CYLD regulates angiogenesis by mediating vascular endothelial cell migration.
Cylindromatosis (CYLD) is a deubiquitinase that was initially identified as a tumor suppressor and has recently been implicated in diverse normal physiologic processes. In this study, we have investigated the involvement of CYLD in angiogenesis, the formation of new blood vessels from preexisting ones. We find that knockdown of CYLD expression significantly impairs angiogenesis in vitro in both matrigel-based tube formation assay and collagen-based 3-dimensional capillary sprouting assay. Disruption of CYLD also remarkably inhibits angiogenic response in vivo, as evidenced by diminished blood vessel growth into the angioreactors implanted in mice. Mechanistic studies show that CYLD regulates angiogenesis by mediating the spreading and migration of vascular endothelial cells. Silencing of CYLD dramatically decreases microtubule dynamics in endothelial cells and inhibits endothelial cell migration by blocking the polarization process. Furthermore, we identify Rac1 activation as an important factor contributing to the action of CYLD in regulating endothelial cell migration and angiogenesis. Our findings thus uncover a previously unrecognized role for CYLD in the angiogenic process and provide a novel mechanism for Rac1 activation during endothelial cell migration and angiogenesis.
Gao
Jinmin
J
Department of Genetics and Cell Biology, Key Laboratory of Bioactive Materials of Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China.
Sun
Lei
L
Huo
Lihong
L
Liu
Min
M
Li
Dengwen
D
Zhou
Jun
J
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D000074749:Deubiquitinating Enzyme CYLD; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014945:Wound Healing; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
C107953:RAC1 protein, human; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD; D020830:rac1 GTP-Binding Protein