Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases

Wnt signaling regulates many aspects of vertebrate development and adult stem cells. Deregulation of Wnt signaling causes development defect and cancer. The signaling is categorized in two pathways: canonical and noncanonical. Both pathways are initiated by Wnt ligands and Frizzled receptors. Canonical pathway leads to β-catenin:T-cell factor/lymphoid enhancer factor-mediated gene expression, which regulates proliferation and differentiation of cells. Noncanonical Wnt signaling is mediated by intracellular calcium ion and JNK. This signaling leads to NFAT, a key transcriptional factor regulating gene expression. In addition, β-catenin:T-cell factor/lymphoid enhancer factor-mediated gene expression is downregulated by CaMKII-TAK1-NLK. Cellular polarity and motility are the main outcomes of the signaling. During development, noncanonical Wnt signaling is required for tissue formation. Recent studies have shown that atypical cadherin Flamingo contributes to noncanonical Wnt signaling by directing the migration of cells. Also, noncanonical Wnt signaling is required for maintenance of adult stem cells. In the field of cancer research, noncanonical Wnt signaling has been considered a tumor suppressor; however, recent evidence has shown that the signaling also enhances cancer progression in the later stages of disease. In this review, we describe and discuss components of noncanonical Wnt signaling, diseases caused by deregulation of the signaling, regulation of adult stem cells by the signaling, and implications in cancer biology.