4,685 research outputs found
sj-docx-1-tam-10.1177_17588359231206259 – Supplemental material for Classification of HER2-negative breast cancers by ERBB2 copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations
No full textSupplemental material, sj-docx-1-tam-10.1177_17588359231206259 for Classification of HER2-negative breast cancers by ERBB2 copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations by Jui Wan Loh, Abner Herbert Lim, Jason Yongsheng Chan and Yoon-Sim Yap in Therapeutic Advances in Medical Oncology</p
sj-xlsx-2-tam-10.1177_17588359231206259 – Supplemental material for Classification of HER2-negative breast cancers by ERBB2 copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations
No full textSupplemental material, sj-xlsx-2-tam-10.1177_17588359231206259 for Classification of HER2-negative breast cancers by ERBB2 copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations by Jui Wan Loh, Abner Herbert Lim, Jason Yongsheng Chan and Yoon-Sim Yap in Therapeutic Advances in Medical Oncology</p
The LKB1–TSSK1B axis controls YAP phosphorylation to regulate the Hippo–YAP pathway
No full textAbstract The Hippo pathway’s main effector, Yes-associated protein (YAP), plays a crucial role in tumorigenesis as a transcriptional coactivator. YAP’s phosphorylation by core upstream components of the Hippo pathway, such as mammalian Ste20 kinase 1/2 (MST1/2), mitogen-activated protein kinase kinase kinase kinases (MAP4Ks), and their substrate, large tumor suppressor 1/2 (LATS1/2), influences YAP’s subcellular localization, stability, and transcriptional activity. However, recent research suggests the existence of alternative pathways that phosphorylate YAP, independent of these core upstream Hippo pathway components, raising questions about additional means to inactivate YAP. In this study, we present evidence demonstrating that TSSK1B, a calcium/calmodulin-dependent protein kinase (CAMK) superfamily member, is a negative regulator of YAP, suppressing cellular proliferation and oncogenic transformation. Mechanistically, TSSK1B inhibits YAP through two distinct pathways. Firstly, the LKB1–TSSK1B axis directly phosphorylates YAP at Ser94, inhibiting the YAP–TEAD complex’s formation and suppressing its target genes’ expression. Secondly, the TSSK1B–LATS1/2 axis inhibits YAP via phosphorylation at Ser127. Our findings reveal the involvement of TSSK1B-mediated molecular mechanisms in the Hippo–YAP pathway, emphasizing the importance of multilevel regulation in critical cellular decision-making processes
YAP and TAZ control peripheral myelination and the expression of laminin receptors in Schwann cells
No full textMyelination is essential for nervous system function. Schwann cells interact with neurons and the basal lamina to myelinate axons using known receptors, signals and transcription factors. In contrast, the transcriptional control of axonal sorting and the role of mechanotransduction in myelination are largely unknown. Yap and Taz are effectors of the Hippo pathway that integrate chemical and mechanical signals in cells. We describe a previously unknown role for the Hippo pathway in myelination. Using conditional mutagenesis in mice, we show that Taz is required in Schwann cells for radial sorting and myelination and that Yap is redundant with Taz. Yap and Taz are activated in Schwann cells by mechanical stimuli and regulate Schwann cell proliferation and transcription of basal lamina receptor genes, both necessary for radial sorting of axons and subsequent myelination. These data link transcriptional effectors of the Hippo pathway and of mechanotransduction to myelin formation in Schwann cells
YAP inhibits HCMV replication by impairing STING-mediated nuclear transport of the viral genome.
No full textYES-associated protein (YAP), a critical actor of the mammalian Hippo signaling pathway involved in diverse biological events, has gained increased recognition as a cellular factor regulated by viral infections, but very few studies have investigated their relationship vice versa. In this study, we show that YAP impairs HCMV replication as assessed by viral gene expression analysis and progeny assays, and that this inhibition occurs at the immediate-early stages of the viral life cycle, at the latest. Using YAP mutants lacking key functional domains and shRNA against TEAD, we show that the inhibitory effects of YAP on HCMV replication are nuclear localization- and TEAD cofactor-dependent. Quantitative real-time PCR (qPCR) and subcellular fractionation analyses reveal that YAP does not interfere with the viral entry process but inhibits transport of the HCMV genome into the nucleus. Most importantly, we show that the expression of stimulator of interferon genes (STING), recently identified as an important component for nuclear delivery of the herpesvirus genome, is severely downregulated by YAP at the level of gene transcription. The functional importance of STING is further confirmed by the observation that STING expression restores YAP-attenuated nuclear transport of the HCMV genome, viral gene expression, and progeny virus production. We also show that HCMV-upregulated YAP reduces expression of STING. Taken together, these findings indicate that YAP possesses both direct and indirect regulatory roles in HCMV replication at different infection stages
Targeting YAP/TAZ-TEAD protein-protein interactions using fragment-based and computational modeling approaches.
No full textThe Hippo signaling pathway, which is implicated in the regulation of organ size, has emerged as a potential target for the development of cancer therapeutics. YAP, TAZ (transcription co-activators) and TEAD (transcription factor) are the downstream transcriptional machinery and effectors of the pathway. Formation of the YAP/TAZ-TEAD complex leads to transcription of growth-promoting genes. Conversely, disrupting the interactions of the complex decreases cell proliferation. Herein, we screened a 1000-member fragment library using Thermal Shift Assay and identified a hit fragment. We confirmed its binding at the YAP/TAZ-TEAD interface by X-ray crystallography, and showed that it occupies the same hydrophobic pocket as a conserved phenylalanine of YAP/TAZ. This hit fragment serves as a scaffold for the development of compounds that have the potential to disrupt YAP/TAZ-TEAD interactions. Structure-activity relationship studies and computational modeling were also carried out to identify more potent compounds that may bind at this validated druggable binding site
HCMV replication is inhibited by YAP expression.
No full text(A) Schematic representation of the retroviral vector used in this study. A retroviral vector which bicistronically expresses YAP and GFP using an internal ribosome entry site (IRES) was used to transduce HFF cells. As a negative control, retroviral vectors containing only the GFP gene were used. Therefore, GFP was used as a marker for transgene expression throughout the study. LTR, long terminal repeat; MCS, multicloning site. (B) HCMV progeny virus titration assay. 24 h prior to HCMV infection, HFF cells were transduced with a retroviral vector bicistronically expressing YAP and GFP. The cells were then infected with HCMV at an MOI of 0.1 or 0.5, and progeny viruses were harvested at 72, 96, and 120 hpi. Before infection for viral titration, all the MOI 0.5 samples were diluted to 1:10. Titration of progeny viruses collected from control- or YAP-transduced HFF cells infected with HCMV at an MOI of (C) 0.1 and (E) 0.5 at the indicated time points by anti-IE1 immunostaining (red). Cells were counterstained with DAPI to visualize nuclei (blue). (G) Western blot analysis for YAP proteins in HFF cells transduced with a dominant negative form of LATS1/2 (dnLATS1/2) together with or without shRNA specific to YAP (shYAP). (I) HFF cells were transduced with dnLATS1/2 and/or shYAP and then infected with HCMV at an MOI of 0.5. Progeny viruses were titered by IE1 immunostaining after HFF cell infection (red). (D, F, H, J) Quantification of (C, E, G, I), respectively. For (D, F, J), numbers of IE1+ cells in each control were set to 1. Scale bars, 100 μm. n = 3 biological replicates for each experiment. Error bars represent SEM. Student’s t-test (for D, F), one-way ANOVA with Turkey’s multiple comparison test (for H, J) was used to determine statistical significance. *P P P < 0.001.</p
OTUB2 promotes cancer metastasis via Hippo independent activation of YAP and TAZ, Zhang et al.
No full textThe transcriptional regulators YAP and TAZ play important roles in development, physiology and tumorigenesis and are negatively controlled by the Hippo pathway. Upon activation of Hippo signaling, YAP and TAZ are phosphorylated by LATS1/2 and Casein 1δ/ε kinases, leading to poly-ubiquitination by SCF E3 ubiquitin ligase and proteasomal degradation. Although YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active, it is yet unknown whether YAP/TAZ can be stabilized via deubiquitination and thereby escape from the negative Hippo control. Here, by a gain-of-function cancer metastasis screen we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on Lysine 233 and this SUMOylation enables it to bind YAP/TAZ. We also identified an as yet unknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2. Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activating YAP/TAZ. Our results not only establish OTUB2 as an essential modulator of YAP/TAZ, but also reveal a novel regulatory mechanism via which YAP/TAZ activity is induced by oncogenic KRAS
OTUB2 promotes cancer metastasis via Hippo independent activation of YAP and TAZ, Zhang et al.
No full textThe transcriptional regulators YAP and TAZ play important roles in development, physiology and tumorigenesis and are negatively controlled by the Hippo pathway. Upon activation of Hippo signaling, YAP and TAZ are phosphorylated by LATS1/2 and Casein 1δ/ε kinases, leading to poly-ubiquitination by SCF E3 ubiquitin ligase and proteasomal degradation. Although YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active, it is yet unknown whether YAP/TAZ can be stabilized via deubiquitination and thereby escape from the negative Hippo control. Here, by a gain-of-function cancer metastasis screen we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on Lysine 233 and this SUMOylation enables it to bind YAP/TAZ. We also identified an as yet unknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2. Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activating YAP/TAZ. Our results not only establish OTUB2 as an essential modulator of YAP/TAZ, but also reveal a novel regulatory mechanism via which YAP/TAZ activity is induced by oncogenic KRAS
OTUB2 promotes cancer metastasis via Hippo independent activation of YAP and TAZ, Zhang et al.
No full textThe transcriptional regulators YAP and TAZ play important roles in development, physiology and tumorigenesis and are negatively controlled by the Hippo pathway. Upon activation of Hippo signaling, YAP and TAZ are phosphorylated by LATS1/2 and Casein 1δ/ε kinases, leading to poly-ubiquitination by SCF E3 ubiquitin ligase and proteasomal degradation. Although YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active, it is yet unknown whether YAP/TAZ can be stabilized via deubiquitination and thereby escape from the negative Hippo control. Here, by a gain-of-function cancer metastasis screen we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on Lysine 233 and this SUMOylation enables it to bind YAP/TAZ. We also identified an as yet unknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2. Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activating YAP/TAZ. Our results not only establish OTUB2 as an essential modulator of YAP/TAZ, but also reveal a novel regulatory mechanism via which YAP/TAZ activity is induced by oncogenic KRAS.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV
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