Endothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2

Abstract

Activation of endothelial YAP/TAZ signaling is crucial for physiological and pathological angiogenesis. The mechanisms of endothelial YAP/TAZ regulation are, however, incompletely understood. Here we report that the protocadherin FAT1 acts as a critical upstream regulator of endothelial YAP/TAZ which limits the activity of these transcriptional cofactors during developmental and tumor angiogenesis by promoting their degradation. We show that loss of endothelial FAT1 results in increased endothelial cell proliferation in vitro and in various angiogenesis models in vivo. This effect is due to perturbed YAP/TAZ protein degradation, leading to increased YAP/TAZ protein levels and expression of canonical YAP/TAZ target genes. We identify the E3 ubiquitin ligase Mind Bomb-2 (MIB2) as a FAT1-interacting protein mediating FAT1-induced YAP/TAZ ubiquitination and degradation. Loss of MIB2 expression in endothelial cells in vitro and in vivo recapitulates the effects of FAT1 depletion and causes decreased YAP/TAZ degradation and increased YAP/TAZ signaling. Our data identify a pivotal mechanism of YAP/TAZ regulation involving FAT1 and its associated E3 ligase MIB2, which is essential for YAP/TAZ-dependent angiogenesis.

Updated Review Article: Cyclin-Dependent Kinase 4/6 Inhibitor Impact, FDA Approval, and Resistance Pathways

“…A few resistance pathways that affect CDK4/6 activity include FAT1, YAP/TAZ, and TP53. 38,39 In previous studies, the loss of FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway, which regulates transcriptional coactivators. 39 A summary of the FAT1 resistance pathway and components of the Hippo signaling pathway is found in Figure 2.…”

“…38,39 In previous studies, the loss of FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway, which regulates transcriptional coactivators. 39 A summary of the FAT1 resistance pathway and components of the Hippo signaling pathway is found in Figure 2. A study by Li et al, revealed that FAT1 loss led to CDK6 overexpression and increased minimum inhibitory concentration of CDK4/6 inhibitors by 4 to 6 folds.…”

“…When FAT1 is active, cell growth will be perturbed due to the degradation of YAP/TAZ, which are major components of the Hippo signaling pathway. 39 The loss of FAT1, as seen on the right (CDK4/6 inhibitor resistant pathway), will not have any effect on YAP/TAZ phosphorylation. The YAP/TAZ complex translocates to the nucleus and binds to TEADs (major DNA binding transcription factors), which further activate the expression of CDK6 to maintain cell proliferation.…”

“…The YAP/TAZ complex translocates to the nucleus and binds to TEADs (major DNA binding transcription factors), which further activate the expression of CDK6 to maintain cell proliferation. 38,39…”

SUMOylation of RALY promotes vasculogenic mimicry in glioma cells via the FOXD1/DKK1 pathway

“…However, neovascularization in tumors is a highly complicated process. Besides sprouting angiogenesis, many other vascularization mechanisms, such as endothelial progenitor cell (EPC) recruitment, vascular co-option, intussusceptive angiogenesis, and VM, have been discovered in tumors (Li et al 2023 ; Ayala-Dominguez et al 2019 ). VM represents a tumor microcirculation model that refers to the formation of non-endothelial blood vessels by tumor cells through extracellular matrix remodeling and deformation (Fernandez-Cortes et al 2019 ).…”