PMID- 30510113
OWN - NLM
STAT- MEDLINE
DCOM- 20200227
LR  - 20200227
IS  - 1477-9137 (Electronic)
IS  - 0021-9533 (Linking)
VI  - 132
IP  - 1
DP  - 2019 Jan 2
TI  - The Robo4-TRAF7 complex suppresses endothelial hyperpermeability in inflammation.
LID - jcs220228 [pii]
LID - 10.1242/jcs.220228 [doi]
AB  - Roundabout guidance receptor 4 (Robo4) is an endothelial cell-specific receptor 
      that stabilizes the vasculature in pathological angiogenesis. Although Robo4 has 
      been shown to suppress vascular hyperpermeability induced by vascular endothelial 
      growth factor (VEGF) in angiogenesis, the role of Robo4 in inflammation is poorly 
      understood. In this study, we investigated the role of Robo4 in vascular 
      hyperpermeability during inflammation. Endotoxemia models using Robo4(-/-) mice 
      showed increased mortality and vascular leakage. In endothelial cells, Robo4 
      suppressed tumor necrosis factor alpha (TNFalpha)-induced hyperpermeability by 
      stabilizing VE-cadherin at cell junctions, and deletion assays revealed that the 
      C-terminus of Robo4 was involved in this suppression. Through binding and 
      localization assays, we demonstrated that in endothelial cells, Robo4 binds to 
      TNF receptor-associated factor 7 (TRAF7) through interaction with the C-terminus 
      of Robo4. Gain- and loss-of-function studies of TRAF7 with or without Robo4 
      expression showed that TRAF7 is required for Robo4-mediated suppression of 
      hyperpermeability. Taken together, our results demonstrate that the Robo4-TRAF7 
      complex is a novel negative regulator of inflammatory hyperpermeability. We 
      propose this complex as a potential future target for protection against 
      inflammatory diseases.
CI  - (c) 2019. Published by The Company of Biologists Ltd.
FAU - Shirakura, Keisuke
AU  - Shirakura K
AUID- ORCID: 0000-0002-9487-9495
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Ishiba, Ryosuke
AU  - Ishiba R
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Kashio, Taito
AU  - Kashio T
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Funatsu, Risa
AU  - Funatsu R
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Tanaka, Toru
AU  - Tanaka T
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Fukada, So-Ichiro
AU  - Fukada SI
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Ishimoto, Kenji
AU  - Ishimoto K
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Hino, Nobumasa
AU  - Hino N
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Kondoh, Masuo
AU  - Kondoh M
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Ago, Yukio
AU  - Ago Y
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Fujio, Yasushi
AU  - Fujio Y
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan.
FAU - Yano, Kiichiro
AU  - Yano K
AD  - The Center for Vascular Biology Research and Division of Molecular and Vascular 
      Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
FAU - Doi, Takefumi
AU  - Doi T
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan okadabos@phs.osaka-u.ac.jp doi@phs.osaka-u.ac.jp.
FAU - Aird, William C
AU  - Aird WC
AD  - The Center for Vascular Biology Research and Division of Molecular and Vascular 
      Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
FAU - Okada, Yoshiaki
AU  - Okada Y
AUID- ORCID: 0000-0002-2962-244X
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, 565-0781, 
      Japan okadabos@phs.osaka-u.ac.jp doi@phs.osaka-u.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190102
PL  - England
TA  - J Cell Sci
JT  - Journal of cell science
JID - 0052457
RN  - 0 (Antigens, CD)
RN  - 0 (Cadherins)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Robo4 protein, mouse)
RN  - 0 (Traf7 protein, mouse)
RN  - 0 (Tumor Necrosis Factor Receptor-Associated Peptides and Proteins)
RN  - 0 (cadherin 5)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antigens, CD/metabolism
MH  - Cadherins/metabolism
MH  - *Cell Membrane Permeability
MH  - Disease Models, Animal
MH  - Endothelium, Vascular/metabolism/*pathology
MH  - Endotoxemia/chemically induced/*complications
MH  - Inflammation/etiology/metabolism/*pathology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Neovascularization, Pathologic/etiology/metabolism/*pathology
MH  - Receptors, Cell Surface/*physiology
MH  - Signal Transduction
MH  - Tumor Necrosis Factor Receptor-Associated Peptides and 
      Proteins/genetics/*metabolism
OTO - NOTNLM
OT  - Endothelial permeability
OT  - Inflammation
OT  - Robo4
OT  - TRAF7
COIS- Competing interestsThe authors declare no competing or financial interests.
EDAT- 2018/12/05 06:00
MHDA- 2020/02/28 06:00
CRDT- 2018/12/05 06:00
PHST- 2018/05/07 00:00 [received]
PHST- 2018/11/28 00:00 [accepted]
PHST- 2018/12/05 06:00 [pubmed]
PHST- 2020/02/28 06:00 [medline]
PHST- 2018/12/05 06:00 [entrez]
AID - jcs.220228 [pii]
AID - 10.1242/jcs.220228 [doi]
PST - epublish
SO  - J Cell Sci. 2019 Jan 2;132(1):jcs220228. doi: 10.1242/jcs.220228.