MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway.

The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members--Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway

Determinants of Unlawful File Sharing: A Scoping Review

We employ a scoping review methodology to consider and assess the existing evidence on the determinants of unlawful file sharing (UFS) transparently and systematically. Based on the evidence, we build a simple conceptual framework to model the psychological decision to engage in UFS, purchase legally or do nothing. We identify social, moral, experiential, technical, legal and financial utility sources of the decision to purchase or to file share. They interact in complex ways. We consider the strength of evidence within these areas and note patterns of results. There is good evidence for influences on UFS within each of the identified determinants, particularly for self-reported measures, with more behavioral research needed. There are also indications that the reasons for UFS differ across media; more studies exploring media other than music are required

Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade

The Hippo pathway senses cellular conditions and regulates YAP/TAZ to control cellular and tissue homeostasis, while TBK1 is central for cytosolic nucleic acid sensing and antiviral defence. The correlation between cellular nutrient/physical status and host antiviral defence is interesting but not well understood. Here we find that YAP/TAZ act as natural inhibitors of TBK1 and are vital for antiviral physiology. Independent of transcriptional regulation and through the transactivation domain, YAP/TAZ associate directly with TBK1 and abolish virus-induced TBK1 activation, by preventing TBK1 Lys63-linked ubiquitylation and the binding of adaptors/substrates. Accordingly, YAP/TAZ deletion/depletion or cellular conditions inactivating YAP/TAZ through Lats1/2 kinases relieve TBK1 suppression and boost antiviral responses, whereas expression of the transcriptionally inactive YAP dampens cytosolic RNA/DNA sensing and weakens the antiviral defence in cells and zebrafish. Thus, we describe a function of YAP/TAZ and the Hippo pathway in innate immunity, by linking cellular nutrient/physical status to antiviral host defence

Characterization of Hippo pathway regulation and the physiological implications of its downstream effectors YAP and TAZ

The Hippo pathway and its downstream effectors, transcriptional coactivators YAP and TAZ, are important for regulating tissue homeostasis and their dysregulation has been implicated in many human diseases and cancer. However, it is not clear how the Hippo pathway becomes dysregulated because few mutations have been identified in Hippo pathway components. Therefore, recent work in the Hippo field has focused on identifying upstream regulators of the Hippo pathway. Nevertheless, it is not always clear which components are most physiologically relevant in regulating YAP/TAZ. To provide an overview of which components are most physiologically relevant in regulating YAP/TAZ, we used CRISPR/Cas9 to create knockout cell lines for many of these components and tested their responses to a variety of physiological signals to determine which components are most critical in regulating YAP/TAZ. By this approach, we demonstrate that NF2 and RHOA are important regulators of YAP/TAZ, and TAOK1/3 are direct kinases for LATS1/2.Additionally, YAP and TAZ are traditionally viewed as being largely redundant, although there are evolutionary, structural, and physiological differences that suggest there may be differences in how they are regulated and in their downstream functions. To delineate any differences between YAP and TAZ, we compared LATS1/2 KO cells, in which YAP/TAZ are constitutively-active, YAP KO, TAZ KO, and YAP/TAZ KO cells, in which YAP/TAZ are constitutively-inactive. We found that inactivation of YAP had a much greater negative effect on many measures of cell physiology, including cell spreading, cell volume, glucose uptake and metabolism, cell proliferation, and migration, while YAP activation in the LATS1/2 KO cells had the opposite effect. Differences between YAP and TAZ may be explained by differences in protein stability and expression, as YAP protein expression is much higher than that of TAZ. We also identified some differences in the transcriptional profiles induced by YAP and TAZ, suggesting that, although they are largely similar, there may be important distinctions between YAP and TAZ

Disease implications of the Hippo/YAP pathway.

The Hippo signaling pathway is important for controlling organ size and tissue homeostasis. Originally identified in Drosophila melanogaster, the core components of the Hippo pathway are highly conserved in mammals. The Hippo pathway can be modulated by a wide range of stimuli, including G protein-coupled receptor (GPCR) signaling, changes in the actin cytoskeleton, cell-cell contact, and cell polarity. When activated, the Hippo pathway functions as a tumor suppressor to limit cell growth. However, dysregulation by genetic inactivation of core pathway components or amplification or gene fusion of its downstream effectors results in increased cell proliferation and decreased apoptosis and differentiation. Unsurprisingly, this can lead to tissue overgrowth, tumorigenesis, and many other diseases

Critical roles of phosphoinositides and NF2 in Hippo pathway regulation

The Hippo pathway is a master regulator of tissue homeostasis and organ size. NF2 is a well-established tumor suppressor, and loss of NF2 severely compromises Hippo pathway activity. However, the precise mechanism of how NF2 mediates upstream signals to regulate the Hippo pathway is not clear. Here we report that, in mammalian cells, NF2's lipid-binding ability is critical for its function in activating the Hippo pathway in response to osmotic stress. Mechanistically, osmotic stress induces PI(4,5)P2 plasma membrane enrichment by activating the PIP5K family, allowing for NF2 plasma membrane recruitment and subsequent downstream Hippo pathway activation. An NF2 mutant deficient in lipid binding is unable to activate the Hippo pathway in response to osmotic stress, as measured by LATS and YAP phosphorylation. Our findings identify the PIP5K family as novel regulators upstream of Hippo signaling, and uncover the importance of phosphoinositide dynamics, specifically PI(4,5)P2, in Hippo pathway regulation