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The Hippo-YAP pathway is a central regulator of cell contact inhibition, proliferation and death. There are conflicting reports regarding the role of Angiomotin (Amot) in regulating this pathway. While some studies suggest a YAP-inhibitory function other studies indicate Amot is required for YAP activity. Here, we describe an Amot-dependent complex comprised of Amot, YAP and Merlin. The phosphorylation of Amot at Serine 176 shifts localization of this complex to the plasma membrane, where it associates with the tight-junction proteins Pals1/PATJ and E-cadherin. Conversely, hypophosphorylated Amot shifts localization of the complex to the nucleus, where it facilitates the association of YAP and TEAD, induces transcriptional activation of YAP target genes and promotes YAP-dependent cell proliferation. We propose that phosphorylation of AmotS176 is a critical post-translational modification that suppresses YAP’s ability to promote cell proliferation and tumorigenesis by altering the subcellular localization of an essential YAP co-factor. Cells in animals and other multi-cellular organisms need to know when and where they should grow and divide. Individual cells communicate with their surrounding environment and each other via signaling pathways such as the Hippo-YAP pathway, which stimulates cells to grow and therefore influences the size of organs. When the Hippo part of the pathway is active it causes a protein known as YAP to move out of a compartment in the cell called the nucleus. Inside the nucleus, YAP helps to activate genes that promote cell growth. If the Hippo pathway can no longer respond to cues from the environment, YAP becomes over-active and can contribute to the development of various cancers. Therefore researchers are trying to better understand how it is regulated. Many signals both from inside and outside the cell influence YAP activity. For example, some signals block YAP from entering the nucleus, whereas others cause YAP to be broken down entirely. Several studies have recently identified a signal protein called angiomotin as a regulator of YAP. However, the studies provide conflicting reports as to whether angiomotin promotes or inhibits cell growth. Like many other proteins, angiomotin can be tagged with a small molecule called a phosphate group that can alter its activity. Moleirinho, Hoxha et al. studied human cells containing versions of angiomotin that mimic different forms of the protein with or without the phosphate. The experiments indicate that when a phosphate is attached at a particular position (known as serine 176), angiomotin predominantly interacts with YAP and another protein called Merlin at the cell surface. On the other hand, when angiomotin does not have a phosphate attached to it, all three proteins can move into the nucleus, where YAP is able to activate genes and promote cell growth. Overall, these findings indicate that adding a phosphate group to angiomotin can act as a switch to regulate where in the cell it and YAP are found and thus, whether YAP is active. Future experiments will investigate which enzymes add the phosphate group to serine 176, and when they are able to do so.

This Analysis compares four commonly used assays to measure food intake in flies and identifies radioisotope-labeling and the capillary feeder (CAFE) as the most reproducible and sensitive. Food intake is a fundamental parameter in animal studies. Despite the prevalent use of Drosophila in laboratory research, precise measurements of food intake remain challenging in this model organism. Here, we compare several common Drosophila feeding assays: the capillary feeder (CAFE), food labeling with a radioactive tracer or colorimetric dye and observations of proboscis extension (PE). We show that the CAFE and radioisotope labeling provide the most consistent results, have the highest sensitivity and can resolve differences in feeding that dye labeling and PE fail to distinguish. We conclude that performing the radiolabeling and CAFE assays in parallel is currently the best approach for quantifying Drosophila food intake. Understanding the strengths and limitations of methods for measuring food intake will greatly advance Drosophila studies of nutrition, behavior and disease.

Changes in body temperature can profoundly affect survival. The dramatic longevity-enhancing effect of cold has long been known in organisms ranging from invertebrates to mammals, yet the underlying mechanisms have only recently begun to be uncovered. In the nematode Caenorhabditis elegans, this process is regulated by a thermosensitive membrane TRP channel and the DAF-16/FOXO transcription factor, but in more complex organisms the underpinnings of cold-induced longevity remain largely mysterious. We report that, in Drosophila melanogaster, variation in ambient temperature triggers metabolic changes in protein translation, mitochondrial protein synthesis, and posttranslational regulation of the translation repressor, 4E-BP (eukaryotic translation initiation factor 4E-binding protein). We show that 4E-BP determines Drosophila lifespan in the context of temperature changes, revealing a genetic mechanism for cold-induced longevity in this model organism. Our results suggest that the 4E-BP pathway, chiefly thought of as a nutrient sensor, may represent a master metabolic switch responding to diverse environmental factors.

Contact inhibition (CI) of proliferation is a fundamental and highly regulated process by which cells enter cell cycle arrest as they reach high density. CI is essential for embryonic development and maintenance of tissue architecture in adult organisms, but is often dysregulated in tumor cells. Evasion of growth suppressor is one of the main hallmarks of cancer associated with loss of contact inhibition and uncontrolled proliferation. The precise underlying molecular mechanisms employed by cancer cells to bypass CI remain largely unknown. Here we focus on understanding the molecular mechanisms of CI and how these become dysregulated in cancer. Recent evidence has implicated the evolutionary conserved Hippo-YAP pathway as a mediator of CI. The Hippo-YAP was initially characterized in flies and shown to play a role in organ size control by maintaining the balance between proliferation and apoptosis. Subsequent studies demonstrated the pathway is conserved in mammals and functions as a mediator of cell CI, regulation of cell fate and proliferation. Multiple inputs appear to feed into the pathway including G-coupled receptors, cadherins and cell-cell junctional complexes. The core of the pathway is composed of a kinase cascade, which is relatively well-defined. Downstream of the Hippo pathway is the co-transcriptional factor, YAP, which when nuclear can drive the expression of pro-proliferative or anti-apoptotic genes. To understand the role of YAP in the nucleus, we employed genome-wide chromatin profiling and bioinformatics analysis, to assess how YAP might regulate CI. During these studies, we have identified genes activated by YAP and in addition, we uncovered an unexpected function for YAP as a direct transcriptional repressor of key cell-cycle regulators, which likely mediate CI. Moreover, we elucidated the mechanism through which YAP represses gene transcription by recruiting the YY1 transcription factor and EZH2 regulator from the polycomb repressive complex (PRC) to repress these genes. We have validated our results in vivo using transgenic mouse and fruit fly models. Overall, we propose a novel model where YAP, which was previously thought of mostly as an activator, can also act as a transcriptional repressor. Given the oncogenic role of YAP in cancer, our study provides support for the use of EZH2 inhibitors in the treatment of YAP-mediated cancer.

Studies on cancer resistance in the naked mole-rat (NMR) have generally failed to interrogate possible resistance mechanisms in a physiological context. Here, we provide evidence that the NMR presents as a novel model of tumor initiation. We developed an endogenous lung cancer model in NMRs, driven by an oncogenic Eml4-Alk fusion protein introduced through CRISPR- mediated genome editing. While this is sufficient to drive tumorigenesis in mice, the development of progressive disease in NMRs required the additional loss of key tumor suppressors. Our results show that tumor initiation in NMRs more closely recapitulates that of human tumors. This suggests that the proposed “resistance” of NMRs to cancer development may stem from tumor initiation events that are likely to be comparable to the mechanisms in human cells. Tumor development in the cancer-resistant naked mole-rat more accurately represents the tumor initiation process in humans.