Rapid, Wnt-Induced Changes in GSK3β Associations that Regulate β-Catenin Stabilization Are Mediated by Gα Proteins
201
Citation
46
Reference
10
Related Paper
Citation Trend
Keywords:
Beta-catenin
Wnts are secreted signaling molecules that can transduce their signals through several different pathways. Wnt-5a is considered a noncanonical Wnt as it does not signal by stabilizing beta-catenin in many biological systems. We have uncovered a new noncanonical pathway through which Wnt-5a antagonizes the canonical Wnt pathway by promoting the degradation of beta-catenin. This pathway is Siah2 and APC dependent, but GSK-3 and beta-TrCP independent. Furthermore, we provide evidence that Wnt-5a also acts in vivo to promote beta-catenin degradation in regulating mammalian limb development and possibly in suppressing tumor formation.
Beta-catenin
LRP5
LRP6
WNT3A
Cite
Citations (718)
β-catenin-dependent Wnt signaling is initiated as Wnt binds to both the receptor FZD and coreceptor LRP5/6, which then assembles a multimeric complex at the cytoplasmic membrane face to recruit and inactivate the kinase GSK3. The large number and sequence diversity of Wnt isoforms suggest the possibility of domain-specific ligand-coreceptor interactions, and distinct binding sites on LRP6 for Wnt3a and Wnt9b have recently been identified in vitro. Whether mechanistically different interactions between Wnts and coreceptors might mediate signaling remains to be determined. It is also not clear whether coreceptor homodimerization induced extracellularly can activate Wnt signaling, as is the case for receptor tyrosine kinases. We generated monoclonal antibodies against LRP6 with the unexpected ability to inhibit signaling by some Wnt isoforms and potentiate signaling by other isoforms. In cell culture, two antibodies characterized further show reciprocal activities on most Wnts, with one antibody antagonizing and the other potentiating. We demonstrate that these antibodies bind to different regions of LRP6 protein, and inhibition of signaling results from blocking Wnt binding. Antibody-mediated dimerization of LRP6 can potentiate signaling only when a Wnt isoform is also able to bind the complex, presumably recruiting FZD. Endogenous autocrine Wnt signaling in different tumor cell lines can be either antagonized or enhanced by the LRP6 antibodies, indicating expression of different Wnt isoforms. As anticipated from the roles of Wnt signaling in cancer and bone development, antibody activities can also be observed in mice for inhibition of tumor growth and in organ culture for enhancement of bone mineral density. Collectively, our results indicate that separate binding sites for different subsets of Wnt isoforms determine the inhibition or potentiation of signaling conferred by LRP6 antibodies. This complexity of coreceptor-ligand interactions may allow for differential regulation of signaling by Wnt isoforms during development, and can be exploited with antibodies to differentially manipulate Wnt signaling in specific tissues or disease states.
LRP6
LRP5
Beta-catenin
WNT3A
Cite
Citations (201)
The Wnt/β-catenin signaling pathway is an evolutionarily conserved signaling cascade involved in a broad range of biological roles. Dysregulation of the Wnt/β-catenin pathway is implicated in congenital malformations and various kinds of cancers. We discovered a novel Wnt/β-catenin inhibitor, talaverrucin A (1), featuring an unprecedented 6/6/6/5/5/5/6 fused ring system, from an Antarctica sponge-derived fungus Talaromyces sp. HDN151403. Talaverrucin A exhibits inhibitory activity on the Wnt/β-catenin pathway in both zebrafish embryos in vivo and cultured mammalian cells in vitro, providing a naturally inspired small molecule therapeutic lead to target the Wnt/β-catenin pathway.
Sponge
Beta-catenin
WNT3A
Cite
Citations (17)
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
Dishevelled
LRP6
Beta-catenin
LRP5
WNT3A
Cite
Citations (0)
目的：探讨 Wnt/β-catenin 信号通路 Wnt-7a、Frlzzled、β-catenin 和 MMP-9基因在子宫内膜异位症患者在位内膜组织、异位内膜组织和正常子宫内膜组织的表达及其意义。方法采用免疫组织化学 SP 方法和Western blot 方法分别检测子宫内膜异位症患者在位内膜组织、异位内膜组织和正常子宫内膜组织中 Wnt-7a、Fr-lzzled、β-catenin 和 MMP-9基因蛋白质表达水平；用实时定量 RT-PCR 方法检测 Wnt-7a、Frlzzled、β-catenin 和MMP-9基因的 mRNA 表达水平。结果免疫组织化学实验显示，Wnt-7a 在3种内膜组织中均无表达，3种不同组织的内膜中 Frizzled、β-catenin 和 MMP-9蛋白质在异位组织表达明显高于正常内膜组织（P ＜0．01）；在异位内膜组织表达明显高于在位内膜组织（P ＜0．05）。Western blot 实验显示 Wnt-7a、Frizzled、β-catenin 和 MMP-9在子宫内膜异位组织蛋白质表达水平高于正常子宫内膜组织和在位子宫内膜组织。Wnt-7a、Frlzzled、β-catenin 和MMP-9基因 mRNA 表达水平异位内膜组织高于在位内膜组织和正常内膜组织，Wnt-7a、Frlzzled、β-catenin 基因mRNA 表达水平在位内膜组织高于正常内膜组织，MMP-9基因 mRNA 表达水平在位内膜组织低于正常内膜组织。结论Wnt/β-catenin 信号通路 Wnt-7a、Frlzzled、β-catenin 和 MMP-9基因可能共同参与了子宫内膜异位症的发生，并且β-catenin 可能通过对上游 Wnt-7a、Frizzled 和下游信号靶基因 MMP-9mRNA 的传导调控成为子宫内膜异位症疾病发展过程中的作用机制。
LRP6
LRP5
Beta-catenin
Cite
Citations (0)
Wnt/${\beta}$ -catenin 신호는 세포의 운명 결정, 증식, 분화 등을 조절하는 척추 동물 배아 발생과 성체의 항상성 유지에 필수적인 세포신호전달경로이다. 이러한 Wnt/${\beta}$ -catenin의 비정상적인 조절에 의해 선천적 기형, 암, 대사질환 등을 비롯한 다양한 질병이 유발된다. 이를 바탕으로 최근 Wnt/${\beta}$ -catenin 신호의 조절을 통한 암을 비롯한 질병의 치료를 위한 연구가 활발히 진행되고 있다. 따라서 Wnt/${\beta}$ -catenin 신호를 조절하는 인자의 발굴 및 자세한 작용 기전에 대한 연구가 절실히 필요하다. 본 총설에서는 최근 새롭게 알려진 Wnt/${\beta}$ -catenin 신호 조절 기작에 대해 설명하고, 현재까지 알려진 Wnt/${\beta}$ 조절하는 인산화 효소(kinase)의 종류와 작용 기전과 새로운 약물 타겟으로 전망을 알아 보고자 한다. The Wnt/${\beta}$ -catenin signaling pathway is an evolutionarily conserved signaling network that is critical for embryonic development and adult tissue maintenance. In addition, aberrant activation of Wnt/${\beta}$ -catenin signaling is implicated in the formation of various human diseases, including cancers. Thus, study of the underlying molecular mechanism of Wnt/${\beta}$ -catenin signaling regulation is important to understand and treat diseases. Inhibition of aberrant Wnt pathway activity in cancer cell lines efficiently blocks their growth, highlighting the great potential of therapeutics designed to achieve this in cancer patients. Recently, protein kinases have emerged as key regulating components of Wnt/${\beta}$ -catenin signaling. In this review, we provide the most recent information on Wnt/${\beta}$ -catenin signaling, describe protein kinases involved in Wnt/${\beta}$ -catenin signaling, and discuss their potential as drug targets.
Beta-catenin
LRP6
LRP5
Cite
Citations (5)
LRP5
LRP6
Beta-catenin
WNT4
WNT3A
Cite
Citations (138)
β catenin belongs to the armadillo family of proteins. It plays a crucial role in developmental and homeostatic processes. Wnts are a family of 19 secreted glycoproteins that transduce multiple signaling cascades, including the canonical Wnt/β catenin pathway, Wnt/Ca2+ pathway and the Wnt/polarity pathway. This is a review on β catenin, Wnt proteins and their secretion, the signaling pathway, the associated factors and the crucial role of β catenin in odontogenesis.
LRP6
LRP5
Beta-catenin
Cite
Citations (23)
Wnt/β-catenin signaling pathway is an important cellular signal transduction pathway and plays an important role in cell proliferation and differentiation. Current researchs indicate that Wnt/β-catenin signaling pathway is significant in bone metabolism and its abnormalities relate to the occurrence of osteoporosis. Wnt/β-catenin signaling pathway antagonists can inhibit the Wnt/β-catenin signaling pathway and cause the pathway abnormal expression. Further studys of the Wnt/β-catenin signaling pathway antagonists and designing the materials to block the pathway antagonists can provide a new kind of osteoporosis treatment approach.
LRP6
LRP5
HMGA2
Hes3 signaling axis
Cite
Citations (0)
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.
Dishevelled
LRP6
Beta-catenin
LRP5
Cite
Citations (454)