Naslov
The role of Frizzled-4 and -6 in angiogenesis

Autori
Samarzija, Ivana ; Sini, Patrizia ; Schlange, Thomas ; Hynes, Nancy

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, ostalo

Skup
Targeting the Kinome

Mjesto i datum
Basel, Švicarska, 04.12.2006. - 06.12.2006

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Wnt, angiogenesis

Sažetak
The Wnt family of secreted signaling molecules and the downstream components of Wnt signal transduction are highly conserved among animal species. Wnt molecules bind to and activate cell surface receptors encoded by the Frizzled (Fzd) gene family leading to phosphorylation of an intracellular intermediate Dishevelled (Dvl). Several Wnt-mediated independent intracellular signaling pathways have been characterized. These include the canonical pathway, which results in stabilization and nuclear translocation of β-catenin, the planar cell polarity (PCP) pathway and the Ca2+ pathway. Accumulating evidence suggests that the particular pathway activated depends on multiple factors, including the cell identity as well as the specific Wnt:Fzd pair. Several groups have identified a role for signaling through the Wnt pathway in both normal as well as situations of pathological angiogenesis, such as neovascularization of tumours. Wnt ligands as well as their receptors, are expressed by endothelial and vascular smooth muscle cells. β-catenin, a key downstream component of the Wnt signaling pathway, is stabilized in the neovascular endothelium and numerous genes essential for angiogenesis have been demonstrated to be targets of the Wnt signaling pathway. Despite this, detailed characterization of the role that activation of specific Fzd receptors plays in vascular development is lacking. We have initiated studies to determine the identity of the Fzd receptors expressed on endothelial cells and how these receptors directly regulate endothelial cell biology. Analysis of the gene expression profile of various endothelial cell lines indicated that Fzd-4 and Fzd-6 are the only members of this family expressed in both human and mouse endothelial cells. We examined the effect of recombinant Wnt-3a and Wnt-5a on Dvl phoshorylation, apoptosis and survival of Human Umbilical Vein Endothelial Cells (HUVEC). We observed that, although both the ligands induced Dvl phosphorylation, only Wnt-3a led to an increase proliferation, but not survival, of HUVEC. The Wnt- induced response was blocked by co-addition of a soluble form of Fzd-4. The effect on endothelial cell biology was not VEGF-(FGF/EGF) signaling dependent. Indeed, specific inhibitors for VEGFR, EGFR, and FGFR did not affect Wnt-induced HUVEC proliferation. Currently, we are carrying out studies to further delineate the signaling cascades and how canonical and non-canonical Wnt signaling pathway may regulate the biological response in endothelial cells. In addition, we are addressing the role of Fzd-4 and Fzd6 in the in vivo development of normal as well as pathology associated vasculature employing Fzd-4 and Fzd-6-null mice.

Izvorni jezik
Engleski

Znanstvena područja
Biologija

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