The Biology of YAP/TAZ: Hippo Signaling and Beyond

Abstract

The transcriptional regulators YAP and TAZ are the focus of intense interest given their remarkable biological properties in development, tissue homeostasis and cancer. YAP and TAZ activity is key for the growth of whole organs, for amplification of tissue-specific progenitor cells during tissue renewal and regeneration, and for cell proliferation. In tumors, YAP/TAZ can reprogram cancer cells into cancer stem cells and incite tumor initiation, progression and metastasis. As such, YAP/TAZ are appealing therapeutic targets in cancer and regenerative medicine. Just like the function of YAP/TAZ offers a molecular entry point into the mysteries of tissue biology, their regulation by upstream cues is equally captivating. YAP/TAZ are well known for being the effectors of the Hippo signaling cascade, and mouse mutants in Hippo pathway components display remarkable phenotypes of organ overgrowth, enhanced stem cell content and reduced cellular differentiation. YAP/TAZ are primary sensors of the cell's physical nature, as defined by cell structure, shape and polarity. YAP/TAZ activation also reflects the cell "social" behavior, including cell adhesion and the mechanical signals that the cell receives from tissue architecture and surrounding extracellular matrix (ECM). At the same time, YAP/TAZ entertain relationships with morphogenetic signals, such as Wnt growth factors, and are also regulated by Rho, GPCRs and mevalonate metabolism. YAP/TAZ thus appear at the centerpiece of a signaling nexus by which cells take control of their behavior according to their own shape, spatial location and growth factor context.

The sweet side of YAP/TAZ

“…We thus propose that the enzyme mediating the first committed step of glycolysis, at the heart of several allosteric and signaling mechanisms, also informs nuclear gene transcription through YAP/TAZ. This study highlights the notion that YAP/TAZ are atypical oncogenic molecules that, rather than being activated by genetic events, lay downstream of multiple cancer hallmarks embedded in the tumor microenvironment 3 . Our data, together with the recent observation that cholesterol biosynthesis and energy stress also regulate YAP/TAZ, [4][5][6] indicates that YAP/TAZ are activated downstream of metabolic pathways, possibly triggered by other oncogenic insults; in this view, YAP/TAZ may thus represent a general "bottleneck" for tumorigenesis, bridging information from the glucose and lipid metabolic state into cell proliferation and aggressive behaviors of cancer cells.…”

“…2 Starting from this provocative idea, we explored what happens to gene transcription in breast cancer cells upon inhibition of glucose metabolism by 2-deoxy-glucose, and found by gene set enrichment analyses (GSEA) a striking correlation between genes regulated by glucose metabolism and those regulated by YAP/ TAZ, transcriptional cofactors downstream of the Hippo pathway. 3 Prompted by this observation we then found that glucose uptake and a sustained flux of glucose through aerobic glycolysis directly support YAP/TAZ, because treatments that reprogram cellular metabolism away from aerobic glycolysis induce corresponding reductions in YAP/TAZ transcriptional activity. Accordingly, inhibition of glucose uptake, or knockdown of key enzymes of glycolysis, hampered YAP/TAZ-induced in vitro tumorigenic phenotypes in breast cancer cells, such as proliferation, clonogenic activity and self-renewal properties.…”

Oscillatory Strain Promotes Vessel Stabilization and Alignment through Fibroblast YAP‐Mediated Mechanosensitivity

“…YAP can be localized in the cytoplasm or translocated to the nucleus, where it associates with TEAD transcription factors 7. Previous studies have shown that various forms of mechanical stimulation, such as substrate stiffness, strain, and shear stress, affected YAP localization by actin fiber remodeling 6, 8, 9, 10. YAP was shown to be involved in the effect of shear stress on ECs and blood vessels,10 however its role in the effect of mechanical strain on vascularization is yet to be established.…”

The emerging role of YAP/TAZ in mechanotransduction

“…Recently, YAP/TAZ-the main transcriptional effectors of the Hippo signalling pathway, a major growth regulatory pathway within metazoa-have been identified as key mechanotransducers acting by nuclear relays of mechanical stimuli (1).…”

“…YAP/TAZ nuclear accumulation and activation has been associated with organ growth, increase in cell size, loss of contact inhibition and tumour growth, cellular proliferation and inhibition of apoptotic signals (1,2). The emergence of these functions have been realized through binding to TEAD, SMAD1/2/3, PPARγ, TBX5 and TTF1 where YAP/TAZ acts as a transcriptional co-factor, thereby regulating >400 genes (1,2).…”