title: DOCK180 is a Rac activator that regulates cardiovascular development by acting downstream of CXCR4.
abstract: BACKGROUND
  During embryogenesis, the CXC chemokine ligand (CXCL)12 acts on endothelial cells to control cardiac development and angiogenesis. Although biological functions of CXCL12 are exerted in part through activation of the small GTPase Rac, the pathway leading from its receptor CXC chemokine receptor (CXCR)4 to Rac activation remains to be determined.
  
  
  OBJECTIVE
  DOCK180 (dedicator of cytokinesis), an atypical Rac activator, has been implicated in various cellular functions. Here, we examined the role of DOCK180 in cardiovascular development.
  
  
  RESULTS
  DOCK180 associates with ELMO (engulfment and cell motility) through the N-terminal region containing a Src homology 3 domain. We found that targeted deletion of the Src homology 3 domain of DOCK180 in mice leads to embryonic lethality with marked reduction of DOCK180 expression at the protein level. These mutant mice, as well as DOCK180-deficient mice, exhibited multiple cardiovascular abnormalities resembling those seen in CXCR4-deficient mice. In DOCK180 knocked down endothelial cells, CXCL12-induced Rac activation was impaired, resulting in a marked reduction of cell motility.
  
  
  CONCLUSIONS
  These results suggest that DOCK180 links CXCR4 signaling to Rac activation to control endothelial cell migration during cardiovascular development.
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sanematsu
authors.forename: Masanori
authors.initials: M
authors.lastname: Hirashima
authors.forename: Mélanie
authors.initials: M
authors.lastname: Laurin
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takii
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishikimi
authors.forename: Keiko
authors.initials: K
authors.lastname: Kitajima
authors.forename: Guo
authors.initials: G
authors.lastname: Ding
authors.forename: Mamiko
authors.initials: M
authors.lastname: Noda
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Murata
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Sadahiko
authors.initials: S
authors.lastname: Masuko
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Chikara
authors.initials: C
authors.lastname: Meno
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Côté
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagasawa
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D004730:Endothelium, Vascular / Q000196:embryology / Q000254:growth & development / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000502:physiology*; D006321:Heart / Q000196:embryology* / Q000254:growth & development*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: C514936:CXCR4 protein, mouse; C528110:Dock180 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D019718:Receptors, CXCR4; D020744:rac GTP-Binding Proteins