Activation of the planar cell polarity formin DAAM1 leads to inhibition of endothelial cell proliferation, migration, and angiogenesis.
The Wnt/planar cell polarity (PCP) pathway regulates directed cell movement during development and was recently found to play a critical role in endothelial cell proliferation and angiogenesis [Zhang Y, et al. (2006) Chem Biol 13:1001-1009; Masckauchan TN, et al. (2006) Mol Biol Cell 17:5163-5172]. However, the mechanisms by which PCP signaling components regulate angiogenesis remain unknown. We report that expression of a constitutively active C-terminal domain of Dishevelled-associated activator of morphogenesis 1 (DAAM1) selectively inhibited endothelial cell proliferation. Moreover, this activated construct suppressed endothelial cell migration and the ability to form coordinated networks in vivo and in vitro. Although constitutively active DAAM1 (CDAAM1) induced both actin polymerization and microtubule (MT) stabilization, the stabilization of MTs alone was sufficient to inhibit endothelial cell growth selectively. Inhibition of actin polymerization alone by jasplakinolide treatment failed to reproduce the inhibitory effects of CDAAM1. These results indicate that DAAM1 regulates endothelial cell growth through MT stabilization in a cell type-selective manner and suggest that PCP signaling plays a pivotal role in angiogenesis by regulating MT stabilization.
Ju
Rong
R
Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
Cirone
Pasquale
P
Lin
Shengda
S
Griesbach
Hilary
H
Slusarski
Diane C
DC
Crews
Craig M
CM
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D016764:Cell Polarity / Q000235:genetics; D049109:Cell Proliferation; D004285:Dogs; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008840:Microfilament Proteins; D008954:Models, Biological; D009389:Neovascularization, Pathologic; D015398:Signal Transduction; D015027:Zebrafish; D020741:rho GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; C499094:DAAM1 protein, human; D008840:Microfilament Proteins; D049452:Green Fluorescent Proteins; D020741:rho GTP-Binding Proteins