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Deficiency of tumor suppressor Merlin facilitates metabolic adaptation by co-operative engagement of SMAD-Hippo signaling in breast cancer.

ABSTRACT: The NF2 gene encodes the tumor and metastasis suppressor protein Merlin. Merlin exerts its tumor suppressive role by inhibiting proliferation and inducing contact-growth inhibition and apoptosis. In the current investigation, we determined that loss of Merlin in breast cancer tissues is concordant with the loss of the inhibitory SMAD, SMAD7, of the TGF-β pathway. This was reflected as dysregulated activation of TGF-β signaling that co-operatively engaged with effectors of the Hippo pathway (YAP/TAZ/TEAD). As a consequence, the loss of Merlin in breast cancer resulted in a significant metabolic and bioenergetic adaptation of cells characterized by increased aerobic glycolysis and decreased oxygen consumption. Mechanistically, we determined that the co-operative activity of the Hippo and TGF-β transcription effectors caused upregulation of the long non-coding RNA Urothelial Cancer-Associated 1 (UCA1) that disengaged Merlin's check on STAT3 activity. The consequent upregulation of Hexokinase 2 (HK2) enabled a metabolic shift towards aerobic glycolysis. In fact, Merlin deficiency engendered cellular dependence on this metabolic adaptation, endorsing a critical role for Merlin in regulating cellular metabolism. This is the first report of Merlin functioning as a molecular restraint on cellular metabolism. Thus, breast cancer patients whose tumors demonstrate concordant loss of Merlin and SMAD7 may benefit from an approach of incorporating STAT3 inhibitors.

SUBMITTER: Mota MSV

PROVIDER: S-EPMC6148973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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NEDD4L-mediated Merlin ubiquitination facilitates Hippo pathway activation

Project description:The tumor suppressor Merlin/NF2, a key activator of the Hippo pathway in growth control, is regulated by phosphorylation. However, it is uncertain whether additional post-translational modifications regulate Merlin. Here, we show that ubiquitination is required to activate Merlin in the Hippo pathway. Ubiquitinated Merlin is mostly conjugated by one or two ubiquitin molecules. Such modification is promoted by serine 518 dephosphorylation in response to Ca2+ signaling or cell detachment. Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.

| S-SCDT-EMBOR-2020-50642V1 | biostudies-other

NEDD4L-mediated Merlin ubiquitination facilitates Hippo pathway activation.

Project description:The tumor suppressor Merlin/NF2, a key activator of the Hippo pathway in growth control, is regulated by phosphorylation. However, it is uncertain whether additional post-translational modifications regulate Merlin. Here, we show that ubiquitination is required to activate Merlin in the Hippo pathway. Ubiquitinated Merlin is mostly conjugated by one or two ubiquitin molecules. Such modification is promoted by serine 518 dephosphorylation in response to Ca2+ signaling or cell detachment. Merlin ubiquitination is mediated by the E3 ubiquitin ligase, NEDD4L, which requires a scaffold protein, AMOTL1, to approach Merlin. Several NF2-patient-derived Merlin mutations disrupt its binding to AMOTL1 and its regulation by the AMOTL1-NEDD4L apparatus. Lysine (K) 396 is the major ubiquitin conjugation residue. Disruption of Merlin ubiquitination by the K396R mutation or NEDD4L depletion diminishes its binding to Lats1 and inhibits Lats1 activation. These effects are also accompanied by loss of Merlin's anti-mitogenic and tumor suppressive properties. Thus, we propose that dephosphorylation and ubiquitination compose an intramolecular relay to activate Merlin functions in activating the Hippo pathway during growth control.

| S-EPMC7726808 | biostudies-literature

Tumor suppressor Nf2/merlin drives Schwann cell changes following electromagnetic field exposure through Hippo-dependent mechanisms.

Project description:Previous evidence showed mutations of the neurofibromin type 2 gene (Nf2), encoding the tumor suppressor protein merlin, in sporadic and vestibular schwannomas affecting Schwann cells (SCs). Accordingly, efforts have been addressed to identify possible factors, even environmental, that may regulate neurofibromas growth. In this context, we investigated the exposure of SC to an electromagnetic field (EMF), which is an environmental issue modulating biological processes. Here, we show that SC exposed to 50?Hz EMFs changes their morphology, proliferation, migration and myelinating capability. In these cells, merlin is downregulated, leading to activation of two intracellular signaling pathways, ERK/AKT and Hippo. Interestingly, SC changes their phenotype toward a proliferative/migrating state, which in principle may be pathologically relevant for schwannoma development.

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Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2.

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| S-EPMC3835333 | biostudies-literature

Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded.

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| S-EPMC2858562 | biostudies-literature

Hippo pathway phylogenetics predicts monoubiquitylation of Salvador and Merlin/Nf2.

Project description:Recently we employed phylogenetics to predict that the cellular interpretation of TGF-β signals is modulated by monoubiquitylation cycles affecting the Smad4 signal transducer/tumor suppressor. This prediction was subsequently validated by experiments in flies, frogs and mammalian cells. Here we apply a phylogenetic approach to the Hippo pathway and predict that two of its signal transducers, Salvador and Merlin/Nf2 (also a tumor suppressor) are regulated by monoubiquitylation. This regulatory mechanism does not lead to protein degradation but instead serves as a highly efficient "off/on" switch when the protein is subsequently deubiquitylated. Overall, our study shows that the creative application of phylogenetics can predict new roles for pathway components and new mechanisms for regulating intercellular signaling pathways.

| S-EPMC3522738 | biostudies-literature

Regulation of Drosophila glial cell proliferation by Merlin-Hippo signaling.

Project description:Glia perform diverse and essential roles in the nervous system, but the mechanisms that regulate glial cell numbers are not well understood. Here, we identify and characterize a requirement for the Hippo pathway and its transcriptional co-activator Yorkie in controlling Drosophila glial proliferation. We find that Yorkie is both necessary for normal glial cell numbers and, when activated, sufficient to drive glial over-proliferation. Yorkie activity in glial cells is controlled by a Merlin-Hippo signaling pathway, whereas the upstream Hippo pathway regulators Fat, Expanded, Crumbs and Lethal giant larvae have no detectable role. We extend functional characterization of Merlin-Hippo signaling by showing that Merlin and Hippo can be physically linked by the Salvador tumor suppressor. Yorkie promotes expression of the microRNA gene bantam in glia, and bantam promotes expression of Myc, which is required for Yorkie and bantam-induced glial proliferation. Our results provide new insights into the control of glial growth, and establish glia as a model for Merlin-specific Hippo signaling. Moreover, as several of the genes we studied have been linked to human gliomas, our results suggest that this linkage could reflect their organization into a conserved pathway for the control of glial cell proliferation.

| S-EPMC3210499 | biostudies-literature

MIR22HG acts as a tumor suppressor via TGF?/SMAD signaling and facilitates immunotherapy in colorectal cancer.

Project description:BACKGROUND:Long noncoding RNAs (lncRNAs) are emerging as critical regulatory elements and play fundamental roles in the biology of various cancers. However, we are still lack of knowledge about their expression patterns and functions in human colorectal cancer (CRC). METHODS:Differentially expressed lncRNAs in CRC were identified by bioinformatics screen and the level of MIR22HG in CRC and control tissues were determined by qRT-PCR. Cell viability and migration capacities were examined by MTT and transwell assay. Mouse model was used to examine the function and rational immunotherapy of MIR22HG in vivo. RESULTS:We systematically investigated the expression pattern of lncRNAs and revealed MIR22HG acts as a tumor suppressor in CRC. The expression of MIR22HG was significantly decreased in CRC, which was mainly driven by copy number deletion. Reduced expression of MIR22HG was significantly associated with poor overall survival. Silencing of MIR22HG promoted cell survival, proliferation and tumor metastasis in vitro and in vivo. Mechanistically, MIR22HG exerts its tumor suppressive activity by competitively interacting with SMAD2 and modulating the activity of TGF? pathway. Decreased MIR22HG promoted the epithelial-mesenchymal transition in CRC. Importantly, we found that MIR22HG expression is significantly correlated with CD8A and overexpression of MIR22HG triggers T cell infiltration, enhancing the clinical benefits of immunotherapy. CONCLUSION:MIR22HG acts as a tumor suppressor in CRC. Our data provide mechanistic insights into the regulation of MIR22HG in TGF? pathway and facilitates immunotherapy in cancer.

| S-EPMC7055097 | biostudies-literature

Tumor suppressor NF2/Merlin is a microtubule stabilizer.

Project description:Cancer-associated mutations in oncogene products and tumor suppressors contributing to tumor progression manifest themselves, at least in part, by deregulating microtubule-dependent cellular processes that play important roles in many cell biological pathways, including intracellular transport, cell architecture, and primary cilium and mitotic spindle organization. An essential characteristic of microtubules in the performance of these varied cell processes is their ability to continuously remodel, a phenomenon known as dynamic instability. It is therefore conceivable that part of the normal function of certain cancer-causing genes is to regulate microtubule dynamic instability. Here, we report the results of a high-resolution live-cell image-based RNA interference screen targeting a collection of 70 human tumor suppressor genes to uncover cancer genes affecting microtubule dynamic instability. Extraction and computational analysis of microtubule dynamics from EB3-GFP time-lapse image sequences identified the products of the tumor suppressor genes NF1 and NF2 as potent microtubule-stabilizing proteins. Further in-depth characterization of NF2 revealed that it binds to and stabilizes microtubules through attenuation of tubulin turnover by lowering both rates of microtubule polymerization and depolymerization as well as by reducing the frequency of microtubule catastrophes. The latter function appears to be mediated, in part, by inhibition of hydrolysis of tubulin-bound GTP on the growing microtubule plus end.

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Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway.

Project description:The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4(DCAF1). Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2-binding site on the Merlin FERM domain is physically blocked by Merlin's auto-inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto-inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway.

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