Two decades of studies in multiple model organisms have established the Hippo pathway as a key regulator of organ size and tissue homeostasis. By inhibiting YAP and TAZ transcription co-activators, ...the Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein-coupled receptors, and cellular energy status. Dysregulation of the Hippo pathway exerts a significant impact on cancer development. Further investigation of the functions and regulatory mechanisms of this pathway will help uncovering the mystery of organ size control and identify new targets for cancer treatment.
In response to a variety of cellular signals, the Hippo pathway plays key roles in regulating tissue homeostasis, stemness, and cancer development.
The Motin family proteins (Motins) are a class of scaffolding proteins consisting of Angiomotin (AMOT), AMOT‐like protein 1 (AMOTL1), and AMOT‐like protein 2 (AMOTL2). Motins play a pivotal role in ...angiogenesis, tumorigenesis, and neurogenesis by modulating multiple cellular signaling pathways. Recent findings indicate that Motins are components of the Hippo pathway, a signaling cascade involved in development and cancer. This review discusses how Motins are integrated into the Hippo signaling network, as either upstream regulators or downstream effectors, to modulate cell proliferation and migration. The repression of YAP/TAZ by Motins contributes to growth inhibition, whereas subcellular localization of Motins and their interactions with actin fibers are critical in regulating cell migration. The net effect of Motins on cell proliferation and migration may contribute to their diverse biological functions.
Motin family proteins (Motins) comprise Angiomotin (AMOT), AMOT‐like protein 1 (AMOTL1), and AMOTL2. This review discusses the function of Motins, as upstream regulators or downstream effectors of the Hippo signaling pathway, in angiogenesis, tumorigenesis, and neurogenesis.
Control of cell number is crucial in animal development and tissue homeostasis, and its dysregulation may result in tumor formation or organ degeneration. The Hippo pathway in both Drosophila and ...mammals regulates cell number by modulating cell proliferation, cell death, and cell differentiation. Recently, numerous upstream components involved in the Hippo pathway have been identified, such as cell polarity, mechanotransduction, and G-protein-coupled receptor (GPCR) signaling. Actin cytoskeleton or cellular tension appears to be the master mediator that integrates and transmits upstream signals to the core Hippo signaling cascade. Here, we review regulatory mechanisms of the Hippo pathway and discuss potential implications involved in different physiological and pathological conditions.
While several organs in mammals retain partial regen- erative capability following tissue damage, the underly- ing mechanisms remain unclear. Recently, the Hippo signaling pathway, better known for ...its function in organ size control, has been shown to play a pivotal role in regulating tissue homeostasis and regeneration. Upon tissue injury, the activity of YAP, the major effector of the Hippo pathway, is transiently induced, which in turn promotes expansion of tissue-resident progenitors and facilitates tissue regeneration. In this review, with a general focus on the Hippo pathway, we will discuss its major components, functions in stem cell biology, involvement in tissue regeneration in different organs, and potential strategies for developing Hippo pathway- targeted regenerative medicines.
Big data with its vast volume and complexity is increasingly concerned, developed and used for all professions and trades. Remote sensing, as one of the sources for big data, is generating ...earth-observation data and analysis results daily from the platforms of satellites, manned/unmanned aircrafts, and ground-based structures. Agricultural remote sensing is one of the backbone technologies for precision agriculture, which considers within-field variability for site-specific management instead of uniform management as in traditional agriculture. The key of agricultural remote sensing is, with global positioning data and geographic information, to produce spatially-varied data for subsequent precision agricultural operations. Agricultural remote sensing data, as general remote sensing data, have all characteristics of big data. The acquisition, processing, storage, analysis and visualization of agricultural remote sensing big data are critical to the success of precision agriculture. This paper overviews available remote sensing data resources, recent development of technologies for remote sensing big data management, and remote sensing data processing and management for precision agriculture. A five-layer-fifteenlevel (FLFL) satellite remote sensing data management structure is described and adapted to create a more appropriate four-layer-twelve-level (FLTL) remote sensing data management structure for management and applications of agricultural remote sensing big data for precision agriculture where the sensors are typically on high-resolution satellites, manned aircrafts, unmanned aerial vehicles and ground-based structures. The FLTL structure is the management and application framework of agricultural remote sensing big data for precision agriculture and local farm studies, which outlooks the future coordination of remote sensing big data management and applications at local regional and farm scale.
The Hippo pathway is a central regulator of organ size and tumorigenesis and is commonly depicted as a kinase cascade, with an increasing number of regulatory and adaptor proteins linked to its ...regulation over recent years. Here, we propose that two Hippo signaling modules, MST1/2–SAV1–WWC1‐3 (HPO1) and MAP4K1‐7–NF2 (HPO2), together regulate the activity of LATS1/2 kinases and YAP/TAZ transcriptional co‐activators. In mouse livers, the genetic inactivation of either HPO1 or HPO2 module results in partial activation of YAP/TAZ, bile duct hyperplasia, and hepatocellular carcinoma (HCC). On the contrary, inactivation of both HPO1 and HPO2 modules results in full activation of YAP/TAZ, rapid development of intrahepatic cholangiocarcinoma (iCCA), and early lethality. Interestingly, HPO1 has a predominant role in regulating organ size. HPO1 inactivation causes a homogenous YAP/TAZ activation and cell proliferation across the whole liver, resulting in a proportional and rapid increase in liver size. Thus, this study has reconstructed the order of the Hippo signaling network and suggests that LATS1/2 and YAP/TAZ activities are finetuned by HPO1 and HPO2 modules to cause different cell fates, organ size changes, and tumorigenesis trajectories.
Synopsis
The Hippo pathway inhibits YAP/TAZ transcriptional co‐activators to regulate organ size and tumorigenesis. This study shows that upstream kinases and associated adaptor proteins of the Hippo pathway form two signaling modules that differentially regulate YAP/TAZ activity and its function in the liver.
The HPO1 module is formed by MST1/2 kinases and the adaptor proteins SAV1 and WWC1‐3, while the HPO2 module includes MAP4K1‐7 and the adaptor protein NF2.
Simultaneous deletion of HPO1 and HPO2 components leads to full activation of YAP/TAZ in a manner comparable with LATS1/2 deficiency.
Liver‐specific inactivation of either HPO1 or HPO2 module results in partial YAP/TAZ activation, bile duct hyperplasia, and hepatocellular carcinoma.
Inactivation of both HPO1 and HPO2 modules in the liver results in intrahepatic cholangiocarcinoma and early lethality.
HPO1 is the major organ size regulator, and its inactivation causes rapid hepatomegaly.
Two distinct Hippo signaling pathway modules converge on the kinases LATS1/2 to differentially regulate YAP/TAZ activation.
Mutations in the neurofibromatosis type 2 (
) gene that limit or abrogate expression of functional Merlin are common in malignant mesothelioma. Merlin activates the Hippo pathway to suppress nuclear ...translocation of YAP and TAZ, the major effectors of the pathway that associate with the TEAD transcription factors in the nucleus and promote expression of genes involved in cell proliferation and survival. In this article, we describe the discovery of compounds that selectively inhibit YAP/TAZ-TEAD promoted gene transcription, block TEAD auto-palmitoylation, and disrupt interaction between YAP/TAZ and TEAD. Optimization led to potent analogs with excellent oral bioavailability and pharmacokinetics that selectively inhibit
-deficient mesothelioma cell proliferation
and growth of subcutaneous tumor xenografts
These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases.
The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates environmental and intracellular signals to regulate cell growth. Amino acids stimulate mTORC1 activation at the lysosome in a ...manner thought to be dependent on the Rag small guanosine triphosphatases (GTPases), the Regulator complex, and the vacuolar H+–adenosine triphosphatase (v-ATPase). We report that leucine and glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent mechanisms, respectively. Glutamine promoted mTORC1 translocation to the lysosome in RagA and RagB knockout cells and required the v-ATPase but not the Regulator. Furthermore, we identified the adenosine diphosphate ribosylation factor–1 GTPase to be required for mTORC1 activation and lysosomal localization by glutamine. Our results uncover a signaling cascade to mTORC1 activation independent of the Rag GTPases and suggest that mTORC1 is differentially regulated by specific amino acids.
Oncogenic activation of the PI3K/Akt pathway is known to play an important role to promote glucose metabolism in cancer cells. However, the molecular mechanism through which the PI3K/Akt signalling ...pathway promotes glucose utilisation in cancer cells is still not well understood. It has recently been shown that the oncogenic activation of the PI3K/Akt/mTOR signalling in lung adenocarcinoma is important in promoting the localisation of glucose transporter 1 (GLUT1) at the plasma membrane. We thus hypothesised that the effect of constitutive activation of the PI3K/AKT signalling on glucose metabolism is mediated by thioredoxin interacting protein (TXNIP), a known regulator of the GLUT1 plasma membrane localisation. Consistent with previous studies, inhibition of the PI3K/Akt pathway decreased cellular glucose uptake. Furthermore, inhibition of PI3K/Akt signalling in non-small cell lung cancer (NSCLC) cell lines using clinically used tyrosine kinase inhibitors (TKIs) resulted in a decrease in GLUT1 membrane localisation. We also observed that inhibition of the PI3K/Akt pathway in various cell lines, including NSCLC cells, resulted in an increase in TXNIP expression. Importantly, knockdown of TXNIP using siRNA in the NSCLC cells promoted GLUT1 to be localised at the plasma membrane and reversed the effect of PI3K/Akt inhibitors. Together, our results suggest that the oncogenic activation of PI3K/Akt signalling promotes cellular glucose uptake, at least in part, through the regulation of TXNIP expression. This mechanism may contribute to the Warburg effect in cancer cells.
•Activation of PI3K/Akt/mTOR suppresses TXNIP.•Tyrosine kinase inhibitors upregulate TXNIP expression in lung cancer cells.•Induction of TXNIP is accompanied by a decrease in GLUT1 membrane localisation.•Silencing TXNIP reverses the effect of TKIs, promoting GLUT1 membrane localisation.
YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are major downstream effectors of the Hippo pathway that influences tissue homeostasis, organ size, and ...cancer development. Aberrant hyperactivation of YAP/TAZ causes tissue overgrowth and tumorigenesis, whereas their inactivation impairs tissue development and regeneration. Dynamic and precise control of YAP/TAZ activity is thus important to ensure proper physiological regulation and homeostasis of the cells. Here, we show that YAP/TAZ activation results in activation of their negative regulators, LATS1/2 (large tumor suppressor 1/2) kinases, to constitute a negative feedback loop of the Hippo pathway in both cultured cells and mouse tissues. YAP/TAZ in complex with the transcription factor TEAD (TEA domain family member) directly induce LATS2 expression. Furthermore, YAP/TAZ also stimulate the kinase activity of LATS1/2 through inducing NF2 (neurofibromin 2). This feedback regulation is responsible for the transient activation of YAP upon lysophosphatidic acid (LPA) stimulation and the inhibition of YAP-induced cell migration. Thus, this LATS-mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP/TAZ regulation.
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