TY - JOUR
T1 - The NADPH oxidase NOX4 promotes the directed migration of endothelial cells by stabilizing vascular endothelial growth factor receptor 2 protein
AU - Miyano, Kei
AU - Okamoto, Shuichiro
AU - Yamauchi, Akira
AU - Kawai, Chikage
AU - Kajikawa, Mizuho
AU - Kiyohara, Takuya
AU - Tamura, Minoru
AU - Taura, Masahiko
AU - Kuribayashi, Futoshi
N1 - Funding Information:
Funding and additional information—This study was supported in part by JSPS KAKENHI grant numbers JP17K08637 (to K. M.), JP18K07804 (to F. K.), and JP19K07676 (to A. Y.), in part by the Wesco Scientific Promotion Foundation (to K. M. and A. Y.), in part by the Ryobi Teien Memory Foundation (to K. M. and A. Y.), and in part by Research Project Grants (nos. R01S-003 (to K. M.), H30Y-002 (to S. O.), R01B-081 (to F. K.), and R01B-093 (to A. Y.)) from Kawasaki Medical School.
Publisher Copyright:
© 2020 Miyano et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2020/8/14
Y1 - 2020/8/14
N2 - Directed migration of endothelial cells (ECs) is an important process during both physiological and pathological angiogenesis. The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the EC surface is necessary for directed migration of these cells. Here, we used TAXIScan, an optically accessible real-time horizontal cell dynamics assay approach, and demonstrate that reactive oxygen species (ROS)-producing NADPH oxidase 4 (NOX4), which is abundantly expressed in ECs, mediates VEGF/VEGFR-2-dependent directed migration. We noted that a continuous supply of endoplasmic reticulum (ER)-retained VEGFR-2 to the plasma membrane is required to maintain VEGFR-2 at the cell surface. siRNA-mediated NOX4 silencing decreased the ER-retained form of VEGFR-2, resulting in decreased cell surface expression levels of the receptor. We also found that ER-localized NOX4 interacts with ER-retained VEGFR-2 and thereby stabilizes this ER-retained form at the protein level in the ER. We conclude that NOX4 contributes to the directed migration of ECs by maintaining VEGFR-2 levels at their surface.
AB - Directed migration of endothelial cells (ECs) is an important process during both physiological and pathological angiogenesis. The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the EC surface is necessary for directed migration of these cells. Here, we used TAXIScan, an optically accessible real-time horizontal cell dynamics assay approach, and demonstrate that reactive oxygen species (ROS)-producing NADPH oxidase 4 (NOX4), which is abundantly expressed in ECs, mediates VEGF/VEGFR-2-dependent directed migration. We noted that a continuous supply of endoplasmic reticulum (ER)-retained VEGFR-2 to the plasma membrane is required to maintain VEGFR-2 at the cell surface. siRNA-mediated NOX4 silencing decreased the ER-retained form of VEGFR-2, resulting in decreased cell surface expression levels of the receptor. We also found that ER-localized NOX4 interacts with ER-retained VEGFR-2 and thereby stabilizes this ER-retained form at the protein level in the ER. We conclude that NOX4 contributes to the directed migration of ECs by maintaining VEGFR-2 levels at their surface.
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U2 - 10.1074/jbc.ra120.014723
DO - 10.1074/jbc.ra120.014723
M3 - Article
C2 - 32616654
AN - SCOPUS:85089787287
VL - 295
SP - 11877
EP - 11890
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 33
ER -