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

Shuang Liu, Li Lai, Qiuhong Zuo, Fujun Dai, Lin Wu, Yan Wang, Qingxia Zhou, Jian Liu, Jiang Liu, Lei Li, Qingxiang Lin, Chad J. Creighton, Myra Grace Costello, Shixia Huang, Caifeng Jia, Lujian Liao, Honglin Luo, Junjiang Fu, Mingyao Liu, Zhengfang YiJianru Xiao, Xiaotao Li

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)28-38
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume72
DOIs
StatePublished - Jul 2014

Keywords

  • Angiogenesis
  • E-Selectin
  • FoxO1
  • PKAca
  • REGγ
  • VCAM-1

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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