Functional divergence of WWC family proteins in human endothelial cells

The Hippo signaling pathway plays a crucial role in regulating endothelial cell (EC) proliferation, migration, and vascular development. While the functions of upstream scaffold proteins within this pathway are not well understood, the human genome contains a third member of the WWC family, WWC3, which is absent in mice. This disparity suggests that human endothelial Hippo signaling may be regulated differently than in mice.

To investigate the roles of WWC2 and WWC3 in human ECs, researchers utilized siRNA-mediated knockdown. Surprisingly, they discovered that WWC3 is the primary regulator of canonical Hippo signaling, exerting a more substantial impact on LATS1/2 phosphorylation, YAP/TAZ localization, and expression of Hippo target genes compared to WWC2. Moreover, WWC3 deletion led to alterations in endothelial morphology and a partial endothelial-to-mesenchymal transition-like (EndoMT-like) phenotype.

In contrast, WWC2 demonstrated a lesser effect on canonical Hippo signaling but was essential for maintaining normal VEGF signaling dynamics. Despite their distinct molecular functions, the depletion of either WWC2 or WWC3 impaired EC proliferation, migration, and cord formation in vitro. The findings of this study indicate that WWC family proteins exhibit overlapping yet unique roles in human ECs.

Specifically, WWC3 acts as the primary regulator of canonical Hippo signaling, while WWC2 more effectively modulates VEGF signaling. These results highlight the unexpected functional specialization among WWC proteins and suggest that the regulation of Hippo signaling in human ECs diverges from the conclusions drawn from mouse studies.