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

Abstract

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.

Upregulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice

“…The REGγ gene is located in 17q21 in humans, a region with high genetic linkage to schizophrenia in Latino populations (Escamilla et al, 2009;Lewis et al, 2003) and implicated in several other CNS diseases, such as autism (Cantor et al, 2005), and bipolar disorder (Ewald et al, 2005), which share at least some symptoms with schizophrenia and schizoaffective disorders. Since the discovery of a mammalian target of REGγ, SRC3 (Steroid receptor co-activator protein; Li et al, 2006), accumulating evidence has revealed diverse functions for the ATP-and ubiquitin-independent REGγ-proteasome pathway, including regulation of cell cycle (Kobayashi et al, 2013;Li et al, 2007), angiogenesis (Liu et al, 2014), and hepatic lipid metabolism (Dong et al, 2013). REGγ is widely expressed in tissues , especially in the brain.…”

Regulation of c-Myc protein stability by proteasome activator REGγ

“…11 REGγ also affects angiogenesis by regulating PKA activity. 12 REGγ is conserved in Drosophila and one Drosophila Reg (identified as dReg) has been identified. 13 However, the biological function of dReg is largely unknown.…”

REGγ accelerates melanoma formation by regulating Wnt/β‐catenin signalling pathway

“…Previous studies demonstrated that REGγ is overexpressed in multiple types of cancer including breast, thyroid, colorectal and liver cancers . A recent study found that REGγ promoted VEGF‐induced angiogenesis by regulating PKA signal pathway . Moreover, our previous study showed that REGγ promoted skin tumor development in a two‐stage skin carcinogenesis mouse model .…”