The Hippo pathway is the key player in various signaling processes, including organ development and maintenance of tissue homeostasis. This pathway comprises a core kinases module and transcriptional activation module, representing a highly conserved mechanism from Drosophila to vertebrates. The central MST1/2-LATS1/2 kinase cascade in this pathway negatively regulates YAP/TAZ transcription co-activators in a phosphorylation-dependent manner. Nuclear YAP/TAZ bind to transcription factors to stimulate gene expression, contributing to the regenerative potential and regulation of cell growth and death. Recent studies have also highlighted the potential role of Hippo pathway dysfunctions in the pathology of several diseases. Here, we review the functional characteristics of the Hippo pathway in organ fibrosis and tumorigenesis, and discuss its potential as new therapeutic targets.

Tae Hwan Shin, Da Yeon Lee, Hyeon-Seong Lee, Hyung Jin Park, Moon Suk Jin, Man-Jeong Paik, Balachandran Manavalan, Jung-Soon Mo & Gwang Lee. BMB Reports 2018;51:14-20. https://doi.org/10.5483/BMBRep.2018.51.1.237

Nanoparticles (NPs) in biomedical applications have benefits owing to their small size. However, their intricate and sensitive nature makes an evaluation of the adverse effects of NPs on health necessary and challenging. Since there are limitations to conventional toxicological methods and omics analyses provide a more comprehensive molecular profiling of multifactorial biological systems, omics approaches are necessary to evaluate nanotoxicity. Compared to a single omics layer, integrated omics across multiple omics layers provides more sensitive and comprehensive details on NP-induced toxicity based on network integration analysis. As multi-omics data are heterogeneous and massive, computational methods such as machine learning (ML) have been applied for investigating correlation among each omics. This integration of omics and ML approaches will be helpful for analyzing nanotoxicity. To that end, mechanobiology has been applied for evaluating the biophysical changes in NPs by measuring the traction force and rigidity sensing in NP-treated cells using a sub-elastomeric pillar. Therefore, integrated omics approaches are suitable for elucidating mechanobiological effects exerted by NPs. These technologies will be valuable for expanding the safety evaluations of NPs. Here, we review the integration of omics, ML, and mechanobiology for evaluating nanotoxicity.

The role of extracellular biophysical cues in modulating the Hippo-YAP pathway YAP;TAZ;Hippo pathway;Mechanical cues;GPCR;Nutrient; The Hippo signaling pathway plays an essential role in adult-tissue homeostasis and organ-size control. In Drosophila and vertebrates, it consists of a highly conserved kinase cascade, which involves MST and Lats that negatively regulate the activity of the downstream transcription coactivators, YAP and TAZ. By interacting with TEADs and other transcription factors, they mediate both proliferative and antiapoptotic gene expression and thus regulate tissue repair and regeneration. Dysregulation or mutation of the Hippo pathway is linked to tumorigenesis and cancer development. Recent studies have uncovered multiple upstream inputs, including cell density, mechanical stress, G-protein-coupled receptor (GPCR) signaling, and nutrients, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway as effector of these biophysical cues and its potential implications in tissue homeostasis and cancer.

Genomic instability resulting from defective DNA damage responses or repair causes several abnormalities, including progressive cerebellar ataxia, for which the molecular mechanisms are not well understood. Here, we report a new murine model of cerebellar ataxia resulting from concomitant inactivation of POLB and ATM. POLB is one of key enzymes for the repair of damaged or chemically modified bases, including methylated cytosine, but selective inactivation of Polb during neurogenesis affects only a subpopulation of cortical interneurons despite the accumulation of DNA damage throughout the brain. However, dual inactivation of Polb and Atm resulted in ataxia without significant neuropathological defects in the cerebellum. ATM is a protein kinase that responds to DNA strand breaks, and mutations in ATM are responsible for Ataxia Telangiectasia, which is characterized by progressive cerebellar ataxia. In the cerebella of mice deficient for both Polb and Atm, the most downregulated gene was Itpr1, likely because of misregulated DNA methylation cycle. ITPR1 is known to mediate calcium homeostasis, and ITPR1 mutations result in genetic diseases with cerebellar ataxia. Our data suggest that dysregulation of ITPR1 in the cerebellum could be one of contributing factors to progressive ataxia observed in human genomic instability syndromes.