|---|---|
| Title: | Endothelial PKA activity regulates angiogenesis by limiting autophagy through phosphorylation of ATG16L1 | ||||
| Creators Name: | Zhao, X. and Nedvetsky, P. and Stanchi, F. and Vion, A.C. and Popp, O. and Zühlke, K. and Dittmar, G. and Klussmann, E. and Gerhardt, H. | ||||
| Abstract: | The cAMP-dependent protein kinase A (PKA) regulates various cellular functions in health and disease. In endothelial cells PKA activity promotes vessel maturation and limits tip cell formation. Here, we used a chemical genetic screen to identify endothelial-specific direct substrates of PKA in human umbilical vein endothelial cells (HUVEC) that may mediate these effects. Amongst several candidates, we identified ATG16L1, a regulator of autophagy, as novel target of PKA. Biochemical validation, mass spectrometry and peptide spot arrays revealed that PKA phosphorylates ATG16L1α at Ser268 and ATG16L1β at Ser269, driving phosphorylation-dependent degradation of ATG16L1 protein. Reducing PKA activity increased ATG16L1 protein levels and endothelial autophagy. Mouse in vivo genetics and pharmacological experiments demonstrated that autophagy inhibition partially rescues vascular hypersprouting caused by PKA deficiency. Together these results indicate that endothelial PKA activity mediates a critical switch from active sprouting to quiescence in part through phosphorylation of ATG16L1, which in turn reduces endothelial autophagy. | ||||
| Keywords: | Autophagy, Autophagy-Related Proteins, Cell Line, Cyclic AMP-Dependent Protein Kinases, Endothelial Cells, Phosphorylation, Physiologic Neovascularization, Post-Translational Protein Processing, Animals, Mice | ||||
| Source: | eLife | ||||
| ISSN: | 2050-084X | ||||
| Publisher: | eLife Sciences Publications | ||||
| Volume: | 8 | ||||
| Page Range: | e46380 | ||||
| Date: | 3 October 2019 | ||||
| Additional Information: | Erratum in: eLife 9: e58195. | ||||
| Official Publication: | https://doi.org/10.7554/eLife.46380 | ||||
| PubMed: | View item in PubMed | ||||
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