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Review
. 2010 Jan;239(1):34-44.
doi: 10.1002/dvdy.22019.

Regulation of Wnt/beta-catenin signaling by protein kinases

Esther M Verheyen  1 , Cara J Gottardi
Affiliations
Review

Regulation of Wnt/beta-catenin signaling by protein kinases

Esther M Verheyen et al. Dev Dyn. 2010 Jan.

Abstract

The Wnt/beta-catenin signaling pathway plays essential roles during development and adult tissue homeostasis. Inappropriate activation of the pathway can result in a variety of malignancies. Protein kinases have emerged as key regulators at multiple steps of the Wnt pathway. In this review, we present a synthesis covering the latest information on how Wnt signaling is regulated by diverse protein kinases.

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Figures

Fig. 1
Fig. 1
Wnt/β-catenin signaling pathway. A: In the absence of Wnt ligand, cytoplasmic b-catenin is targeted for destruction by the Axin–scaffolded protein complex containing Axin, APC, GSK3, and CKI. Association of DNA-bound Tcf with Gro and other transcriptional corepressors inhibits Wnt target genes. B: Upon ligand binding, the destruction complex is inhibited and cytoplasmic β-catenin accumulates and enters the nucleus where it can activate gene expression through Tcf and CBP binding.
Fig. 2
Fig. 2
Phosphorylation sites on β-catenin. β-Catenin is phosphorylated on its N-terminus by GSK3 (shown in orange) and CKI (shown in orange). These phosphorylations target β-catenin for ubiquitination and subsequent proteasomal degradation. β-Catenin is also phosphorylated on the indicated sites by the diverse kinases PKA, AKT, and JNK2. These events are believed to promote β-catenin activity.
Fig. 3
Fig. 3
Phosphorylation sites in the cytoplasmic domain of LRP6. A: The cytoplasmic domain of LRP6 is shown, indicating the sites of GSK3 (red) and CKIγ (orange) phosphorylation. Five clusters of GSK3 sites followed by CKIγ sites are shown as blue boxes labeled A–E. TM, transmembrane domain. B: The amino acid sequence of LRP6 repeat A (adapted from Davidson et al., 2005). Cluster 1 contains the T1479 CKIγ target site and Cluster 2 follows the GSK3 site and contains a second CKIγ site (T1493).
Fig. 4
Fig. 4
LRP6 signalosome assembly. Wnt ligand binding triggers assembly of LRP6-associated complexes termed signalosomes. Ligand association results in receptor association and recruitment of Dvl. Subsequently, GSK3 and Axin are recruited to the complex, along with membrane associated CKIγ, and LRP6 is phosphorylated.
Fig. 5
Fig. 5
Phosphorylation sites on Lef-1. Lef/Tcf family members can be phosphorylated by Nlk, CKI, and CK2. CK2 phosphorylates human Lef-1 at residues S42 and S61 within the β-catenin binding domain (β-cat BD). Nlk can phosphorylate Lef-1 at residues T155 and S166, as well as in the corresponding T178 and T189 in Tcf4. The HMG DNA-binding domain (DNAB) is at the C-terminus of the protein.
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