title: 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.
abstract: Engulfment and cell motility 1/dedicator of cytokinesis 180 (Elmo1/Dock180) 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.
authors.affiliation: From the Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM) and Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany, and.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schäker
authors.affiliation: From the Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM) and.
authors.forename: Susanne
authors.initials: S
authors.lastname: Bartsch
authors.affiliation: From the Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM) and.
authors.forename: Christian
authors.initials: C
authors.lastname: Patry
authors.affiliation: From the Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM) and.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Stoll
authors.affiliation: Department of Pathology and Medical Biology, Division of Pathology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.
authors.forename: Jan-Luuk
authors.initials: JL
authors.lastname: Hillebrands
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.affiliation: From the Department of Vascular Biology and Tumor Angiogenesis, Center for Biomedicine and Medical Technology Mannheim (CBTM) and Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany, and jens.kroll@medma.uni-heidelberg.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Kroll
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001808:Blood Vessels / Q000254:growth & development / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018919:Neovascularization, Physiologic; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D020744:rac GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099818:DOCK1 protein, human; C465214:ELMO1 protein, human; D020662:Guanine Nucleotide Exchange Factors; C107953:RAC1 protein, human; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein
keywords: Dock180; ELMO1; Ras-related C3 botulinum toxin substrate 1 (Rac1); angiogenesis; apoptosis; endothelial cell; guanine nucleotide exchange factor (GEF); survival