Project description:VEGF is a major driver of blood vessel formation. However, the signal transduction pathways culminating into the biological consequences of VEGF signaling are partially understood. Here we show that the Hippo pathway effectors YAP and TAZ, work as a regulatory hub in mediating VEGF-VEGFR2 signaling during angiogenesis. We demonstrate that YAP/TAZ are essential for vascular development as endothelium specific deletion of YAP/TAZ leads to impaired vascularization and embryonic lethality. Mechanistically, we show that VEGF activates YAP/TAZ via its effects on actin cytoskeleton remodeling, and that activated YAP/TAZ induce a transcriptional program that results in the expression of a set of genes to further control cytoskeleton dynamics, and thus ensure a proper angiogenic response. YAP/TAZ deletion also results in VEGFR2 trafficking defects from the Golgi to the plasma membrane. Together, our study establishes YAP/TAZ as a central regulatory hub that mediates VEGF signaling, and hence, regulates angiogenesis.
Project description:VEGF is a major driver of blood vessel formation. However, the signal transduction pathways culminating into the biological consequences of VEGF signaling are partially understood. Here we show that the Hippo pathway effectors YAP and TAZ, work as a regulatory hub in mediating VEGF-VEGFR2 signaling during angiogenesis. We demonstrate that YAP/TAZ are essential for vascular development as endothelium specific deletion of YAP/TAZ leads to impaired vascularization and embryonic lethality. Mechanistically, we show that VEGF activates YAP/TAZ via its effects on actin cytoskeleton remodeling, and that activated YAP/TAZ induce a transcriptional program that results in the expression of a set of genes to further control cytoskeleton dynamics, and thus ensure a proper angiogenic response. YAP/TAZ deletion also results in VEGFR2 trafficking defects from the Golgi to the plasma membrane. Together, our study establishes YAP/TAZ as a central regulatory hub that mediates VEGF signaling, and hence, regulates angiogenesis.
Project description:The transcriptional co-activators YAP and TAZ are key regulators of organ size and tissue homeostasis, and their dysregulation contributes to human cancer. Here, we discover YAP/TAZ as bona fide downstream effectors of the alternative Wnt signaling pathway. Wnt5a/b and Wnt3a induce YAP/TAZ activation independent of canonical Wnt/β-catenin signaling. Mechanistically, we delineate the "alternative Wnt-YAP/TAZ signaling axis" that consists of Wnt-FZD/ROR-Gα12/13-Rho GTPases-Lats1/2 to promote YAP/TAZ activation and TEAD-mediated transcription. YAP/TAZ mediate the biological functions of alternative Wnt signaling, including gene expression, osteogenic differentiation, cell migration, and antagonism of Wnt/β-catenin signaling. Together, our work establishes YAP/TAZ as critical mediators of alternative Wnt signaling.
