Article

Supplemental Data Wnt/β-Catenin Signaling: Components, Mechanisms, and Diseases

F. M. Kirby Neurobiology Center, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Developmental Cell (Impact Factor: 9.71). 08/2009; 17(1):9-26. DOI: 10.1016/j.devcel.2009.06.016
Source: PubMed

ABSTRACT

Signaling by the Wnt family of secreted glycolipoproteins via the transcriptional coactivator beta-catenin controls embryonic development and adult homeostasis. Here we review recent progress in this so-called canonical Wnt signaling pathway. We discuss Wnt ligands, agonists, and antagonists, and their interactions with Wnt receptors. We also dissect critical events that regulate beta-catenin stability, from Wnt receptors to the cytoplasmic beta-catenin destruction complex, and nuclear machinery that mediates beta-catenin-dependent transcription. Finally, we highlight some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications.

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    • "Recent studies have also implicated the mTOR pathway in neurodevelopmental and neuropsychiatric disorders, including schizophrenia (Gururajan and Van Den Buuse 2014). GSK-3, the major downstream target of Akt, is critical for the regulation of transcription factors including β-catenin, which is an important component of the Wnt signal transduction pathway (MacDonald et al. 2009). GSK-3 also plays a central role in the regulation of the mammalian target of rapamycin complex 1 (mTORC1) (Ma and Blenis 2009), which includes mTOR and p70S6K. "
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    • "Induction of Wnt signaling can promote transcriptional activation through several mechanisms. Loss of APC results in the stabilization and nuclear translocation of βcatenin , which interacts with TCF to directly control gene expression (MacDonald et al. 2009). A key transcriptional target of β-catenin/TCF is Myc, which has been shown to mediate many of the cellular responses to Wnt signaling (Sansom et al. 2007). "
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    • "At the heart of canonical Wnt signaling is the transcriptional regulator b-catenin, which in unstimulated cells is phosphorylated by glycogen synthase kinase 3 (GSK3) and then polyubiquitinated and thereby targeted for proteasomal degradation. Binding of Wnt proteins to the Frizzled (Fz) receptors and their low-density lipoprotein receptor related protein (LRP) 5 and 6 co-receptors triggers GSK3 inhibition to stabilize b-catenin, which enter the nucleus and regulate downstream target genes (Kikuchi et al., 2011; MacDonald et al., 2009). The canonical Wnt signaling cascade is well characterized, and it is widely assumed that this pathway acts primarily through transcriptional response of b-catenin-dependent target genes. "
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