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Updated: Jul 11, 2026

Modeling Paracrine Noncanonical Wnt Signaling In Vitro
Published on: December 10, 2021
Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis
1Genetics and Cell Biology Section, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. mkatoh-kkr@umin.ac.jp
Abstract:
The biological functions of some orthologs within the human genome and model-animal genomes are evolutionarily conserved, but those of others are divergent due to protein evolution and promoter evolution. Because WNT signaling molecules play key roles during embryogenesis, tissue regeneration and carcinogenesis, the author's group has carried out a human WNT-ome project for the comprehensive characterization of human genes encoding WNT signaling molecules. From 1996 to 2002, we cloned and characterized WNT2B/WNT13, WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT9A/WNT14, WNT9B/WNT14B, WNT10A, WNT10B, WNT11, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD10, FRAT1, FRAT2, NKD1, NKD2, VANGL1, RHOU/ARHU, RHOV/ARHV, GIPC2, GIPC3, FBXW11/betaTRCP2, SOX17, TCF7L1/TCF3, and established a cDNA-PCR system for snap-shot and dynamic analyses on the WNT-transcriptome. In 2003, we identified and characterized PRICKLE1, PRICKLE2, DACT1/DAPPER1, DACT2/DAPPER2, DAAM2, and BCL9L. After completion of the human WNT-ome project, we have been working on the stem cell signaling network. WNT signals are transduced to beta-catenin, NLK, NFAT, PKC, JNK and RhoA signaling cascades. FGF20, JAG1 and DKK1 are target genes of the WNT-beta-catenin signaling cascade. Cross-talk of WNT and FGF signaling pathways potentiates beta-catenin and NFAT signaling cascades. BMP signals induce IHH upregulation in co-operation with RUNX. Hedgehog signals induce upregulation of SFRP1, JAG2 and FOXL1, and then FOXL1 induces BMP4 upregulation. The balance between WNT-FGF-Notch and BMP-Hedgehog signaling networks is important for the maintenance of homoestasis among stem and progenitor cells. Disruption of the stem cell signaling network results in pathological conditions, such as congenital diseases and cancer.
Insights
This study comprehensively characterized human WNT signaling genes and their roles in stem cell networks. Understanding these pathways is crucial for maintaining cell homeostasis and preventing diseases like cancer.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genomics
Background:
- Ortholog functions can be conserved or divergent between species due to evolutionary changes.
- WNT signaling is vital in embryogenesis, regeneration, and cancer.
- A comprehensive understanding of the human WNT-ome is essential.
Purpose of the Study:
- To conduct a comprehensive characterization of human genes involved in WNT signaling.
- To analyze the WNT-transcriptome using a cDNA-PCR system.
- To investigate the role of WNT signaling in stem cell networks and its relation to other pathways.
Main Methods:
- Cloning and characterization of WNT signaling pathway genes (1996-2003).
- Development of a cDNA-PCR system for WNT-transcriptome analysis.
- Identification and characterization of additional WNT pathway components (PRICKLE1, PRICKLE2, etc.).
Main Results:
- Successfully cloned and characterized numerous human WNT pathway genes, including WNTs, Frizzleds, and other associated proteins.
- Established a dynamic analysis system for the WNT-transcriptome.
- Identified key signaling cascades (beta-catenin, NLK, NFAT, PKC, JNK, RhoA) downstream of WNT.
- Revealed cross-talk between WNT, FGF, BMP, and Hedgehog signaling pathways crucial for stem cell homeostasis.
Conclusions:
- The human WNT-ome project provided a foundational characterization of WNT signaling components.
- The balance of WNT, FGF, Notch, BMP, and Hedgehog signaling networks is critical for maintaining stem and progenitor cell homeostasis.
- Disruptions in these stem cell signaling networks can lead to congenital diseases and cancer.
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