Characterisation of a nucleo-adhesome

Byron, Adam; Griffith, Billie G. C.; Herrero, Ana; Loftus, Alexander E.P.; Koeleman, Emma S.; Kogerman, Linda; Dawson, John C.; McGivern, Niamh; Culley, Jayne; Grimes, Graeme R.; Serrels, Bryan; Kriegsheim, Alex von; Brunton, Valerie G.; Frame, Margaret C.

doi:10.1038/s41467-022-30556-5

Cited by 6 publications

(5 citation statements)

References 102 publications

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“…Conceptually, the presence of VE-cadherin in the nucleus remains challenging. Recently, a proteomic seminal approach reported by Adam Bryon et al [46] showed that some adhesion proteins like integrin and others involved in adherents junctions have nuclear localization and are called nucleo-adhesome regions nearly to the nucleus. More interestingly, the proteins associated with nucleo-adhesome are FAK-dependent way.…”

Section: Discussionmentioning

confidence: 99%

VE-Cadherin modulates β-catenin/TCF-4 to enhance Vasculogenic Mimicry

et al. 2023

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Vasculogenic Mimicry (VM) refers to the capacity to form a blood network from aggressive cancer cells in an independent way of endothelial cells, to provide nutrients and oxygen leading to enhanced microenvironment complexity and treatment failure. In a previous study, we demonstrated that VE-Cadherin and its phosphorylation at Y658 modulated kaiso-dependent gene expression (CCND1 and Wnt 11) through a pathway involving Focal Adhesion kinase (FAK). In the present research, using a proteomic approach, we have found that β-catenin/TCF-4 is associated with nuclear VE-cadherin and enhances the capacity of malignant melanoma cells to undergo VM in cooperation with VE-Cadherin; in addition, preventing the phosphorylation of Y658 of VE-cadherin upon FAK disabling resulted in VE-Cadherin/β-catenin complex dissociation, increased β-catenin degradation while reducing TCF-4-dependent genes transcription (C-Myc and Twist-1). Uveal melanoma cells knockout for VE-Cadherin loses β-catenin expression while the rescue of VE-Cadherin (but not of the phosphorylation defective VE-Cadherin Y658F mutant) permits stabilization of β-catenin and tumor growth reduction in vivo experiments. In vivo, the concomitant treatment with the FAK inhibitor PF-271 and the anti-angiogenic agent bevacizumab leads to a strong reduction in tumor growth concerning the single treatment. In conclusion, the anomalous expression of VE-Cadherin in metastatic melanoma cells (from both uveal and cutaneous origins), together with its permanent phosphorylation at Y658, favors the induction of the aggressive VM phenotype through the cooperation of β-catenin with VE-Cadherin and by enhancing TCF-4 genes-dependent transcription.

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Section: Discussionmentioning

confidence: 99%

VE-Cadherin modulates β-catenin/TCF-4 to enhance Vasculogenic Mimicry

et al. 2023

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“…In cancer cells, on the other hand, the mechanism is not properly regulated and FAK is overexpressed [ 39 – 41 ]. Control melanoma cells have significant focal points and vinculin around the nucleus, the latter likely resulting from interactions with talin localized in the cell nucleus [ 42 , 43 ]. In treated melanoma cells, we found vinculin to be delocalized over the entire cytoplasmic fluid, consistent with an increase in its inactive form, which is consistent with the activation of FAK regulation mechanisms [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

pH-Selective Reactions to Selectively Reduce Cancer Cell Proliferation: Effect of CaS Nanostructures in Human Skin Melanoma and Benign Fibroblasts

Martínez

Ramos

Acevedo

et al. 2023

BioChem

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An acidic extracellular pH value (pHe) is characteristic of many cancers, in contrast to the physiologic pHe found in most benign cells. This difference in pH offers a unique opportunity to design and engineer chemicals that can be employed for pH-selective reactions in the extracellular fluid of cancer cells. The viability of human skin melanoma and corresponding fibroblasts exposed to CaS dispersions is reported. The viability of melanoma cells decreases with CaS dispersion concentration and reaches 57% at 3%, a value easily distinguishable from melanoma control experiments. In contrast, the viability of benign fibroblasts remains nearly constant within experimental error over the range of dispersion concentrations studied. The CaS dispersions facilitate vinculin delocalization in the cytoplasmic fluid, a result consistent with improved focal adhesion kinase (FAK) regulation in melanoma cells. Thermodynamic considerations are consistent with the formation of H2S from CaS in the presence of protons. The thermodynamic prediction is verified in independent experiments with solid CaS and acidic aqueous solutions. The amount of H2S formed decreases with pH. An activation energy for the process of (30 ± 10) kJ/mol in the temperature range of 280 to 330 K is estimated from initial rate measurements as a function of temperature. The total Gibbs energy minimization approach was employed to establish the distribution of sulfides—including H2S in the gas and aqueous phases—from the dissociation of CaS as a function of pH to mimic physiologically relevant pH values. Theoretical calculations suggest that partially protonated CaS in solution can be stable until the sulfur atom bonds to two hydrogen atoms, resulting in the formation of Ca2+ and H2S, which can be solvated and/or released to the gas phase. Our results are consistent with a model in which CaS is dissociated in the extracellular fluid of melanoma cells selectively. The results are discussed in the context of the potential biomedical applications of CaS dispersions in cancer therapies.

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“…The complexes center on integrin receptors that bind a variety of ECM proteins outside the cell, and a number of adaptor proteins and secondary messengers on their short cytoplasmic tails inside the cell. These adaptors form the direct connection to the cytoskeleton ( Burridge, 2017 ; Byron et al, 2022 ). As mentioned previously, FAs are also major sites of mechanosensing, so the signals received from the ECM range from chemical to physical.…”

Section: Cell Adhesion Proteins As Gene Regulatorsmentioning

confidence: 99%

“…Interestingly, in a major study demonstrating Zyxin’s translocation to the nucleus ( Cattaruzza et al, 2004 ), Vinculin, another well-known mechanosensing adaptor and Actin binding protein, did not shuttle to the nucleus under the same conditions, suggesting some specificity of Zyxin to proteins that will participate in both Actin binding and nuclear transport. Additionally, several key signaling partners to these adaptors such as FAK ( Griffith et al, 2021 ) and ICAP-1 ( Draheim et al, 2017 ), have also been detected in the nucleus under certain conditions, possibly creating a specific nucleo-adhesome protein pool with specific functions to be explored ( Byron et al, 2022 ).…”

Section: Cell Adhesion Proteins As Gene Regulatorsmentioning

confidence: 99%

Working a second job: Cell adhesion proteins that moonlight in the nucleus

Haage

Dhasarathy

2023

Front. Cell Dev. Biol.

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Cells are adept at sensing changes in their environment, transmitting signals internally to coordinate responses to external stimuli, and thereby influencing adaptive changes in cell states and behavior. Often, this response involves modulation of gene expression in the nucleus, which is seen largely as a physically separated process from the rest of the cell. Mechanosensing, whereby a cell senses physical stimuli, and integrates and converts these inputs into downstream responses including signaling cascades and gene regulatory changes, involves the participation of several macromolecular structures. Of note, the extracellular matrix (ECM) and its constituent macromolecules comprise an essential part of the cellular microenvironment, allowing cells to interact with each other, and providing both structural and biochemical stimuli sensed by adhesion transmembrane receptors. This highway of information between the ECM, cell adhesion proteins, and the cytoskeleton regulates cellular behavior, the disruption of which results in disease. Emerging evidence suggests a more direct role for some of these adhesion proteins in chromatin structure and gene regulation, RNA maturation and other non-canonical functions. While many of these discoveries were previously limited to observations of cytoplasmic-nuclear transport, recent advances in microscopy, and biochemical, proteomic and genomic technologies have begun to significantly enhance our understanding of the impact of nuclear localization of these proteins. This review will briefly cover known cell adhesion proteins that migrate to the nucleus, and their downstream functions. We will outline recent advances in this very exciting yet still emerging field, with impact ranging from basic biology to disease states like cancer.

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Characterisation of a nucleo-adhesome

Cited by 6 publications

References 102 publications

VE-Cadherin modulates β-catenin/TCF-4 to enhance Vasculogenic Mimicry

VE-Cadherin modulates β-catenin/TCF-4 to enhance Vasculogenic Mimicry

pH-Selective Reactions to Selectively Reduce Cancer Cell Proliferation: Effect of CaS Nanostructures in Human Skin Melanoma and Benign Fibroblasts

Working a second job: Cell adhesion proteins that moonlight in the nucleus

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