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 Yi; Jianru Xiao; Xiaotao Li

doi:10.1016/j.yjmcc.2014.02.007

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

J Mol Cell Cardiol. 2014 Jul:72:28-38. doi: 10.1016/j.yjmcc.2014.02.007. Epub 2014 Feb 20.

Authors

Shuang Liu¹, Li Lai², Qiuhong Zuo², Fujun Dai², Lin Wu², Yan Wang², Qingxia Zhou², Jian Liu³, Jiang Liu⁴, Lei Li², Qingxiang Lin², Chad J Creighton⁵, Myra Grace Costello³, Shixia Huang³, Caifeng Jia², Lujian Liao², Honglin Luo⁶, Junjiang Fu⁷, Mingyao Liu², Zhengfang Yi⁸, Jianru Xiao⁹, Xiaotao Li¹⁰

Affiliations

¹ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Department of Hematology, Guangdong No. 2 Provincial People's Hospital, No.1 Shiliugang Rd, Guangzhou, Guangdong 510317, China.
² Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.
³ Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁴ Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
⁵ Department of Medicine, Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX, USA.
⁶ The James Hogg Research Centre for Cardiovascular and Pulmonary Research, University of British Columbia-St. Paul's Hospital, 1081 Burrard St., Vancouver, British Columbia V6Z 1Y6, Canada.
⁷ Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Luzhou Medical College, Luzhou 646000, China.
⁸ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. Electronic address: [email protected].
⁹ Department of Orthopaedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. Electronic address: [email protected].
¹⁰ Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Orthopaedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China. Electronic address: [email protected].

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.

Keywords: Angiogenesis; E-Selectin; FoxO1; PKAca; REGγ; VCAM-1.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aorta / drug effects
Aorta / metabolism
Autoantigens / genetics*
Autoantigens / metabolism
Cell Movement
Cornea / blood supply*
Cornea / drug effects
Cornea / metabolism
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / genetics*
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / metabolism
E-Selectin / genetics
E-Selectin / metabolism
Embryo, Mammalian
Fibroblasts / cytology
Fibroblasts / drug effects
Fibroblasts / metabolism
Forkhead Box Protein O1
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / metabolism
Gene Expression Regulation
Human Umbilical Vein Endothelial Cells / cytology
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Mice
Neovascularization, Physiologic
Primary Cell Culture
Proteasome Endopeptidase Complex / drug effects
Proteasome Endopeptidase Complex / genetics*
Proteasome Endopeptidase Complex / metabolism
Proteolysis
Signal Transduction
Vascular Cell Adhesion Molecule-1 / genetics
Vascular Cell Adhesion Molecule-1 / metabolism
Vascular Endothelial Growth Factor A / pharmacology*

Substances

Autoantigens
E-Selectin
FOXO1 protein, human
Forkhead Box Protein O1
Forkhead Transcription Factors
Foxo1 protein, mouse
Ki antigen
Vascular Cell Adhesion Molecule-1
Vascular Endothelial Growth Factor A
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
protein kinase A Calpha
Proteasome Endopeptidase Complex

Abstract

Publication types

MeSH terms

Substances

Grants and funding