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Endothelial PKA targets ATG16L1 to regulate angiogenesis by limiting autophagy

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Item Type:Preprint
Title:Endothelial PKA targets ATG16L1 to regulate angiogenesis by limiting autophagy
Creators Name:Zhao, X. and Nedvetsky, P. 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 a plethora of cellular functions in health and disease. During angiogenesis, PKA activity in endothelial cells controls the transition from sprouting to vessel maturation and limits tip cell formation independently of Notch signaling. The molecular PKA targets mediating these effects remain unknown. We report a chemical genetics screen identifying endothelial-specific substrates of PKA in human umbilical vein endothelial cells (HUVEC). 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. The phosphorylations drive degradation of ATG16L1 protein. Knocking down PKA or inhibiting its activity increased ATG16L1 protein levels and endothelial autophagy. In vivo genetics and pharmacological experiments demonstrated that autophagy inhibition partially rescues vascular hypersprouting caused by PKA deficiency. We propose that endothelial PKA activity restricts active sprouting by reducing endothelial autophagy through phosphorylation of ATG16L1.
Keywords:Animals, Mice
Source:bioRxiv
Publisher:Cold Spring Harbor Laboratory Press (U.S.A)
Article Number:573683
Date:12 March 2019
Official Publication:https://doi.org/10.1101/573683

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