Activation of the planar cell polarity formin DAAM1 leads to inhibition of endothelial cell proliferation, migration, and angiogenesis

Abstract

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 Cterminal 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.Wnt signaling | microtubule stabilization | zebrafish | dishevelledassociated activator of morphogenesis 1 | HUVEC

The Wnt/Planar Cell Polarity Signaling Pathway Contributes to the Integrity of Tight Junctions in Brain Endothelial Cells

“…25 As a next step, hCMEC/D3 cells were treated during 6 days with Wnt5a (40% conditioned medium of Wnt5a producing LM (TK) cells (ATCC #CRL-2814), as previously described. 26 As control, lithium chloride 10 mmol/L was used as an activator of the Wnt/b-catenin canonical pathway: indeed, we observed that hCMEC/D3 cells were treated with control small interfering RNA (si CTR) or two distinct siRNAs against PAR-3 (#A, #B).…”

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

“…The Wnt/PCP pathway also appears to play a role in angiogenesis, particularly vascular morphogenesis and endothelial cell proliferation (44). Recently, the formin Dvl-associated activator of morphogenesis-1, an essential player in cytoskeletal organization, was found to be a downstream intermediate of the Wnt/PCP pathway in regulating endothelial cell proliferation and angiogenesis (45). It has been recently demonstrated that Fz-4 acts in arterial formation and organization through a Wnt/ PCP pathway, altering Golgi organization and tubulin acetylation (46).…”

Vangl2 cooperates with Rab11 and Myosin V to regulate apical constriction during vertebrate gastrulation

“…Although the roles and molecular interactions of PCP proteins in fly epithelia have been studied in some detail (Bastock et al, 2003;Jenny et al, 2005;Tree et al, 2002b;Wu and Mlodzik, 2008), accumulating evidence indicates that vertebrate PCP components have functions that are not directly related to cell polarity in the plane of the tissue. Vertebrate PCP proteins are now known to control a large number of developmental processes, including inner ear polarity (Montcouquiol et al, 2003), left-right patterning (Antic et al, 2010;Borovina et al, 2010;Hashimoto et al, 2010;Song et al, 2010), mesodermal convergent extension (Keller, 2002;Sokol, 2000), neural tube closure (Copp and Greene, 2010;Sokol, 1996), neurite extension, neuronal migration, branching morphogenesis and vascular development (Carroll and Yu, 2012;Gray et al, 2011;Jessen et al, 2002;Ju et al, 2010;Tissir and Goffinet, 2013;Yates et al, 2010b). The molecular mechanisms underlying this pleiotropic behavior of PCP proteins in morphogenesis remain poorly understood.…”