DOCK180 is a rac activator that regulates cardiovascular development by acting downstream of CXCR4

Fumiyuki Sanematsu, Masanori Hirashima, Mélanie Laurin, Ryosuke Takii, Akihiko Nishikimi, Keiko Kitajima, Guo Ding, Mamiko Noda, Yuzo Murata, Yoshihiko Tanaka, Sadahiko Masuko, Toshio Suda, Chikara Meno, Jean François Côté, Takashi Nagasawa, Yoshinori Fukui

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Rationale: 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. Methods and 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.

Original languageEnglish
Pages (from-to)1102-1105
Number of pages4
JournalCirculation research
Volume107
Issue number9
DOIs
Publication statusPublished - Oct 29 2010

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this