Transcript figure 18.2
Chapter 18 WNT Signaling in Skeletal Homeostasis and Diseases Copyright © 2013 Elsevier Inc. All rights reserved. FIGURE 18.1 A) Signal ON. Binding of the appropriate Wnt proteins to the Fzd family of receptors activates the cytoplasmic signaling protein Dvl, which in turn recruits the axin-GSK3 complex, leading to LRP5/6 phosphorylation. LRP5/6 phosphorylation prevents phosphorylation of β-catenin and thereby its degradation. Subsequently β-catenin accumulates in the cytoplasm and enters the nucleus where it interacts with Tcf/Lef transcription factors and recruits coactivators, such as CBP/p300, to initiate gene transcription. R-spondin (Rspo) proteins are secreted agonists that bind to LGR4/5/6, LRP5/6, and/or Fdz to enhance activation of canonical Wnt signaling. Noncanonical Wnt signaling triggers its effects through alternative pathways including Wnt/Ca2+, Wnt/PCP, Wnt/Rho-Rac, Wnt/G-protein coupled receptors, Wnt/Ror, Wnt-aPKC, Wnt-RYK, and Wnt-mTOR pathways. In these pathways, Wnt proteins signal through the Fzd receptors and activate Dvl leading to the activation of multiple distinct downstream effectors. However, Wnt proteins signal through membrane receptors such Ror2 and Ryk, thereby activating downstream Wnt signals independently of Dvl. B) Signal OFF. In the absence of Wnts, the key protein β-catenin is phosphorylated by the destruction complex and degraded by ubiquitin-mediated proteolysis. Tcf/Lef assembles a transcriptional repressor complex to silence Wnt target genes. Secreted Wnt inhibitors can antagonize Wnt signaling by either binding directly to the receptors or by functioning as decoy receptors for Wnt proteins. Members of the Dkk family, sclerostin and Wise interact with the LRP5/6 coreceptor thus preventing formation of the WNT/Fzd/LRP5/6 complex. Dkk binds to and inhibits LRP5/6 in cooperation with the Krm1 and 2. In contrast, sFRPs and Wif-1 binds directly to Wnt proteins, preventing association with their receptors. Copyright © 2013 Elsevier Inc. All rights reserved. 2 FIGURE 18.2 Canonical Wnt signaling regulation of skeletal development and postnatal bone homeostasis. Wnt signaling induces commitment of mesenchymal precursor cells to the osteoblast lineage, while it inhibits differentiation along the adipocyte and chondrocyte lineages. Wnt signaling in committed osteoblasts is required for their proliferation and differentiation and to block apoptosis. Wnt signaling in mature osteoblasts and osteocytes inhibits osteoclastogenesis by increasing the expression of OPG, the decoy receptor for RANKL. Wnt signaling also directly inhibits osteoclastogenesis by decreasing differentiation of osteoclast progenitors. Sclerostin is secreted by osteocyte lacuna, diffuses to the bone surface and inhibits canonical Wnt signaling in osteoblasts. PTH signaling and mechanical loading suppresses Sost expression in osteocytes thereby inducing bone formation. OB: osteoblast; PTH: parathyroid hormone; MSC: mesenchymal stem cell; RANKL: receptor activator of nuclear-factor kappa-B ligand. Copyright © 2013 Elsevier Inc. All rights reserved. 3 FIGURE 18.3 Noncanonical Wnt signaling regulation of skeletal development and postnatal bone homeostasis. Activation of this pathway by Wnt7b favors bone formation by inducing expression of osteoblast specific genes such as Runx2, through the Wnt-Gαq/11-PKCδ Osteoblasts secrete Wnt5a that favors bone formation by repressing the expression of PPARγ via the-CAMKII-TAK1-TAB2-NLK cascade. Wnt5a binds to the Ror2-Fzd receptor complex on osteoclast precursors and induces c-Jun transcription. c-Jun then binds to Sp1 sites on the RANK promoter, activates its transcription and increases RANK expression, which in turn favors osteoclastogenesis and bone resorption. OB: osteoblast; RANK: receptor activator of nuclear-factor kappa-B; RANKL: receptor activator of nuclear-factor kappa-B ligand. Copyright © 2013 Elsevier Inc. All rights reserved. 4