DOCK180 is a Rac activator that regulates cardiovascular development by acting downstream of CXCR4.
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.
Sanematsu
Fumiyuki
F
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
Hirashima
Masanori
M
Laurin
Mélanie
M
Takii
Ryosuke
R
Nishikimi
Akihiko
A
Kitajima
Keiko
K
Ding
Guo
G
Noda
Mamiko
M
Murata
Yuzo
Y
Tanaka
Yoshihiko
Y
Masuko
Sadahiko
S
Suda
Toshio
T
Meno
Chikara
C
Côté
Jean-François
JF
Nagasawa
Takashi
T
Fukui
Yoshinori
Y
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*
C514936:CXCR4 protein, mouse; C528110:Dock180 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D019718:Receptors, CXCR4; D020744:rac GTP-Binding Proteins