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

Journal of Molecular and Cellular Cardiology

PubMedID: 24560667

Liu S, Lai L, Zuo Q, Dai F, Wu L, Wang Y, Zhou Q, Liu J, Liu J, Li L, Lin Q, Creighton CJ, Costello MG, Huang S, Jia C, Liao L, Luo H, Fu J, Liu M, Yi Z, Xiao J, Li X. PKA turnover by the REG?-proteasome modulates FoxO1 cellular activity and VEGF-induced angiogenesis. J Mol Cell Cardiol. 2014;7228-38.
The REG?-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 REG? are not completely understood. Here we demonstrate that REG? controls degradation of protein kinase A catalytic subunit-a (PKAca) both in primary human umbilical vein endothelial cells (HUVECs) and mouse embryonic fibroblast cells (MEFs). Accumulation of PKAca in REG?-deficient HUVECs or MEFs results in phosphorylation and nuclear exclusion of the transcription factor FoxO1, indicating that REG? 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 REG? in a PKA dependent manner. Functionally, REG? is crucial for the migration of HUVECs. REG?(-/-) mice display compromised VEGF-instigated neovascularization in cornea and aortic ring models. Implanted matrigel plugs containing VEGF in REG?(-/-) mice induced fewer capillaries than in REG?(+/+) littermates. Taken together, our study identifies REG? 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 REG?-PKA-FoxO1 pathway in endothelial cells (ECs) provides another potential target for therapeutic intervention in vascular diseases.