PKA turnover by the REGγ-proteasome modulates FoxO1 cellular activity and VEGF-induced angiogenesis.

TitlePKA turnover by the REGγ-proteasome modulates FoxO1 cellular activity and VEGF-induced angiogenesis.
Publication TypeJournal Article
Year of Publication2014
AuthorsLiu, S, Lai, L, Zuo, Q, Dai, F, Wu, L, Wang, Y, Zhou, Q, Liu, J, Liu, J, Li, L, Lin, Q, Creighton, CJ, Costello, MGrace, Huang, S, Jia, C, Liao, L, Luo, H, Fu, J, Liu, M, Yi, Z, Xiao, J, Li, X
JournalJ Mol Cell Cardiol
Date Published2014 Jul

The REGγ-proteasome serves as a short-cut for the destruction of certain intact mammalian proteins in the absence of ubiquitin- and ATP. The biological roles of the proteasome activator REGγ are not completely understood. Here we demonstrate that REGγ controls degradation of protein kinase A catalytic subunit-α (PKAca) both in primary human umbilical vein endothelial cells (HUVECs) and mouse embryonic fibroblast cells (MEFs). Accumulation of PKAca in REGγ-deficient HUVECs or MEFs results in phosphorylation and nuclear exclusion of the transcription factor FoxO1, indicating that REGγ is involved in preserving FoxO1 transcriptional activity. Consequently, VEGF-induced expression of the FoxO1 responsive genes, VCAM-1 and E-Selectin, was tightly controlled by REGγ in a PKA dependent manner. Functionally, REGγ is crucial for the migration of HUVECs. REGγ(-/-) mice display compromised VEGF-instigated neovascularization in cornea and aortic ring models. Implanted matrigel plugs containing VEGF in REGγ(-/-) mice induced fewer capillaries than in REGγ(+/+) littermates. Taken together, our study identifies REGγ as a novel angiogenic factor that plays an important role in VEGF-induced expression of VCAM-1 and E-Selectin by antagonizing PKA signaling. Identification of the REGγ-PKA-FoxO1 pathway in endothelial cells (ECs) provides another potential target for therapeutic intervention in vascular diseases.

Alternate JournalJ. Mol. Cell. Cardiol.
PubMed ID24560667
PubMed Central IDPMC4237316
Grant List1R01CA131914 / CA / NCI NIH HHS / United States
HD08818 / HD / NICHD NIH HHS / United States
P30-DK079638 / DK / NIDDK NIH HHS / United States
P30CA125123 / CA / NCI NIH HHS / United States
R01 CA131914 / CA / NCI NIH HHS / United States