Gen inhibiting the Wnt/Ca2+ signaling pathway alleviates cerebral ischemia/reperfusion injury
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Cerebral ischemia/reperfusion injury (CIRI) is a major complication of acute ischemic stroke (AIS), characterized by calcium overload, oxidative stress, and cell apoptosis. In this study, we investigated the therapeutic potential of Genistein (Gen) in alleviating CIRI by focusing on its effects on the Wnt/Ca2+ signaling pathway. Using a rat model of cerebral ischemia/reperfusion and in vitro experiments on PC12 cells, we observed that Gen treatment reduced infarct size, improved neurological function, and mitigated calcium overload, oxidative stress, and apoptosis. Further analysis revealed that Gen regulates key proteins in the Wnt/Ca2+ signaling pathway, including Wnt5a and Frizzled-2, effectively preventing intracellular calcium accumulation and subsequent damage. The knockdown of Frizzled-2 confirmed the pathway's role in mediating calcium overload and subsequent damage. Our findings suggest that Gen alleviates CIRI by inhibiting the Wnt/Ca2+ signaling pathway, positioning it as a promising candidate for therapeutic intervention in stroke treatment.Keywords:
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Wnt proteins are lipid-modified secreted molecules that initiate signaling by interacting with a receptor complex that includes the serpentine receptor Frizzled and low-density lipoprotein receptor—related protein 5 (LRP5) or LRP6. Wnt receptor activation leads to stabilization of β-catenin, which accumulates in the nucleus and activates transcription of Wnt target genes. Roof plate-specific spondins (R-spondins) are proteins unrelated in sequence to Wnts that, like Wnts, are implicated in regulation of development and that also activate signaling through β-catenin. Conflicting reports have been published as to whether R-spondins use the same receptors as Wnts and whether they bind to Frizzled or LRP6, both, or neither. Wei et al . present data showing that human R-spondin1 (hRspo1) binds to cultured human embryonic kidney (HEK293T) cells transfected with LRP6. Solid-phase binding assays showed that hRspo1 bound to the extracellular domain of LRP6 with high affinity (K d , 1.2 nM) but showed little if any binding to Frizzled. The hRspo1 protein also induced phosphorylation of LRP6 (as does Wnt). hRspo1 had synergistic effects with Wnt3A on phosphorylation of LRP6 in HEK293T cells and on phosphorylation of endogenous LRP6 in mouse embryo fibroblasts. R-spondins thus appear to work differently from Wnts in some ways (Wnts bind with high affinity to Frizzled, with weak or no binding to LRP6), but both ligands activate similar downstream signaling events. Furthermore, expression of R-spondins is stimulated by Wnts, leading the authors to propose that R-spondins may act in a positive feedback loop that reinforces Wnt signaling during development. Q. Wei, C. Yokota, M. V. Semenov, B. Doble, J. Woodgett, X. He, R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and β-catenin signaling. J. Biol. Chem. 282 , 15903-15911 (2007). [Abstract] [Full Text]
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Animals’ Wnt signaling pathways are highly preserved signal transduction pathways, which play a crucial role in embryogenesis and adult tissue homeostasis. This chapter reviews the three major Wnt pathways, focusing on some critical proteins in the Wnt/β-catenin path in terms of their evolution and role in homeostasis. Wnt proteins act as a gateway between extracellular, cytoplasmic, and nuclear components to transmit signaling pathways. The Frizzled (FZD) family as G-protein-coupled receptors activates the signaling pathways by binding to Wnt ligands. LRP5/6, members of the family of low-density lipoprotein receptors (LDLR), associate with FZD receptor and Wnt ligands as co-receptors to initiate the Wnt/β-catenin pathway. The Wnt/β-catenin pathway is regulated by antagonists such as the Dickkopf and secreted Frizzled-related protein (SFRP) families.
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Wnts are secreted glycoproteins that regulate embryonic development through Frizzled (Fz) cell-surface receptors. Subsequent regulation of gene expression occurs through relocalization of intracellular β-catenin to the nucleus. The mechanism by which another extracellular molecule called Dickkopf (DKK) blocks Wnt signaling is now described by Mao et al. DKK binds to LDL-receptor-related protein 6 (LRP6), a transmembrane protein that also regulates β-catenin. DKK binds to a region of LRP6 that is not involved in LRP6's interaction with the Wnt-Fz complex, and the DKK-LRP6 association did not affect Wnt-Fz interaction. The authors used Xenopus embryos to show that LRP6 promotes Wnt-induced posterior development. However, in the presence of DKK, this developmental process is inhibited, resulting in anterior embryonic development instead. R. Nusse offers insights into the signaling link between LRP6 and Fz.B. Mao, W. Wu, Y. Li, D. Hoppe, P. Stannek, A. Glinka, C. Niehrs, LDL-receptor-related protein 6 is a receptor for Dickkopf proteins, Nature 411, 321-325 (2001). [Online Journal]R. Nusse, Making head or tail of Dickkop, Nature 411: 255-256 (2001). [Online Journal]
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Canonical Wnt/beta-catenin signaling has central roles in development and diseases, and is initiated by the action of the frizzled (Fz) receptor, its coreceptor LDL receptor-related protein 6 (Lrp6), and the cytoplasmic dishevelled (Dvl) protein. The functional relationships among Fz, Lrp6 and Dvl have long been enigmatic. We demonstrated previously that Wnt-induced Lrp6 phosphorylation via glycogen synthase kinase 3 (Gsk3) initiates Wnt/beta-catenin signaling. Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. We also show that axin, a key scaffolding protein in the Wnt pathway, is required for Lrp6 phosphorylation via its ability to recruit Gsk3, and inhibition of Gsk3 at the plasma membrane blocks Wnt/beta-catenin signaling. Our results suggest a model that upon Wnt-induced Fz-Lrp6 complex formation, Fz recruitment of Dvl in turn recruits the axin-Gsk3 complex, thereby promoting Lrp6 phosphorylation to initiate beta-catenin signaling. We discuss the dual roles of the axin-Gsk3 complex and signal amplification by Lrp6-axin interaction during Wnt/beta-catenin signaling. PMID: 18077588 Funding information This work was supported by: NINDS NIH HHS, United States Grant ID: R01 NS073159 CIHR, Canada Grant ID: 12043
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Wnt signaling through the canonical β-catenin pathway plays essential roles in development and disease. Low-density-lipoprotein receptor-related proteins 5 and 6 (Lrp5 and Lrp6) in vertebrates, and their Drosophila ortholog Arrow, are single-span transmembrane proteins that are indispensable for Wnt/β-catenin signaling, and are likely to act as Wnt co-receptors. This review highlights recent progress and unresolved issues in understanding the function and regulation of Arrow/Lrp5/Lrp6 in Wnt signaling. We discuss Arrow/Lrp5/Lrp6 interactions with Wnt and the Frizzled family of Wnt receptors, and with the intracellular β-catenin degradation apparatus. We also discuss the regulation of Lrp5/Lrp6 by other extracellular ligands, and LRP5 mutations associated with familial osteoporosis and other disorders.
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WNT factors represent key mediators of many processes in animal development and homeostasis and act through a receptor complex comprised of members of the Frizzled and low density lipoprotein-related receptors (LRP). In mammals, 19 genes encoding Wingless and Int-related factor (WNTs), 10 encoding Frizzled, and 2 encoding LRP proteins have been identified, but little is known of the identities of individual Frizzled-LRP combinations mediating the effects of specific WNT factors. Additionally, several secreted modulators of WNT signaling have been identified, including at least three members of the Dickkopf family. WNT7A is a WNT family member expressed in the vertebrate central nervous system capable of modulating aspects of neuronal plasticity. Gene knock-out models in the mouse have revealed that WNT7A plays a role in cerebellar maturation, although its function in the development of distal limb structures and of the reproductive tract have been more intensely studied. To identify a receptor complex for this WNT family member, we have analyzed the response of the rat pheochromocytoma cell line PC12 to WNT7A. We find that PC12 cells are capable of responding to WNT7A as measured by increased beta-catenin stability and activation of a T-cell factor-based luciferase reporter construct and that these cells express three members of the Frizzled family (Frizzled-2, -5, and -7) and LRP6. Our functional analysis indicates that WNT7A can specifically act via a Frizzled-5.LRP6 receptor complex in PC12 cells and that this activity can be antagonized by Dickkopf-1 and Dickkopf-3.
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Canonical Wnt/beta-catenin signaling has central roles in development and diseases, and is initiated by the action of the frizzled (Fz) receptor, its coreceptor LDL receptor-related protein 6 (Lrp6), and the cytoplasmic dishevelled (Dvl) protein. The functional relationships among Fz, Lrp6 and Dvl have long been enigmatic. We demonstrated previously that Wnt-induced Lrp6 phosphorylation via glycogen synthase kinase 3 (Gsk3) initiates Wnt/beta-catenin signaling. Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. We also show that axin, a key scaffolding protein in the Wnt pathway, is required for Lrp6 phosphorylation via its ability to recruit Gsk3, and inhibition of Gsk3 at the plasma membrane blocks Wnt/beta-catenin signaling. Our results suggest a model that upon Wnt-induced Fz-Lrp6 complex formation, Fz recruitment of Dvl in turn recruits the axin-Gsk3 complex, thereby promoting Lrp6 phosphorylation to initiate beta-catenin signaling. We discuss the dual roles of the axin-Gsk3 complex and signal amplification by Lrp6-axin interaction during Wnt/beta-catenin signaling.
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