FZD10-Gα13 signalling axis points to a role of FZD10 in CNS angiogenesis

Hot, Belma; Valnohová, Jana; Arthofer, Elisa; Simon, Katharina; Shin, Jaekyung; Uhlén, Mathias; Kostenis, Evi; Mulder, Jan; Schulte, Gunnar

doi:10.1016/j.cellsig.2017.01.023

Cited by 28 publications

(16 citation statements)

References 252 publications

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“…More work needs to be done to structurally define the distinct receptor conformations and structural features in Class F receptors that define coupling selectivity to different transducer proteins, such as heterotrimeric G proteins and DVL. However, these findings merge well with previous data showing that overexpression of DVL negatively impacts FZD-G protein interaction and signaling 14,16 . Based on different signaling profiles of purified WNTs in FZD-expressing mouse microglia-like N13 cells or FZD-free 32D cells stably expressing individual FZD isoforms, we had proposed that WNTs could act as biased ligands of FZDs distinguishing G protein over DVL signaling, even though this interpretation still needs to be pharmacologically and quantitatively validated 67,68 .…”

Section: Discussionsupporting

confidence: 91%

A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection

et al. 2019

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Class F receptors are considered valuable therapeutic targets due to their role in human disease, but structural changes accompanying receptor activation remain unexplored. Employing population and cancer genomics data, structural analyses, molecular dynamics simulations, resonance energy transfer-based approaches and mutagenesis, we identify a conserved basic amino acid in TM6 in Class F receptors that acts as a molecular switch to mediate receptor activation. Across all tested Class F receptors (FZD4,5,6,7, SMO), mutation of the molecular switch confers an increased potency of agonists by stabilizing an active conformation as assessed by engineered mini G proteins as conformational sensors. Disruption of the switch abrogates the functional interaction between FZDs and the phosphoprotein Dishevelled, supporting conformational selection as a prerequisite for functional selectivity. Our studies reveal the molecular basis of a common activation mechanism conserved in all Class F receptors, which facilitates assay development and future discovery of Class F receptor-targeting drugs.

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Section: Discussionsupporting

confidence: 91%

A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection

et al. 2019

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“…The most important arguments against the GPCR nature of Class F receptors were the lack of conserved motifs that are crucial for GPCR‐G protein activation in Class A, such as the DR(E)Y or the NPxxY motifs (despite the fact that bona fide GPCRs from Class B and C also lack these particular motifs), and the conflicting data about the role of heterotrimeric G proteins in the most studied WNT‐induced signalling avenue, the WNT/β‐catenin pathway (for a recent review, see ). Data from our laboratory support the idea that (a) FZDs functionally interact with heterotrimeric G proteins, (b) WNTs dissociate inactive‐state FZD‐G protein complexes, (c) WNTs act through FZDs to activate heterotrimeric G proteins and to initiate downstream signalling in a FZD‐dependent manner, and (d) WNT interaction with FZDs leads to conformational rearrangements in FZDs reminiscent of those observed in agonist‐stimulated classical GPCRs . These findings have been corroborated by work from others for select isoforms of FZDs and SMO .…”

Section: Introductionsupporting

confidence: 82%

Structural insight into Class F receptors – What have we learnt regarding agonist‐induced activation?

Schulte

Kozielewicz

2019

Basic Clin Pharma Tox

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Class F receptors, including the ten Frizzleds (FZD 1-10 ) and SMO, mediate the effects of WNTs and hedgehog proteins and belong to the superfamily of G proteincoupled receptors (GPCRs). While the recent, high-resolution insight into mechanisms of GPCR activation provides a better understanding of receptor activation in Class A, B and C GPCRs, it remains unclear how Class F receptors bind their ligands, how ligand binding is translated to receptor activation and how signal initiation and specification are achieved. Here, we summarize recent efforts in elucidating Class F receptor structure and activation mechanisms and critically discuss the progress made in this area. A better understanding of the activation mechanisms of Class F receptors is required to engage in mechanism-based and structure-guided drug discovery to exploit the large therapeutic potential of targeting these receptors pharmacologically.

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“…ROR1 is involved in HER3-Y1307 trans -phosphorylation and subsequent NSUN6-dependent MST1-K59 methylation, which induces YAP/TAZ-dependent transcriptional activation through LATS1/LATS2 inhibition ( 78 ). WNT/PCP signaling can also induce Rho-mediated LATS1/LATS2 inhibition for transcriptional activation of YAP/TAZ-target genes ( 91 , 92 ), whereas non-canonical WNT signaling through FZD10 induces YAP/TAZ activation through Gα13 ( 93 ). Non-canonical WNT signaling promotes survival and therapeutic resistance of CSCs through PI3K-AKT signaling activation and YAP/TAZ-mediated transcriptional activation.…”

Section: Non-canonical Wnt Signaling In Cscs and Their Nichesmentioning

confidence: 99%

Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

Katoh

2017

International Journal of Oncology

369

338

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Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological and metabolic reprogramming to adapt to the tumor microenvironment and survive host defense or therapeutic insults. Intra-tumor heterogeneity and cancer-cell plasticity give rise to therapeutic resistance and recurrence through clonal replacement and reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with the FGF, Notch, Hedgehog and TGFβ/BMP signaling cascades and regulate expression of functional CSC markers, such as CD44, CD133 (PROM1), EPCAM and LGR5 (GPR49). Aberrant canonical and non-canonical WNT signaling in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate and uterine cancers, leukemia and melanoma, are involved in CSC survival, bulk-tumor expansion and invasion/metastasis. WNT signaling-targeted therapeutics, such as anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 mAb (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 and WNT974), tankyrase inhibitors (AZ1366, G007-LK, NVP-TNKS656 and XAV939) and β-catenin inhibitors (BC2059, CWP232228, ICG-001 and PRI-724), are in clinical trials or preclinical studies for the treatment of patients with WNT-driven cancers. WNT signaling-targeted therapeutics are applicable for combination therapy with BCR-ABL, EGFR, FLT3, KIT or RET inhibitors to treat a subset of tyrosine kinase-driven cancers because WNT and tyrosine kinase signaling cascades converge to β-catenin for the maintenance and expansion of CSCs. WNT signaling-targeted therapeutics might also be applicable for combination therapy with immune checkpoint blockers, such as atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab, to treat cancers with immune evasion, although the context-dependent effects of WNT signaling on immunity should be carefully assessed. Omics monitoring, such as genome sequencing and transcriptome tests, immunohistochemical analyses on PD-L1 (CD274), PD-1 (PDCD1), ROR1 and nuclear β-catenin and organoid-based drug screening, is necessary to determine the appropriate WNT signaling-targeted therapeutics for cancer patients.

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FZD10-Gα13 signalling axis points to a role of FZD10 in CNS angiogenesis

Cited by 28 publications

References 252 publications

A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection

A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection

Structural insight into Class F receptors – What have we learnt regarding agonist‐induced activation?

Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

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