@article{50606fa186624672a2654188d8e4d85b,
title = "Endothelial PKA activity regulates angiogenesis by limiting autophagy through phosphorylation of ATG16L1",
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 ATG16L1a 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.",
author = "Xiaocheng Zhao and Pavel Nedvetsky and Fabio Stanchi and Vion, {Anne Clemence} and Oliver Popp and Kerstin Z{\"u}hlke and Gunnar Dittmar and Enno Klussmann and Holger Gerhardt",
note = "Funding Information: We are grateful to Evy Timmerman and Francis Impens for their help to identify the phosphorylation sites of ATG16L1 in MS analysis at the VIB proteomics core facility. We are grateful to professor Chantal Boulanger for providing the ATG5flox/flox mice. This work was supported by grants from the Fonds voor Wetenschappelijk Onderzoek (FWO) [G.0742.15N to HG]; the Vlaams Instituut voor Bio-technologie (VIB) Tech watch grant [Q3 2015 to PIN]; the Elsa-Kroener-Stiftung [2014_A26 to HG and PIN]; the European Research Consortil [ERC Consolidator grant REshape 311719 to HG]; This work was supported by grants from the German Centre for Cardiovascular Research (DZHK) partner site Berlin (81XZ100146), the Deutsche Forschungsgemeinschaft (DFG KL1415/7-1 and 394046635-SFB 1365) and the Bundesministerium f?r Bildung und Forschung (BMBF; 16GW0179K) to EK. Funding Information: We are grateful to Evy Timmerman and Francis Impens for their help to identify the phosphorylation sites of ATG16L1 in MS analysis at the VIB proteomics core facility. We are grateful to professor Chantal Boulanger for providing the ATG5flox/flox mice. This work was supported by grants from the Fonds voor Wetenschappelijk Onderzoek (FWO) [G.0742.15N to HG]; the Vlaams Instituut voor Bio-technologie (VIB) Tech watch grant [Q3 2015 to PIN]; the Elsa-Kroener-Stiftung [2014_A26 to HG and PIN]; the European Research Consortil [ERC Consolidator grant REshape 311719 to HG]; This work was supported by grants from the German Centre for Cardiovascular Research (DZHK) partner site Berlin (81XZ100146), the Deutsche Forschungsgemeinschaft (DFG KL1415/7-1 and 394046635-SFB 1365) and the Bundesministerium fu€r Bildung und Forschung (BMBF; 16GW0179K) to EK. Publisher Copyright: {\textcopyright} Zhao et al.T.",
year = "2019",
month = oct,
doi = "10.7554/eLife.46380",
language = "English",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}