Wnt ligand–dependent activation of the negative feedback regulator Nkd1

Larraguibel, Jahdiel Isaac; Weiss, Alexander Ross; Pasula, Daniel; Dhaliwal, Rasmeet Singh; Kondra, Roman; Raay, Terence J. Van

doi:10.1091/mbc.e14-12-1648

Cited by 34 publications

(31 citation statements)

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“…NKD1 is an antagonist of the canonical Wnt/β-catenin pathway (8). Dysregulation of Wnt signaling is at the root of multiple diseases, including cancer (17). Guo et al (12) demonstrated that specific NKD1 mutations may promote Wnt-dependent tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of NKD1 in human osteosarcoma and its clinical significance

Chen

Jun

et al. 2017

Mol Med Report

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Naked cuticle homolog 1 (NKD1), a negative modulator of the canonical Wnt/β‑catenin pathway, is expressed in multiple normal tissues. However, there is little information regarding NKD1 expression in osteosarcoma. The aim of the present study was to explore the expression and clinicopathological significance of NKD1 in human osteosarcoma. In the present study, NKD1 protein and mRNA expression levels were detected by western blotting and reverse transcription‑quantitative polymerase chain reaction, respectively. The results revealed that NKD1 expression levels were significantly lower in osteosarcoma tissues compared with normal bone tissue, and were significantly lower in patients with lung metastasis compared with patients without lung metastasis. In addition, with increasing Enneking stage, the NKD1 expression levels decreased. These data indicated that reduction of NKD1 may be associated with carcinogenesis, lung metastasis and Enneking stage in osteosarcoma. This interpretation is consistent with the results obtained from experiments on MG63 osteosarcoma cells in vitro. In order to explore the function of NKD1 in osteosarcoma, the expression of NKD1 in the human osteosarcoma MG‑63 cell line was upregulated by transfection with an adenovirus containing an NKD1 vector. The results revealed that upregulation of NKD1 expression reduced the proliferation and migration of osteosarcoma cells by inhibiting expression of β‑catenin, cyclin D1 and MMP‑9 protein. These data suggested that the downregulation of NKD1 may be involved in the proliferation and migration of osteosarcoma cells through the activation of the canonical Wnt signaling pathway, and it may be a potential prognostic marker and therapeutic target for patients with osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

Downregulation of NKD1 in human osteosarcoma and its clinical significance

Chen

Jun

et al. 2017

Mol Med Report

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“…Accumulating evidence indicates that NKD1 antagonizes Wnt signaling by preventing the nuclear accumulation of β-catenin 7 8 . However, activation of the Wnt/β-catenin signaling pathway results in the up-regulation of downstream genes such as NKD1 9 .…”

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confidence: 99%

The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells

Zhang

et al. 2016

Sci Rep

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Hepatocellular carcinoma (HCC) is complicated by aggressive migration and invasion, which contribute to the increased mortality of HCC patients. The NKD1 protein is abnormally expressed in many neoplasms and plays an important role in tumor progression. However, the regulation and underlying molecular mechanisms of NKD1 in HCC cell invasion and migration remain poorly understood. In the present study, ectopic expression of NKD1 in HCC cells attenuated migration and invasion in vitro and in vivo by down-regulating Rac1 expression level and activity, which affected the HCC cell cytoskeleton and E-cadherin expression. Mechanistic studies showed that NKD1 interacted with Rac1 in the cytoplasm and promoted its degradation by the ubiquitin-proteasome pathway. Over-expression of Rac1 enhanced the transcription of the NKD1 gene and protein expression conversely owing to its negative regulation of EZH2. Analysis of clinical samples showed that abnormal expression of NKD1 and Rac1 was associated with the poor prognosis of HCC patients. In summary, our data indicate a new role for NKD1 as a regulator of HCC cell invasion and migration via a feedback loop involving Rac1.

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“…Mutations in RNF43 could be subdued after ETC-1922159 has suppressed the Wnt pathway as has been shown in [25]. NKD1 is enigmatic in nature and known to be a negative regulator of the Wnt pathway [102]. Mutations in NKD1 have been found to be prevalent in colorectal cancer cases [103].…”

Section: Resultsmentioning

confidence: 84%

Sensitivity analysis based ranking reveals unknown biological hypotheses for down regulated genes in time buffer during administration of PORCN-WNT inhibitor ETC-1922159 in CRC^†

Sinha¹

2017

Preprint

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In a recent development of the PORCN-WNT inhibitor ETC-1922159 for colorectal cancer, a list of down-regulated genes were recorded in a time buffer after the administration of the drug. The regulation of the genes were recorded individually but it is still not known which higher (≥ 2) order interactions might be playing a greater role after the administration of the drug. In order to reveal the priority of these higher order interactions among the down-regulated genes or the likely unknown biological hypotheses, a search engine was developed based on the sensitivity indices of the higher order interactions that were ranked using a support vector ranking algorithm and sorted. For example, LGR family (Wnt signal enhancer) is known to neutralize RNF43 (Wnt inhibitor). After the administration of ETC-1922159 it was found that using HSIC (and rbf, linear and laplace variants of kernel) the rankings of the interaction between LGR5-RNF43 were 61, 114 and 85 respectively. Rankings for LGR6-RNF43 were 1652, 939 and 805 respectively. The down-regulation of LGR family after the drug treatment is evident in these rankings as it takes bottom priorities for LGR5-RNF43 interaction. The LGR6-RNF43 takes higher ranking than LGR5-RNF43, indicating that it might not be playing a greater role as LGR5 during the Wnt enhancing signals. These rankings confirm the efficacy of the proposed search engine design. Prioritized unknown biological hypothesis form the basis of further wet lab tests with the aim to reduce the cost of (1) wet lab experiments (2) combinatorial search and (3) lower the testing time for biologist who search for influential interactions in a vast combinatorial search forest. From in silico perspective, a framework for a search engine now exists which can generate rankings for n th order interactions in Wnt signaling pathway, thus revealing unknown/untested/unexplored biological hypotheses and aiding in understanding the mechanism of the pathway. The generic nature of the design can be applied to any signaling pathway or phenomena under investigation where a prioritized order of interactions among the involved factors need to be investigated for deeper understanding. Future improvements of the design are bound to facilitate medical specialists/oncologists in their respective investigations. SignificanceRecent development of PORCN-WNT inhibitor enantiomer ETC-1922159 cancer drug show promise in suppressing some types * Corresponding Author : shriprakash sinha; E-mail : sinha.shriprakash@yandex.com Author worked on this project as an independent researcher. Aspects of unpublished work were presented in a poster session at the recently concluded first ever Wnt Gordon Conference, from 6-11 August 2017, held in Stowe, VT 05672, USA. of colorectal cancer. However, the search and wet lab testing of unknown/unexplored/untested biological hypotheses in the form of combinations of various intra/ extracellular factors/genes/proteins affected by ETC-1922159 is not known. Currently, a major problem in biology is to cherry p...

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Wnt ligand–dependent activation of the negative feedback regulator Nkd1

Abstract: Nkd1, a negative feedback regulator of the Wnt pathway, localizes with Dvl2 to the putative Wnt signalosome, where it becomes activated by Wnt. Activated Nkd1 moves away from the membrane to become more cytosolic, where it interacts with β-catenin to prevent nuclear accumulation.

Cited by 34 publications

References 50 publications

Downregulation of NKD1 in human osteosarcoma and its clinical significance

Downregulation of NKD1 in human osteosarcoma and its clinical significance

The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells

Sensitivity analysis based ranking reveals unknown biological hypotheses for down regulated genes in time buffer during administration of PORCN-WNT inhibitor ETC-1922159 in CRC^†

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Wnt ligand–dependent activation of the negative feedback regulator Nkd1

Abstract: Nkd1, a negative feedback regulator of the Wnt pathway, localizes with Dvl2 to the putative Wnt signalosome, where it becomes activated by Wnt. Activated Nkd1 moves away from the membrane to become more cytosolic, where it interacts with β-catenin to prevent nuclear accumulation.

Cited by 34 publications

References 50 publications

Downregulation of NKD1 in human osteosarcoma and its clinical significance

Downregulation of NKD1 in human osteosarcoma and its clinical significance

The NKD1/Rac1 feedback loop regulates the invasion and migration ability of hepatocarcinoma cells

Sensitivity analysis based ranking reveals unknown biological hypotheses for down regulated genes in time buffer during administration of PORCN-WNT inhibitor ETC-1922159 in CRC†

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Product

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Sensitivity analysis based ranking reveals unknown biological hypotheses for down regulated genes in time buffer during administration of PORCN-WNT inhibitor ETC-1922159 in CRC^†