Frizzled Receptors as Potential Therapeutic Targets in Human Cancers

Zeng, Chui-Mian; Chen, Zhe; Fu, Li

doi:10.3390/ijms19051543

Cited by 86 publications

(81 citation statements)

References 108 publications

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“…With the exception of FZD5, other FZDs, including FZD3, FZD4, FZD8, and especially FZD9, can also significantly promote LRP5/␤-catenin signaling in a ligand-independent manner. Because ectopic expression of FZDs in tumor cells is a common phenomenon (34,35), these findings may provide an alternative mechanism to comprehensively understand the molecular basis underlying tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…6H), implying that the endogenous canonical WNT glycoproteins were not involved in suppressing GSK3␤-AXIN-APC complexes. Therefore, we concluded that ectopic expression of Frizzled receptors (34,35), such as FZD3/4/5/9, which cause ligand-independent LRP5/6 signalosome activation, might be the putative pathological factor for the constitutive activation of WNT/␤-catenin signaling in HepG2 cells.…”

Section: Ligand-independent Fzd-lrp5/6 Signaling May Be Involved In Tmentioning

confidence: 92%

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Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/β-catenin pathway

Yue

Yang

et al. 2018

Journal of Biological Chemistry

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Edited by Xiao-Fan WangUpon binding to the canonical WNT glycoproteins, Frizzled family receptors (FZDs) and low-density lipoprotein receptorrelated protein 5/6 (LRP5/6) undergo a series of polymerizations on the cell surface that elicit canonical WNT/␤-catenin signaling. The hyperactivation of WNT/␤-catenin signaling is the major cause of tumorigenesis, but the mechanism in tumors such as hepatoma remains unclear. Here, we observed that WNT3A manifested the hyperactivity in ␤-catenindependent signaling after binding to FZD's competitive inhibitory molecule secreted Frizzled-related protein 2 (SFRP2). To understand the mechanism of FZDs in the presence of SFRP2, we explored how FZDs can bind and activate the LRP5/6 signalosome independently of WNT glycoproteins. Our findings further revealed that oligomerizations of FZDs and LRP5/6 can integrate the cytoplasmic protein Dishevelled into the LRP5/6 signalosome, resulting in a robust activation of ligand-independent ␤-catenin signaling. We propose that besides WNT-bridged FZD-WNT-LRP5/6 protein complexes, the homo-and hetero-oligomerizations of WNT receptors may contribute to the formation of the LRP5/6 signalosome on the cell surface. Of note, we identified four highly expressed FZDs in the hepatoma cell line HepG2, all of which significantly promoted ligand-independent LRP5/␤catenin signaling. As FZDs are ectopically expressed in numerous tumors, our findings may provide a new perspective on tumor pathologies. Furthermore, the results in our study suggest that the composition and stoichiometry of FZDs and LRP5/6 within the LRP5/6 signalosome may tune the selection of bound WNT glycoproteins and configure downstream WNT/ ␤-catenin signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Ligand-independent Fzd-lrp5/6 Signaling May Be Involved In Tmentioning

confidence: 92%

Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/β-catenin pathway

Yue

Yang

et al. 2018

Journal of Biological Chemistry

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“…The functions of WNT ligands, which bind to the frizzled family of seven transmembrane receptors ( Zeng et al, 2018 ), are modulated by FGF10 signaling during stomach ( Nyeng et al, 2007 ) and lung ( Volckaert and De Langhe, 2015 ) development. FGF10 also regulates Bone Morphogenetic Protein 4 (BMP4) during lung branching ( Weaver et al, 2000 ).…”

Section: Fgf10-dependent Regulators Of Intracellular Signalingmentioning

confidence: 99%

Regulation of FGF10 Signaling in Development and Disease

Watson

Francavilla

2018

Front. Genet.

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Fibroblast Growth Factor 10 (FGF10) is a multifunctional mesenchymal-epithelial signaling growth factor, which is essential for multi-organ development and tissue homeostasis in adults. Furthermore, FGF10 deregulation has been associated with human genetic disorders and certain forms of cancer. Upon binding to FGF receptors with heparan sulfate as co-factor, FGF10 activates several intracellular signaling cascades, resulting in cell proliferation, differentiation, and invasion. FGF10 activity is modulated not only by heparan sulfate proteoglycans in the extracellular matrix, but also by hormones and other soluble factors. Despite more than 20 years of research on FGF10 functions, context-dependent regulation of FGF10 signaling specificity remains poorly understood. Emerging modes of FGF10 signaling regulation will be described, focusing on the role of FGF10 trafficking and sub-cellular localization, heparan sulfate proteoglycans, and miRNAs. Systems biology approaches based on quantitative proteomics will be considered for globally investigating FGF10 signaling specificity. Finally, current gaps in our understanding of FGF10 functions, such as the relative contribution of receptor isoforms to signaling activation, will be discussed in the context of genetic disorders and tumorigenesis.

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“…Genetic or pharmacological inhibition of elements of the Wnt/Fzd pathway (Fzd4, LRP-5, Dishevelled, and β-catenin) impairs retinal NV and vascular permeability. [24][25][26] Recent studies have demonstrated that the anti-Fzd7 antibody [27][28][29][30] antagonized Wnt/β-catenin signaling in Fzd7-expressing cancer cells, and suppressed tumor progression and metastasis. 21,22 Dysregulation of Wnt signaling is also associated with ocular diseases with an emphasis on DR. 23 Previously, we have demonstrated that Frizzled-7 (Fzd7) signaling controls post natal vessel formation in the retina, 20 however its role in pathological angiogenesis is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model

et al. 2019

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Retinopathies remain major causes of visual impairment in diabetic patients and premature infants. Introduction of anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) has transformed therapy for these proliferative retinopathies.However, limitations associated with anti-VEGF medications require to unravel new pathways of vessel growth to identify potential drug targets. Here, we investigated the role of Wnt/Frizzled-7 (Fzd7) pathway in a mouse model of oxygen-induced retinopathy (OIR). Using transgenic mice, which enabled endothelium-specific and time-specific Fzd7 deletion, we demonstrated that Fzd7 controls both vaso-obliteration and neovascular phases (NV). Deletion of Fzd7 at P12, after the ischemic phase of OIR, prevented formation of aberrant neovessels into the vitreous by suppressing proliferation of endothelial cells (EC) in tufts. Next we validated in vitro two Frd7 blocking strategies: a monoclonal antibody (mAbFzd7) against Fzd7 and a soluble Fzd7 receptor (CRD). In vivo a single intravitreal microinjection of mAb-Fzd7 or CRD significantly attenuated retinal neovascularization (NV) in mice with OIR. Molecular analysis revealed that Fzd7 may act through the activation of Wnt/βcatenin and Jagged1 expression to control EC proliferation in extra-retinal neovessels. We identified Fzd7/β-catenin signaling as new regulator of pathological retinal NV. Fzd7 appears to be a potent pharmacological target to prevent or treat aberrant angiogenesis of ischemic retinopathies. K E Y W O R D S

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Frizzled Receptors as Potential Therapeutic Targets in Human Cancers

Cited by 86 publications

References 108 publications

Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/β-catenin pathway

Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/β-catenin pathway

Regulation of FGF10 Signaling in Development and Disease

Therapies targeting Frizzled‐7/β‐catenin pathway prevent the development of pathological angiogenesis in an ischemic retinopathy model

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