Multiphase coalescence mediates Hippo pathway activation.

The function of biomolecular condensates is often restricted by condensate dissolution. Whether condensates can be suppressed without condensate dissolution is unclear. Here, we show that upstream regulators of the Hippo signaling pathway form functionally antagonizing condensates, and their coalescence into a common phase provides a mode of counteracting the function of biomolecular condensates without condensate dissolution. Specifically, the negative regulator SLMAP forms Hippo-inactivating condensates to facilitate pathway inhibition by the STRIPAK complex. In response to cell-cell contact or osmotic stress, the positive regulators AMOT and KIBRA form Hippo-activating condensates to facilitate pathway activation. The functionally antagonizing SLMAP and AMOT/KIBRA condensates further coalesce into a common phase to inhibit STRIPAK function. These findings provide a paradigm for restricting the activity of biomolecular condensates without condensate dissolution, shed light on the molecular principles of multiphase organization, and offer a conceptual framework for understanding upstream regulation of the Hippo signaling pathway.

Control of stem cell renewal and fate by YAP and TAZ.

Complex physiological processes control whether stem cells self-renew, differentiate or remain quiescent. Two decades of research have placed the Hippo pathway, a highly conserved kinase signalling cascade, and its downstream molecular effectors YAP and TAZ at the nexus of this decision. YAP and TAZ translate complex biological cues acting on stem cells - from mechanical forces to cellular metabolism - into genome-wide effects to mediate stem cell functions. While aberrant YAP/TAZ activity drives stem cell dysfunction in ageing, tumorigenesis and disease, therapeutic targeting of Hippo signalling and YAP/TAZ can boost stem cell activity to enhance regeneration. In this Review, we discuss how YAP/TAZ control the self-renewal, fate and plasticity of stem cells in different contexts, how dysregulation of YAP/TAZ in stem cells leads to disease, and how therapeutic modalities targeting YAP/TAZ may benefit regenerative medicine and cancer therapy.

WWTR1(TAZ)-CAMTA1 reprograms endothelial cells to drive epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a poorly understood and devastating vascular cancer. Sequencing of EHE has revealed a unique gene fusion between the Hippo pathway nuclear effector TAZ (WWTR1) and the brain-enriched transcription factor CAMTA1 in ∼90% of cases. However, it remains unclear whether the TAZ-CAMTA1 gene fusion is a driver of EHE, and potential targeted therapies are unknown. Here, we show that TAZ-CAMTA1 expression in endothelial cells is sufficient to drive the formation of vascular tumors with the distinctive features of EHE, and inhibition of TAZ-CAMTA1 results in the regression of these vascular tumors. We further show that activated TAZ resembles TAZ-CAMTA1 in driving the formation of EHE-like vascular tumors, suggesting that constitutive activation of TAZ underlies the pathological features of EHE. We show that TAZ-CAMTA1 initiates an angiogenic and regenerative-like transcriptional program in endothelial cells, and disruption of the TAZ-CAMTA1-TEAD interaction or ectopic expression of a dominant negative TEAD in vivo inhibits TAZ-CAMTA1-mediated transformation. Our study provides the first genetic model of a TAZ fusion oncoprotein driving its associated human cancer, pinpointing TAZ-CAMTA1 as the key driver and a valid therapeutic target of EHE.

Case Report of Fibro-Adipose Vascular Anomaly (FAVA) with Activating Somatic PIK3CA Mutation.

Fibro-adipose vascular anomaly (FAVA) is a recently described complex and painful benign lesion found in young adults and the pediatric population composed of intramuscular vascular, fibrous, and adipose tissues. A previous report has identified the presence of somatic mosaic mutations in the gene for the catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) in cases of FAVA. Herein, we present a case of FAVA found in a 23-year-old male patient who presented with chronic wrist pain associated with a mass, and we identified an associated somatic activating mutation (H1047R) in PIK3CA. We briefly review the relevant literature surrounding the identification and histology of FAVA, the known mutational spectrum, downstream signaling pathways, and relevant treatment modalities. Our case highlights the association between FAVA and somatic mosaic activating PIK3CA mutations.

The Hippo Pathway in Liver Homeostasis and Pathophysiology.

Studies of the regenerative capacity of the liver have converged on the Hippo pathway, a serine/threonine kinase cascade discovered in Drosophila and conserved from unicellular organisms to mammals. Genetic studies of mouse and rat livers have revealed that the Hippo pathway is a key regulator of liver size, regeneration, development, metabolism, and homeostasis and that perturbations in the Hippo pathway can lead to the development of common liver diseases, such as fatty liver disease and liver cancer. In turn, pharmacological targeting of the Hippo pathway may be utilized to boost regeneration and to prevent the development and progression of liver diseases. We review current insights provided by the Hippo pathway into liver pathophysiology. Furthermore, we present a path forward for future studies to understand how newly identified components of the Hippo pathway may control liver physiology and how the Hippo pathway is regulated in the liver.

TERRA and the histone methyltransferase Dot1 cooperate to regulate senescence in budding yeast.

The events underlying senescence induced by critical telomere shortening are not fully understood. Here we provide evidence that TERRA, a non-coding RNA transcribed from subtelomeres, contributes to senescence in yeast lacking telomerase (tlc1Δ). Levels of TERRA expressed from multiple telomere ends appear elevated at senescence, and expression of an artificial RNA complementary to TERRA (anti-TERRA) binds TERRA in vivo and delays senescence. Anti-TERRA acts independently from several other mechanisms known to delay senescence, including those elicited by deletions of EXO1, TEL1, SAS2, and genes encoding RNase H enzymes. Further, it acts independently of the senescence delay provided by RAD52-dependent recombination. However, anti-TERRA delays senescence in a fashion epistatic to inactivation of the conserved histone methyltransferase Dot1. Dot1 associates with TERRA, and anti-TERRA disrupts this interaction in vitro and in vivo. Surprisingly, the anti-TERRA delay is independent of the C-terminal methyltransferase domain of Dot1 and instead requires only its N-terminus, which was previously found to facilitate release of telomeres from the nuclear periphery. Together, these data suggest that TERRA and Dot1 cooperate to drive senescence.