| 1. |
- Fukuda, Tomohiko, et al.
(författare)
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BMP2-induction of FN14 promotes protumorigenic signaling in gynecologic cancer cells
- 2021
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Ingår i: Cellular Signalling. - : Elsevier. - 0898-6568 .- 1873-3913. ; 87
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Tidskriftsartikel (refereegranskat)abstract
- We previously reported that bone morphogenetic protein (BMP) signaling promotes tumorigenesis in gynecologic cancer cells. BMP2 enhances proliferation of ovarian and endometrial cancer cells via c-KIT induction, and triggers epithelial-mesenchymal transition (EMT) by SNAIL and/or SLUG induction, leading to increased cell migration. However, the downstream effectors of BMP signaling in gynecological cancer cells have not been clearly elucidated. In this study, we performed RNA-sequencing of Ishikawa endometrial and SKOV3 ovarian cancer cells after BMP2 stimulation, and identified TNFRSF12A, encoding fibroblast growth factor-inducible 14 (FN14) as a common BMP2-induced gene. FN14 knockdown suppressed BMP2-induced cell proliferation and migration, confirmed by MTS and scratch assays, respectively. In addition, FN14 silencing augmented chemosensitivity of SKOV3 cells. As a downstream effector of BMP signaling, FN14 modulated both c-KIT and SNAIL expression, which are important for growth and migration of ovarian and endometrial cancer cells. These results support the notion that the tumor promoting effects of BMP signaling in gynecological cancers are partially attributed to FN14 induction.
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| 2. |
- Heldin, Paraskevi, et al.
(författare)
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Involvement of hyaluronan and CD44 in cancer and viral infections
- 2020
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Ingår i: Cellular Signalling. - : ELSEVIER SCIENCE INC. - 0898-6568 .- 1873-3913. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- Hyaluronan and its major receptor CD44 are ubiquitously distributed. They have important structural as well as signaling roles, regulating tissue homeostasis, and their expression levels are tightly regulated. In addition to signaling initiated by the interaction of the intracellular domain of CD44 with cytoplasmic signaling molecules, CD44 has important roles as a co-receptor for different types of receptors of growth factors and cytokines. Dysregulation of hyaluronan-CD44 interactions is seen in diseases, such as inflammation and cancer. In the present communication, we discuss the mechanism of hyaluronan-induced signaling via CD44, as well as the involvement of hyaluronan-engaged CD44 in malignancies and in viral infections.
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| 3. |
- Lind, Simon, 1993, et al.
(författare)
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Allosteric receptor modulation uncovers an FFA2R antagonist as a positive orthosteric modulator/agonist in disguise.
- 2021
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Ingår i: Cellular signalling. - : Elsevier BV. - 1873-3913 .- 0898-6568. ; 90:February 2022
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Tidskriftsartikel (refereegranskat)abstract
- A novel receptor crosstalk activation mechanism, through which signals generated by the agonist-occupied P2Y2R (the neutrophil receptor for ATP) activate allosterically modulated free fatty acid 2 receptor (FFA2R) without the involvement of any FFA2R agonist, was used to determine the inhibitor profiles of two earlier-described, FFA2R-specific antagonists, CATPB and GLPG0974. These antagonists have been shown to have somewhat different receptor-interaction characteristics at the molecular/functional level, although both are recognized by the orthosteric site in FFA2R. The antagonists inhibited neutrophil activation induced by ATP, an activation occurred only in the presence of either of the two positive allosteric FFA2R modulators (PAMs) AZ1729 and Cmp58. No neutrophil activation was induced by either AZ1729 or Cmp58 alone, whereas together they acted as co-agonistic PAMs and activated the superoxide-generating NADPH-oxidase in neutrophils. This response was inhibited by CATPB but not by GLPG0974. In contrast, GLPG0974 acted as a positive modulator, increasing the potency, albeit not the efficacy, of the co-agonistic PAMs. GLPG0974 also altered signaling downstream of FFA2R when activated by the co-agonistic PAMs. In the presence of GLPG0974, the response of neutrophils induced by the co-agonistic PAMs included an increase in the cytosolic concentration of free calcium ions (Ca2+), and this effect was reciprocal in that GLPG0974 triggered an increase in intracellular Ca2+, demonstrating that GLPG0974 acted as an FFA2R agonist. In summary, by studying the effects of the FFA2R ligand GLPG0974 on neutrophil activation induced by the co-agonists AZ1729+Cmp58, we show that GLPG0974 is not only an FFA2R antagonist, but also displays agonistic and positive FFA2R-modulating functions that affect NADPH-oxidase activity and alter the receptor-downstream signaling induced by the co-agonistic PAMs.
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| 4. |
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| 6. |
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| 7. |
- Negoita, Florentina, et al.
(författare)
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JUP/plakoglobin is regulated by salt-inducible kinase 2, and is required for insulin-induced signalling and glucose uptake in adipocytes
- 2020
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Ingår i: Cellular Signalling. - : Elsevier BV. - 1873-3913 .- 0898-6568. ; 76
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Salt-inducible kinase 2 (SIK2) is abundant in adipocytes, but downregulated in adipose tissue from individuals with obesity and insulin resistance. Moreover, SIK isoforms are required for normal insulin signalling and glucose uptake in adipocytes, but the underlying molecular mechanisms are currently not known. The adherens junction protein JUP, also termed plakoglobin or γ-catenin, has recently been reported to promote insulin signalling in muscle cells.OBJECTIVE: The objective of this study was to analyse if JUP is required for insulin signalling in adipocytes and the underlying molecular mechanisms of this regulation.METHODS: Co-expression of SIK2 and JUP mRNA levels in adipose tissue from a human cohort was analysed. siRNA silencing and/or pharmacological inhibition of SIK2, JUP, class IIa HDACs and CRTC2 was employed in 3T3-L1- and primary rat adipocytes. JUP protein expression was analysed by western blot and mRNA levels by qPCR. Insulin signalling was evaluated by western blot as levels of phosphorylated PKB/Akt and AS160, and by monitoring the uptake of 3H-2-deoxyglucose.RESULTS: mRNA expression of SIK2 correlated with that of JUP in human adipose tissue. SIK2 inhibition or silencing resulted in downregulation of JUP mRNA and protein expression in 3T3-L1- and in primary rat adipocytes. Moreover, JUP silencing reduced the expression of PKB and the downstream substrate AS160, and consequently attenuated activity in the insulin signalling pathway, including insulin-induced glucose uptake. The known SIK2 substrates CRTC2 and class IIa HDACs were found to play a role in the SIK-mediated regulation of JUP expression.CONCLUSIONS: These findings identify JUP as a novel player in the regulation of insulin sensitivity in adipocytes, and suggest that changes in JUP expression could contribute to the effect of SIK2 on insulin signalling in these cells.
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| 8. |
- Wåhlén, Erik, et al.
(författare)
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Differential impact of lipid raft depletion on platelet-derived growth factor (PDGF)-induced ERK1/2 MAP-kinase, SRC and AKT signaling
- 2022
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Ingår i: Cellular Signalling. - : Elsevier. - 0898-6568 .- 1873-3913. ; 96
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Tidskriftsartikel (refereegranskat)abstract
- It has become clear that lipid rafts functions as signaling hotspots connecting cell surface receptors to intracellular signaling pathways. However, the exact involvement of lipid rafts in receptor tyrosine kinase signaling is still poorly understood. In this study, we have analyzed platelet-derived growth factor (PDGF) receptor β (PDGFR-β) signaling in two different cell lines depleted of cholesterol, and as a consequence, disruption of lipid rafts. Cholesterol depletion of BJ-hTERT fibroblasts using methyl-β-cyclodextrin (MβCD) did not affect PDGFR-β activation as measured by its tyrosine phosphorylation. However, we did observe a small reduction in AKT phosphorylation and a more robust decrease of ERK1/2 activation. In contrast, in the osteosarcoma cell line U2OS, we noticed a deficient receptor activation. Interestingly, in U2OS cells, the ERK1/2 pathway was unaffected, but instead AKT and SRC signaling was reduced. These results suggest that cell type specific wiring of signaling pathways can lead to differential sensitivity to cholesterol depletion. Furthermore, MβCD treatment had a much more pronounced morphological effect on U2OS compared to BJ-hTERT cells. This is consistent with a previous report claiming that cancer cells are more sensitive to cholesterol depletion than normal cells. Our data supports the possibility that cholesterol lowering drugs may impede tumor growth.
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| 9. |
- Yang, Mingyu, et al.
(författare)
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Indicator-dependent differences in detection of local intracellular Ca2+release events evoked by voltage-gated Ca2+entry in pancreatic & beta;-cells
- 2023
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Ingår i: Cellular Signalling. - : Elsevier BV. - 0898-6568 .- 1873-3913. ; 109
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Tidskriftsartikel (refereegranskat)abstract
- Genetically encoded Ca2+ indicators have become widely used in cell signalling studies as they offer advantages over cell-loaded dye indicators in enabling specific cellular or subcellular targeting. Comparing responses from dye and protein-based indicators may provide information about indicator properties and cell physiology, but side-by-side recordings in cells are scarce. In this study, we compared cytoplasmic Ca2+ concentration ([Ca2+]i) changes in insulin-secreting & beta;-cells recorded with commonly used dyes and indicators based on circularly permuted fluorescent proteins. Total internal reflection fluorescence (TIRF) imaging of K+ depolarizationtriggered submembrane [Ca2+]i increases showed that the dyes Fluo-4 and Fluo-5F mainly reported stable [Ca2+]i elevations, whereas the proteins R-GECO1 and GCaMP5G more often reported distinct [Ca2+]i spikes from an elevated level. [Ca2+]i spiking occurred also in glucose-stimulated cells. The spikes reflected Ca2+ release from the endoplasmic reticulum, triggered by autocrine activation of purinergic receptors after exocytotic release of ATP and/or ADP, and the spikes were consequently prevented by SERCA inhibition or P2Y1-receptor antagonism. Widefield imaging, which monitors the entire cytoplasm, increased the spike detection by the Ca2+ dyes. The indicator-dependent response patterns were unrelated to Ca2+ binding affinity, buffering and mobility, and probably reflects the much slower dissociation kinetics of protein compared to dye indicators. Ca2+ dyes thus report signalling within the submembrane space excited by TIRF illumination, whereas the protein indicators also catch Ca2+ events originating outside this volume. The study highlights that voltage-dependent Ca2+ entry in & beta;-cells is tightly linked to local intracellular Ca2+ release mediated via an autocrine route that may be more important than previously reported direct Ca2+ effects on phospholipase C or on intracellular channels mediating calcium-induced calcium release.
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| 10. |
- Öhman Fuchs, Peder, 1984-, et al.
(författare)
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Fibrin fragment E potentiates TGF-beta-induced myofibroblast activation and recruitment
- 2020
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Ingår i: Cellular Signalling. - : Elsevier. - 0898-6568 .- 1873-3913. ; 72
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Tidskriftsartikel (refereegranskat)abstract
- Fibrin is an essential constituent of the coagulation cascade, and the formation of hemostatic fibrin clots is central to wound healing. Fibrin clots are over time degraded into fibrin degradation products as the injured tissue is replaced by granulation tissue. Our goal was to study the role of the fibrin degradation product fragment E (FnE) in fibroblast activation and migration. We present evidence that FnE is a chemoattractant for fibroblasts and that FnE can potentiate TGF-beta-induced myofibroblast formation. FnE forms a stable complex with alpha(v)beta(3) integrin, and the integrin beta(3) subunit is required both for FnE-induced fibroblast migration and for potentiation of TGF-beta-induced myofibroblast formation. Finally, subcutaneous infusion of FnE in mice results in a fibrotic response in the hypodermis. These results support a model where FnE released from clots in wounded tissue promote wound healing and fibrosis by both recruitment and activation of fibroblasts. Fibrin fragment E could thus represent a therapeutic target for treatment of pathological fibrosis.
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| 11. |
- Amran, Aqilah, et al.
(författare)
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Functions of the extracellular matrix in development : Lessons from Caenorhabditis elegans
- 2021
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Ingår i: Cellular Signalling. - : Elsevier BV. - 0898-6568. ; 84
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Forskningsöversikt (refereegranskat)abstract
- Cell-extracellular matrix interactions are crucial for the development of an organism from the earliest stages of embryogenesis. The main constituents of the extracellular matrix are collagens, laminins, proteoglycans and glycosaminoglycans that form a network of interactions. The extracellular matrix and its associated molecules provide developmental cues and structural support from the outside of cells during development. The complex nature of the extracellular matrix and its ability for continuous remodeling poses challenges when investigating extracellular matrix-based signaling during development. One way to address these challenges is to employ invertebrate models such as Caenorhabditis elegans, which are easy to genetically manipulate and have an invariant developmental program. C. elegans also expresses fewer extracellular matrix protein isoforms and exhibits reduced redundancy compared to mammalian models, thus providing a simpler platform for exploring development. This review summarizes our current understanding of how the extracellular matrix controls the development of neurons, muscles and the germline in C. elegans.
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| 12. |
- Gu, S. L., et al.
(författare)
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beta-Sitosterol blocks the LEF-1-mediated Wnt/beta-catenin pathway to inhibit proliferation of human colon cancer cells
- 2023
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Ingår i: Cellular Signalling. - : Elsevier BV. - 0898-6568. ; 104
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: This study aimed to investigate the LEF-1-mediated Wnt/beta-catenin pathway for its biological functions and prognostic value in colon cancer (CC). Furthermore, the potential molecular mechanism of beta-sitosterol in CC was investigated in vitro.Methods: Clinical information and gene expression profiles from CC patients were obtained based on Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. In addition, we applied R software "Limma" package for the differential analysis of LEF-1 between cancer and para-carcinoma tissue samples. Kaplan-Meier (KM) survival analysis was adopted for analyzing whether LEF-1 was of prognostic significance. Moreover, gene set enrichment analysis (GSEA) was adopted for pathway enrichment analysis and visualization. In addition, CCK8, plate cloning, scratch and high-content screening (HCS) imaging assays were performed to examine the therapeutic efficacy of beta-sitosterol in human CC HCT116 cells. siRNA technology was employed to knock down LEF1 expression in HCT116 cells. qRT-PCR and Western-blot (WB) analysis were carried out to analyze the HCT-116 mRNA and protein expression levels, respectively.Results: LEF-1 was up-regulated within CC and acted as an oncogenic gene. LEF-1 up-regulation predicted the dismal prognostic outcome and activated the Wnt/beta-catenin pathway. beta-sitosterol effectively suppressed HCT116 cells proliferation and invasion. For the mechanism underlying beta-sitosterol, beta-sitosterol was found to significantly down-regulate LEF-1 gene and protein expression and disrupt Wnt/beta-catenin pathway transmission in HCT116 cells. After suppressing LEF-1 expression, its downstream targets including C-myc, Survivin and CCND1 were also down-regulated.Conclusion: According to our results, LEF-1 down-regulation can effectively block Wnt/beta-catenin pathway, inhibit CC cell growth and migration. Collectively, beta-sitosterol can be used to treat CC, which can provide anti-tumor activity by targeting LEF-1.
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| 13. |
- Lind, Simon, 1993, et al.
(författare)
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An increase in the cytosolic concentration of free calcium ions activates the neutrophil NADPH-oxidase provided that the free fatty acid receptor 2 has been allosterically modulated.
- 2023
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Ingår i: Cellular signalling. - 1873-3913. ; 107
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Tidskriftsartikel (refereegranskat)abstract
- Signals generated by free fatty acid receptor 2 (FFA2R) can activate the neutrophil NADPH-oxidase without involvement of any orthosteric FFA2R agonist. The initiating signals may be generated by P2Y2R, the receptor for ATP. An FFA2R specific allosteric modulator (PAM; Cmp58) was required for this response and used to investigate the mechanism by which signals generated by ATP/P2Y2R activate an FFA2R dependent process. The P2Y2R induced signal that together with the modulated FFA2R activates neutrophils, was generated downstream of the Gαq containing G protein coupled to P2Y2R. A rise in the cytosolic concentration of ionized calcium ([Ca2+]i) was hypothesized to be the important signal. The hypothesis gained support from the finding that the modulator transferred the neutrophils to a Ca2+sensitive state. The rise in [Ca2+]i induced by the Ca2+ specific ionophore ionomycin, activated the neutrophils provided that an allosteric modulator was bound to FFA2R. The activity of the superoxide generating NADPH-oxidase induced by ionomycin was rapidly terminated and the FFA2Rs could then no longer be activated by the FFA2R agonist propionate or by the signal generated by ATP/P2Y2R. The non-responding state of FFA2R was, however, revoked by a cross-activating allosteric FFA2R modulator. The [Ca2+]i mediated activation of neutrophils with their FFA2Rs allosterically modulated, represent a unique regulatory receptor crosstalk mechanism by which the activation potency of a G protein coupled receptor is controlled by a receptor-crosstalk signaling system operating from the cytosolic side of the plasma membrane.
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| 14. |
- Riley, Teal R., et al.
(författare)
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Triassic magmatism and metamorphism in the Antarctic Peninsula : Identifying the extent and timing of the Peninsula Orogeny
- 2020
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Ingår i: Journal of South American Earth Sciences. - : Elsevier BV. - 0895-9811 .- 1873-0647. ; 103
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Tidskriftsartikel (refereegranskat)abstract
- The mid to Late Triassic marks an episode of magmatism, deformation and metamorphism along the proto-Pacific margin of the Antarctic Peninsula and Patagonia. Calc-alkaline magmatism at ~227 Ma developed in a convergent margin setting across the central Antarctic Peninsula and North Patagonian Massif. Two distinct deformation and metamorphic events have been identified at ~221 Ma and ~207 Ma based on new U–Pb zircon ages from a metamorphic orthogneiss complex, investigated for the first time, from the elevated plateau region of central Palmer Land. These two events are interpreted to date the timing of the multi-phase Peninsula Orogeny, which correlates with the Chonide Event of central Patagonia. The onset of deformation in the Antarctic Peninsula is linked to tectonic events in central Patagonia and is associated with non-collisional slab dynamic processes during flat slab subduction in the Late Triassic. No consistent tectonic regime is evident during the mid-to Late Triassic episodes of deformation and metamorphism, but an initial period of extension/transtension (mid-Triassic) and a compressional regime in the Late Triassic is favoured in the Antarctic Peninsula and Patagonia. The newly acquired metamorphic ages provide no clear evidence for a segmented terrane model for the Antarctic Peninsula, as Late Triassic metamorphic ages are identified from across the central and eastern domains. New U–Pb zircon ages are also presented from a suite of strongly foliated granitoids that cross-cut the Triassic orthogneisses. They are dated in the interval 140–136 Ma and represent an episode of Early Cretaceous magmatism, transtensional deformation and widespread metamorphism across northwest and central Palmer Land.
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