Abstract
Angiogenesis is an essential process during development. Abnormal angiogenesis also contributes to many disease conditions such as tumor and retinal diseases. Previous studies have established the Hippo signaling pathway effector Yes-associated protein (YAP) as a crucial regulator of angiogenesis. In ECs, activated YAP promotes endothelial cell proliferation, migration and sprouting. YAP activity is regulated by vascular endothelial growth factor (VEGF) and mechanical cues such as extracellular matrix (ECM) stiffness. However, it is unclear how VEGF or ECM stiffness signal to YAP, especially how dephosphorylation of YAP occurs in response to VEGF stimulus or ECM stiffening. Here, we show that protein phosphatase 2A (PP2A) is required for this process. Blocking PP2A activity abolishes VEGF or ECM stiffening mediated YAP activation. Systemic administration of a PP2A inhibitor suppresses YAP activity in blood vessels in developmental and pathological angiogenesis mouse models. Consistently, PP2A inhibitor also inhibits sprouting angiogenesis. Mechanistically, PP2A directly interacts with YAP, and this interaction requires proper cytoskeleton dynamics. These findings identify PP2A as a crucial mediator of YAP activation in ECs and hence as an important regulator of angiogenesis.
Highlights
Extension of the vascular network is mediated by endothelial cell sprouting, migration, and proliferation
By checking the phosphorylation status of Yes-associated protein (YAP), we found that LB100 treatment resulted in a hyper-phosphorylation of YAP in human umbilical vein endothelial cells (HUVECs)
In response to pro-angiogenic stimuli such as vascular endothelial growth factor (VEGF) or extracellular matrix (ECM) rigidity, the phosphorylation of YAP/transcriptional coactivator with PDZ-binding motif (TAZ) is reduced, which further leads to its nuclear translocation and activation
Summary
Extension of the vascular network is mediated by endothelial cell sprouting, migration, and proliferation. Recent studies have established Yes-associated protein (YAP), and its paralog transcriptional coactivator with PDZ-binding motif (TAZ; known as WWTR1), as crucial regulators of angiogenesis (Kim et al, 2017; Wang et al, 2017). YAP/TAZ are the ultimate effectors of the Hippo signaling pathway. They shuttle between the cytoplasm and the nucleus, where they associate with transcriptional factor and regulate a set of target gene expression. The activity of YAP/TAZ can be suppressed by the core components of hippo pathway, containing a kinase cascade including MST1/2 and LATS1/2. MST1/2 phosphorylate LATS1/2, which phosphorylate YAP/TAZ, causing their cytoplasmic sequestration and subsequent degradation (Totaro et al, 2018)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
