Frizzled‐7 turnover at the plasma membrane is differentially regulated by non‐canonical and canonical Wnts and Wnt‐signaling components in endothelial cells.

Abstract

Endothelial cell (EC) migration is a key feature of vascular development, angiogenesis and tissue repair as well as of progression of numerous diseases. The Frizzled (Fz) receptors are cell polarity factors, which control morphogenesis through interaction with the Wnt ligands and activation of the beta‐catenin/TCF, planar cell polarity (PCP) and Ca2+/PKC pathways. We have recently identified a specific cleavage of the Fz7 receptors regulated by cell density and calpain1, a protease involved in the turnover of adhesion complexes. In EC, Fz7 localization at the plasma membrane was restricted to the leading edge of migrating cells and to early cell‐cell adhesion sites where it colocalized with VE‐cadherin and beta‐catenin. Interestingly, in a cell‐autonomous fashion, the non canonical Wnt11 and Wnt5A, and the Wnt‐signaling component dvl2 prevented Fz7 cleavage, while the canonical Wnt13A and stable beta‐catenin forms increased it. Dvl2 prevented also phosphorylation events taking place within Fz7 C‐terminus. Fz7 mutants displaying a decreased cleavage presented an altered phosphorylation pattern, an absence of dvl2 translocation at the plasma membrane and defect of beta‐catenin polarization during EC migration. Together our data show that Fz7 recapitulates a PCP pathway in EC regulated by cell‐cell adhesion and by non canonical Wnts. This work is supported by NIH‐HL68698 grant.