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Networking of WNT, FGF, Notch, BMP, and Hedgehog Signaling Pathways during Carcinogenesis

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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/βTRCP2, 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 β-catenin, NLK, NFAT, PKC, JNK and RhoA signaling cascades. FGF20, JAG1 and DKK1 are target genes of the WNT-β-catenin signaling cascade. Cross-talk of WNT and FGF signaling pathways potentiates β-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.

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Acknowledgements

The author thanks to Drs. Norihiko Sagara, Jun Koike, Hiroyuki Kirikoshi and Tetsuroh Saitoh for their hard work in the Genetics and Cell Biology Section, to Ms. Yuriko Katoh and Masuko Kotoh for their bioinformatics works, to Drs. Momoki Hirai, Koichiro Shiokawa, Herbert Steinbeisser, Serge Fuchs, Scott Heller, and Jesús Chimal-Monroy for their collaboration on WNT signaling molecules, and to Dr. Takashi Sugimura for his warm encouragement. This study was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by a Grant-in-Aid for Cancer Research from the Foundation for Promotion of Cancer Research.

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  1. Genetics and Cell Biology Section, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Masaru Katoh

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Katoh, M. Networking of WNT, FGF, Notch, BMP, and Hedgehog Signaling Pathways during Carcinogenesis. Stem Cell Rev 3, 30–38 (2007). https://doi.org/10.1007/s12015-007-0006-6

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