ZFIN ID: ZDB-PUB-150115-5
The bipartite Rac1 guanine nucleotide exchange factor engulfment and cell motility 1/dedicator of cytokinesis 180 (Elmo1/Dock180) protects endothelial cells from apoptosis in blood vessel development
Schaeker, K., Bartsch, S., Patry, C., Cramer-Stoll, S., Hillebrands, J.L., Wieland, T., Kroll, J.
Date: 2015
Source: The Journal of biological chemistry   290(10): 6408-18 (Journal)
Registered Authors: Kroll, Jens
Keywords: Dock180, ELMO1, Ras-related C3 botulinum toxin substrate 1 (Rac1), angiogenesis, apoptosis, endothelial cell, guanine nucleotide exchange factor (GEF), survival
MeSH Terms:
  • Adaptor Proteins, Signal Transducing/biosynthesis
  • Adaptor Proteins, Signal Transducing/genetics*
  • Adaptor Proteins, Signal Transducing/metabolism
  • Animals
  • Apoptosis/genetics
  • Blood Vessels/growth & development
  • Blood Vessels/metabolism*
  • Endothelial Cells/metabolism
  • Gene Expression Regulation, Developmental
  • Guanine Nucleotide Exchange Factors/genetics
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Neovascularization, Physiologic*
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • rac GTP-Binding Proteins/biosynthesis
  • rac GTP-Binding Proteins/genetics*
  • rac GTP-Binding Proteins/metabolism
  • rac1 GTP-Binding Protein/genetics
  • rac1 GTP-Binding Protein/metabolism*
PubMed: 25586182 Full text @ J. Biol. Chem.
ABSTRACT
Engulfment and cell motility 1/dedicator of cytokinesis 180 (Elmo1/Dock180)4 is a bipartite guanine nucleotide exchange factor for the monomeric GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1). Elmo1/Dock180 regulates Rac1 activity in a specific spatiotemporal manner in endothelial cells (ECs) during zebrafish development and acts downstream of the Netrin-1/Unc5-homolog B (Unc5B) signaling cascade. However, mechanistic details on the pathways by which Elmo1/Dock180 regulates endothelial function and vascular development remained elusive. In this study we aimed to analyze the vascular function of Elmo1 and Dock180 in human ECs and during vascular development in zebrafish embryos. In vitro overexpression of Elmo1 and Dock180 in ECs reduced caspase-3/7 activity and annexin V-positive cell number upon induction of apoptosis. This protective effect of Elmo1 and Dock180 is mediated by activation of Rac1, p21 activated kinase (PAK) and AKT/protein kinase B (AKT) signaling. In zebrafish, Elmo1 and Dock180 overexpression reduced the total apoptotic cell and apoptotic EC number and promoted the formation of blood vessels during embryogenesis. In conclusion, Elmo1 and Dock180 protect ECs from apoptosis by the activation of the Rac1/PAK/AKT signaling cascade in vitro and in vivo. Thus, Elmo1 and Dock180 facilitate blood vessel formation by stabilization of the endothelium during angiogenesis.
ADDITIONAL INFORMATION