The Hippo signalling pathway in bone homeostasis: Under the regulation of mechanics and aging
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Abstract The Hippo signalling pathway is a conserved kinase cascade that orchestrates diverse cellular processes, such as proliferation, apoptosis, lineage commitment and stemness. With the onset of society ages, research on skeletal aging‐mechanics‐bone homeostasis has exploded. In recent years, aging and mechanical force in the skeletal system have gained groundbreaking research progress. Under the regulation of mechanics and aging, the Hippo signalling pathway has a crucial role in the development and homeostasis of bone. We synthesize the current knowledge on the role of the Hippo signalling pathway, particularly its downstream effectors yes‐associated protein (YAP) and transcriptional co‐activator with PDZ‐binding motif (TAZ), in bone homeostasis. We discuss the regulation of the lineage specification and function of different skeletal cell types by the Hippo signalling pathway. The interactions of the Hippo signalling pathway with other pathways, such as Wnt, transforming growth factor beta and nuclear factor kappa‐B, are also mentioned because of their importance for modulating bone homeostasis. Furthermore, YAP/TAZ have been extensively studied as mechanotransducers. Due to space limitations, we focus on reviewing how mechanical forces and aging influence cell fate, communications and homeostasis through a dysregulated Hippo signalling pathway.Keywords:
Hippo signaling pathway
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In the canonical Wnt signaling pathway, Wnts cause stabilization of β-catenin and consequent changes in gene expression. But not all Wnts appear to signal in this way. Developmental actions of Wnt-5, for example, appear not to be mediated by β-catenin, and now two papers show that Wnt-5 actually antagonizes canonical Wnt signaling. Westfall et al. explored developmental roles of WNt-5 in zebrafish. The dorsalization defects they observed when expression of maternal and zygotic Wnt-5 was removed were similar to effects of activation of canonical Wnt-β-catenin signaling and were associated with accumulation of β-catenin. Loss of Wnt-5 caused decreased Ca 2+ release, and overexpression of Ca 2+ -calmodulin-dependent protein kinase II partially rescued the effects of Wnt-5 mutation. Thus, the authors conclude that Wnt-5 actually antagonizes the effects of canonical Wnts, possibly by a Ca 2+ -mediated signal. Topol et al. offer an alternative mechanism. In cultured mammalian 293 cells and in a human colon cancer cell line, ectopic expression of Wnt-5a antagonized canonical Wnt signaling and caused degradation of β-catenin. Their analysis, however, indicated that Wnt-5's effects were largely independent of Ca 2+ -mediated signals. Rather, they propose that Wnt-5a may increase expression of Siah2, a component of the proteasome, which mediates degradation of β-catenin. In 293 cells, dominant-negative Siah2 reduced the effects of Wnt-5a on β-catenin signaling, and ectopic expression of Wnt-5a increased expression of Siah2. In Wnt-5a knockout mice, β-catenin also accumulated in the distal limb bud during development. Thus, in limb buds lacking Wnt-5a, unchecked canonical Wnt signaling may cause developmental abnormalities. Consistent with this idea, chondorgenesis is inhibited in Wnt5a –/– limbs, but was partially rescued by grafted chick embryonic fibroblast cells engineered to express a secreted antagonist of Wnt signaling. Both groups agree that proper development appears to require a balance of opposing Wnt signals and that disruption of that balance could contribute to abnormal canonical Wnt signaling, which is implicated in formation of some human cancers. T. A. Westfall, R. Brimeyer, J. Twedt, J. Gladon, A. Olberding, M. Furutani-Seiki, D. C. Slusarski, Wnt-5/pipetail functions in vertebrate axis formation as a negative regulator of Wnt/β-catenin activity. J. Cell Biol. 162 , 889-898 (2003). [Abstract] [Full Text] L. Topol, X. Jiang, H. Choi, L. Garrett-Beal, P. J. Carolan, Y. Yang, Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent β-catenin degradation. J. Cell Biol. 162 , 899-908 (2003). [Abstract] [Full Text]
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Abstract BACKGROUND Glioblastoma (GBM) is a primary human malignant brain tumor, the most common in adults. Several studies have highlighted the Hippo-pathway as a cancer signalling network. The Hippo pathway is an evolutionarily conserved signal cascade, which is involved in the control of organ growth. Dysregulations among this pathway have been found in lung, ovarian, liver and colorectal cancer. The key downstream effector of the Hippo-pathway is the Yes-associated protein (YAP); in the nucleus, its function as transcription co-activator is to interact with transcription factors, resulting in the expression of target genes involved in pro-proliferating and anti-apoptotic programs. MATERIAL AND METHODS Using western blotting analysis, we determined the nuclear expression of YAP on three GBM cell lines (U87MG, T98G and A172). To investigate which inhibitors against the Hippo-pathway were the most efficient, we performed a cytotoxic assay: we treated all the three cell lines with different inhibitors such as Verteporfin (VP), Cytochalasin D (CIT), Latrunculin A (LAT), Dobutamine (DOB) and Y27632. Afterwards, we performed a treatment using Doxorubicin (DOX) combined with the inhibitors, evaluating its cytotoxic effect on our cell lines, through cell viability experiments. More western blotting experiments were performed to investigate the oncogenic role of YAP at nucleus level. Furthermore, preliminary experiments have been conducted in order to investigate the apoptosis, senescence and autophagy modulation due to the Hippo-pathway. RESULTS We showed our cell lines express nuclear YAP. We assessed the efficiency of the main inhibitors against Hippo-pathway, proving that VP, LAT A and CIT show a strong cytostatic effect, linked to time increase; plus we saw a cytotoxic effect on T98G. The association of DOX with selected inhibitors is able to reduce cell viability and nuclear YAP expression rate in all three GBM lines. Finally, preliminary experiments were set up to assess how and if the mechanisms of apoptosis, autophagy and senescence were affected by the Hippo-pathway. The combination of DOX with inhibitors promotes resistance to apoptosis. CONCLUSION Our results show that nuclear YAP is present in all tumor lines, thus confirming that this molecular pathway is functioning in GBM lines. Nuclear YAP is more highly expressed after DOX administration. Moreover, the combined treatment (DOX with Hippo-pathway inhibitors) reduces both cell proliferation and viability, and increases the rate of apoptosis. Preliminary experiments on senescence and autophagy were used to determine the best Hippo-pathway inhibitor. These data demonstrate that the Hippo-pathway plays a crucial role in GBM proliferation and resistance to apoptosis. Inhibiting this pathway and in particular the transcription factor YAP, in association with DOX, might be an excellent therapeutic target.
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The Wnt/β signaling pathway (Wnt-SP) is a phylogenetically ancient mechanism that regulates development and maintains tissue homeostasis through the control of cell proliferation, differentiation, migration, and apoptosis. The accurate regulation of the canonical Wnt/β-catenin signaling pathway (Wnt-SP) is critical for embryogenesis and postnatal development; and impaired signal transduction at one of its stages leads to various diseases, including organ malformations, cancers, metabolic and neurodegenerative disorders. The literature review discusses the biological role of the canonical Wnt-SP in the development of the skeleton and in the remodeling of bone tissue. The Wnt signal transmission changes observed during genetic mutations cause various human skeletal diseases. Understanding the functional mechanism involved in the development of bone abnormality could open new horizons in the treatment of osteoporosis, by affecting the Wnt-SP. The design of antibodies to sclerostin, a Wnt-SP inhibitor, is most promising now. The paper summarizes the studies that have investigated the canonical Wnt-SP and designed drugs to treat osteoporosis.
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Abstract The Hippo pathway is crucial in organ size control and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include the protein kinases of MST1/2, MAP4Ks, LATS1/2, the transcription co-activators YAP/TAZ, and their DNA binding partners TEADs. LATS phosphorylates YAP/TAZ to promote cytoplasmic localization and degradation, thereby inhibiting YAP/TAZ and cell growth. The Hippo pathway is regulated by a wide range of signals, including cell density, GPCR, cellular energy levels, and mechanical cues. We will present our recent progresses on Hippo pathway regulation and its role in cancer. The emerging role of the Hippo pathway in tumorigenesis suggests the potential therapeutic value of targeting this pathway for cancer treatment. Citation Format: Kun-Liang Guan. Regulation of the Hippo pathway in cancer [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA04.
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Dysregulation of WNT signaling has been reported in many malignancies.This study was conducted to investigate the expression pattern of 14 members of the WNT gene family in different immunophenotypic subtypes of ALL.Semi-quantitative RT-PCR was performed on samples from 71 ALL patients and 36 age-matched healthy individuals. The ALL patients were categorized into B-ALL (76%), T-ALL (22.6%) and mixed lineage (1.4%) and the B-ALL cases were further classified into pro-B, pre-BI, pre-BII and immature/mature-B based on immuno-phenotypic results.Among the WNT genes, WNT-7B (p=0.026), WNT-9A (p=0.020) and WNT-16B (p=0.023) were significantly over-expressed, whereas WNT-2B (p=0.033), WNT-5A (p=0.016), WNT-7A (p<0.0001) and WNT-10A (p<0.0001) were down-regulated in B-ALL. Among the T-ALL subtype, however, significant down-regulation of WNT-2B, WNT-5B, WNT-7A, WNT-10A and WNT-11 was evident. Comparison between B-ALL subtypes showed significant over-expression of WNT-7B, WNT-9A and WNT-5B in certain subtypes.Our results suggest contribution of the WNT genes in leukemogenesis of ALL.
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The Hippo signaling pathway is gaining recognition as an important player in both organ size control and tumorigenesis, which are physiological and pathological processes that share common cellular signaling mechanisms. Upon activation by stimuli such as high cell density in cell culture, the Hippo pathway kinase cascade phosphorylates and inhibits the Yes-associated protein (YAP)/TAZ transcription coactivators representing the major signaling output of the pathway. Altered gene expression resulting from YAP/TAZ inhibition affects cell number by repressing cell proliferation and promoting apoptosis, thereby limiting organ size. Recent studies have provided new insights into the Hippo signaling pathway, elucidating novel phosphorylation-dependent and independent mechanisms of YAP/Yki inhibition by the Hippo pathway, new Hippo pathway components, novel YAP target transcription factors and target genes, and the three-dimensional structure of the YAP–TEAD complex, and providing further evidence for the involvement of YAP and the Hippo pathway in tumorigenesis.
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