A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signaling

Kim, Minseong; Reinhard, Carmen; Niehrs, Christof

doi:10.7554/elife.70885

Cited by 7 publications

(7 citation statements)

References 73 publications

(102 reference statements)

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“…WNT signaling pathway components are expressed in the dental epithelium and mesenchyme regulating developing tooth formation and adult tooth homeostasis [Tamura et al, 2016]. Researches show that HGF and WNT are two responsive signaling cascades regulating epithelial differentiation and survival after injury, and HGF may function through stimulating LRP5/6 phosphorylation and activating canonical WNT signaling [Koraishy et al, 2014] or via reducing ZNRF3-dependent WNT receptor degradation [Kim et al, 2021]. Three WNT signaling antagonist SFRP2, WIF1, and WISP2 were downregulated, one agonist RSPO3 upregulated, and translocation of β-catenin into nucleus increased, which all supported HGF triggered WNT signaling activation.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte Growth Factor Promotes Differentiation Potential and Stress Response of Human Stem Cells from Apical Papilla

Liu¹,

Yan²,

Chen³

et al. 2022

Cells Tissues Organs

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Harsh local microenvironment, such as hypoxia and lack of instructive clues for transplanted stem cells, presents the serious obstacle for stem cell therapies’ efficacy. Therefore, continued efforts have been taken to improve stem cells’ viability and plasticity. Hepatocyte growth factor (HGF) have previously been reported to mitigate complications of various human diseases in animal model studies and in some clinical trials. Besides, human stem cells from root apical papilla (SCAP) are deemed a better resource of mesenchymal stem cells due to derived stem cells holding greater amplification ability in vitro compared with those from other dental resources. To move forward, evaluating effects and understanding underlying molecular mechanisms of HGF on SCAP for periodontal regeneration are needed. In this study, HGF was transgenic expressed in SCAP, and it was found that HGF enhanced osteo/dentinogenic differentiation capacity of SCAP compared with those non-treated control in an ectopic mineralization model. Moreover, HGF reduced apoptosis of SCAP under both normoxia and hypoxia condition, whereas combination of HGF and hypoxia exposure had inhibitory effects on cell proliferation during an eight-day in vitro culture period. Transcriptome analysis further revealed that suppressed cell cycle progression and activated BMP/ TGFβ, Hedgehog, WNT, FGF, HOX and other morphogen family members upon HGF overexpression, which may render SCAP recapitulate part of neural crest stem cells characteristics. Moreover, strengthened stress-response modulation such as unfolded protein response, macroautophagy and anti-apoptotic molecules might explain increased viability of SCAP. In all, our results imply that these potential mechanisms underlying HGF promoting SCAP differentiation could be further elucidated and harnessed to improve dental tissue regeneration.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte Growth Factor Promotes Differentiation Potential and Stress Response of Human Stem Cells from Apical Papilla

Liu¹,

Yan²,

Chen³

et al. 2022

Cells Tissues Organs

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“…A 10-amino acid glycine-serine linker (GSGSGGSGSG) was inserted between RSPO2 FU2 domain and PD1 HAC . Human ZNRF3-HA, ZNRF3 ΔRING -myc and RNF43-Flag constructs were described previously (Chang et al, 2020; Kim et al, 2021). Human PD-L1-GFP (pEGFP-N1/PD-L1) was a gift from Mien-Chie Hung (Addgene plasmid # 121478; http://n2t.net/addgene:121478; RRID: Addgene_121478) (Li et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation

Sun

Lee

Niehrs

2022

Preprint

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Proteolysis-targeting chimeras (PROTACs) are an emerging technology for therapeutic intervention but options to target cell surface proteins and receptors remain limited. Here we introduce ROTACs, bispecific WNT- and BMP signaling-disabled R-spondin (RSPO) chimeras, which leverage the specificity of these stem cell growth factors for ZNRF3/RNF43 E3 transmembrane ligases, to target degradation of transmembrane proteins. As proof of concept, we targeted the immune checkpoint protein programmed death ligand 1 (PD-L1), a prominent cancer therapeutic target, with a bispecific RSPO2 chimera, R2PD1. The R2PD1 chimeric protein bound PD-L1 and at picomolar concentration induced its lysosomal degradation. In three melanoma cell lines, R2PD1 induced between 50-90% PD-L1 protein degradation. PD-L1 degradation was strictly dependent on ZNRF3/RNF43. We conclude that signaling-disabled ROTACs represent a novel strategy to target cell surface proteins for degradation.

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“…Wnt signal participates in the development of embryos, the homeostasis of adult tissues and the regeneration after organ damage 2 . Thereby, ZNRF3 also received great attention for its vital role in the regulation of Wnt signal whose dysregulation frequently occurs in various tumors 3–6 . Recently, aberrant expression of ZNRF3 was found to be closely associated with the occurrence and progression of human tumors 7–9 .…”

Section: Introductionmentioning

confidence: 99%

“…2 Thereby, ZNRF3 also received great attention for its vital role in the regulation of Wnt signal whose dysregulation frequently occurs in various tumors. [3][4][5][6] Recently, aberrant expression of ZNRF3 was found to be closely associated with the occurrence and progression of human tumors. [7][8][9] However, a comprehensive pan-cancer analysis of ZNRF3 has not been available.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of zinc and ring finger 3 in prognostic value and pan‐cancer immunity

Liu,

Zhao,

Peng

et al. 2024

The FASEB Journal

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Zinc and ring finger 3 (ZNRF3) is a negative suppressor of Wnt signal and newly identified as an important regulator in tumorigenesis and development. However, the pan‐cancer analysis of ZNRF3 has not been reported. We found that ZNRF3 was significantly decreased in six tumors including CESC, KIRP, KIRC, SKCM, OV, and ACC, but increased in twelve tumors, namely LGG, ESCA, STES, COAD, STAD, LUSC, LIHC, THCA, READ, PAAD, TGCT, and LAML. Clinical outcomes of cancer patients were closely related to ZNRF3 expression in ESCA, GBM, KIRC, LUAD, STAD, UCEC, LGG, and SARC. The highest genetic alteration frequency of ZNRF3 occurred in ACC. Abnormal expression of ZNRF3 could be attributed to the differences of copy number variation (CNV) and DNA methylation as well as ZNRF3‐interacting proteins. Besides, ZNRF3 were strongly associated with tumor heterogeneity, tumor stemness, immune score, stromal score and ESTIMATE score in certain cancers. In terms of immune cell infiltration, ZNRF3 was positively correlated to infiltration of cancer‐associated fibroblasts in CESC, HNSC, OV, PAAD, PRAD, and THYM, but negatively associated with infiltration of CD8 T cells in HNSC, KIRC, KIRP and THYM. Moreover, ZNRF3 expression was correlated with most immune checkpoint genes in SARC, LUSC, LUAD, PRAD, THCA, UVM, TGCT, and OV, and associated with overwhelming majority of immunoregulatory genes in almost all cancers. Most RNA modification genes were also remarkably related to ZNRF3 level in KIRP, LUAD, LUSC, THYM, UVM, PRAD, and UCEC, indicating that ZNRF3 might have an important effect on cancer epigenetic regulation. Finally, we verified the expression and role of ZNRF3 in clinical specimens and cell lines of renal cancer and liver cancer. This study provides a comprehensive pan‐cancer analysis of ZNRF3 and reveals the complexity of its carcinogenic effect.

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A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signaling

Cited by 7 publications

References 73 publications

Hepatocyte Growth Factor Promotes Differentiation Potential and Stress Response of Human Stem Cells from Apical Papilla

Hepatocyte Growth Factor Promotes Differentiation Potential and Stress Response of Human Stem Cells from Apical Papilla

ROTACs leverage signaling-incompetent R-spondin for targeted protein degradation

Comprehensive analysis of zinc and ring finger 3 in prognostic value and pan‐cancer immunity

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