Hippo-YAP/TAZ signaling in angiogenesis

Abstract

Angiogenesis is a complex, multistep process involving dynamic changes in endothelial cell (EC) shapes and behaviors, especially in specialized cell types such as tip cells (with active filopodial extensions), stalk cells (with less motility) and phalanx cells (with stable junction connections). The Hippo-Yes-associated protein (YAP)/ transcription activator with PDZ binding motif (TAZ) signaling plays a critical role in development, regeneration and organ size by regulating cell-cell contact and actin cytoskeleton dynamics. Recently, with the finding that YAP is expressed in the front edge of the developing retinal vessels, Hippo-YAP/TAZ signaling has emerged as a new pathway for blood vessel development. Intriguingly, the LATS1/2-mediated angiomotin (AMOT) family and YAP/TAZ activities contribute to EC shapes and behaviors by spatiotemporally modulating actin cytoskeleton dynamics and EC junction stability. Herein, we summarize the recent understanding of the role of Hippo-YAP/TAZ signaling in the processes of EC sprouting and junction maturation in angiogenesis. [BMB Reports 2018; 51(3): 157-162].

Fig. 1

Schematic diagram depicting the roles of the Hippo-YAP/TAZ signaling in EC sprouting and junction maturation. (A) VEGF exposure to ECs inactivates LATS1/2, leading to dephosphorylation of AmotL1 and YAP/TAZ in tip and stalk cells. AmotL1 binds with F-actin, regulating the dynamics of F-actin filament via Syx. YAP/TAZ is shuttled into nucleus, increasing expressions of a variety of genes, which are essential for the initiation and expansion of angiogenic sprouting. Syx, Rho GTPase-exchanging factor protein; AmotL1, angiomotin-like 1. (B) Endothelial cell-cell contact induces the Hippo kinase activity. In phalanx cells, LATS1/2 activation phosphorylates AmotL1 and YAP/TAZ. The phosphorylated AmotL1 forms complex with PatJ and Syx to regulate the small Rho GTPase for actomyosin contractility at TJs. The phosphorylated YAP/TAZ leads to the interaction with AmotL1 and ZO proteins at TJs. In addition, the phosphorylated YAP/TAZ is recruited to VE-cadherin-catenin complex at AJs, and degraded in the cytoplasm in the proteasome-dependent proteolysis. Meanwhile, in quiescent ECs, VE-cadherin-mediated Akt activity phosphorylates YAP. AmotL1 is ubiquitinated by Hecw2 and recruited to TJs to promote TJ stability and to seemingly maintain the retention of YAP at EC junction/ cytoplasm. TJ, tight junction; AJ, adherens junction; ZO, zonula occludens; PatJ, polarity-/junction-associated scaffold protein; Hecw2, HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2.