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WNT Signaling Pathway and Stem Cell Signaling Network

Authors' Affiliations: ¹ M&M Medical BioInformatics, Hongo, Japan and ² Genetics and Cell Biology Section, National Cancer Center Research Institute, Tokyo, Japan

Requests for reprints: Masaru Katoh, Genetics and Cell Biology Section, National Cancer Center Research Institute, 5-1-1 Tsukiji, Tokyo 104-0045, Japan. Phone: 81-3-3542-2511; Fax: 81-3-3541-2685; E-mail: mkatoh-kkr{at}umin.ac.jp.

Abstract

WNT signals are transduced to the canonical pathway for cell fate determination, and to the noncanonical pathway for control of cell movement and tissue polarity. Canonical WNT signals are transduced through Frizzled family receptors and LRP5/LRP6 coreceptor to the ß-catenin signaling cascade. Microtubule affinity–regulating kinase (PAR-1) family kinases, casein kinase I (CKI), and FRAT are positive regulators of the canonical WNT pathway, whereas APC, AXIN1, AXIN2, CKI, NKD1, NKD2, ßTRCP1, ßTRCP2, ANKRD6, Nemo-like kinase (NLK), and peroxisome proliferator–activated receptor (PPAR) are negative regulators. Nuclear complex, consisting of T-cell factor/lymphoid enhancer factor, ß-catenin, BCL9/BCL9L, and PYGO, activates transcription of canonical WNT target genes such as FGF20, DKK1, WISP1, MYC, CCND1, and Glucagon (GCG). Noncanonical WNT signals are transduced through Frizzled family receptors and ROR2/RYK coreceptors to the Dishevelled-dependent (Rho family GTPases and c-jun NH₂-terminal kinase) or the Ca²⁺-dependent (NLK and nuclear factor of activated T cells) signaling cascades. WNT signals are context-dependently transduced to both pathways based on the expression profile of WNT, SFRP, WIF, DKK, Frizzled receptors, coreceptors, and the activity of intracellular WNT signaling regulators. Epigenetic silencing and loss-of-function mutation of negative regulators of the canonical WNT pathway occur in a variety of human cancer. WNT, fibroblast growth factor (FGF), Notch, Hedgehog, and transforming growth factor ß/bone morphogenetic protein signaling network are implicated in the maintenance of tissue homeostasis by regulating self-renewal of normal stem cells as well as proliferation or differentiation of progenitor (transit-amplifying) cells. Breakage of the stem cell signaling network leads to carcinogenesis. Nonsteroidal anti-inflammatory drugs and PPAR agonists with the potential to inhibit the canonical WNT signaling pathway are candidate agents for chemoprevention. ZTM000990 and PKF118-310 are lead compounds targeted to the canonical WNT signaling cascade. Anti-WNT1 and anti-WNT2 monoclonal antibodies show in vitro effects in cancer treatment. After the optimization, derivatives of small-molecule compound and human monoclonal antibody targeted to the WNT signaling pathway could be used in cancer medicine.

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