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

ABSTRACT: 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-? (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.

SUBMITTER: Liu S 

PROVIDER: S-EPMC4237316 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature