The Role of Arrestins in Development
ABSTRACT β-Arrestins are versatile scaffolding proteins that are involved in orchestrating a large number of signaling cascades. Because β-arrestin 1 and β-arrestin 2 are individually dispensable during development, it has long been assumed that β-arrestins do not play an important role during embryogenesis. Nonetheless, there is growing evidence from both invertebrate and vertebrate animal models that β-arrestins are integral regulators of developmental pathways. They are involved in diverse processes such as early hematopoiesis, establishment of axial development axes, cell convergence and extension movements leading to axial elongation, musculoskeletal and craniofacial development, cell proliferation, and neuronal development. Most of the developmental roles of arrestins involve interactions with or regulation of novel non-G protein-coupled receptor partners, such as atypical seven-transmembrane receptors, small G proteins, and nuclear transcription factors, revealing surprising diversity in arrestin function. In contrast to their largely overlapping roles in G protein-coupled receptor desensitization and internalization, study of the role of arrestins in development has demonstrated marked functional specialization of the β-arrestin 1 and 2 isoforms.
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ABSTRACT: beta-catenin is a central component of the cadherin cell adhesion complex and plays an essential role in the Wingless/Wnt signaling pathway. In the current model of this pathway, the amount of beta-catenin (or its invertebrate homolog Armadillo) is tightly regulated and its steady-state level outside the cadherin-catenin complex is low in the absence of Wingless/Wnt signal. Here we show that the ubiquitin-dependent proteolysis system is involved in the regulation of beta-catenin turnover. beta-catenin, but not E-cadherin, p120(cas) or alpha-catenin, becomes stabilized when proteasome-mediated proteolysis is inhibited and this leads to the accumulation of multi-ubiquitinated forms of beta-catenin. Mutagenesis experiments demonstrate that substitution of the serine residues in the glycogen synthase kinase 3beta (GSK3beta) phosphorylation consensus motif of beta-catenin inhibits ubiquitination and results in stabilization of the protein. This motif in beta-catenin resembles a motif in IkappaB (inhibitor of NFkappaB) which is required for the phosphorylation-dependent degradation of IkappaB via the ubiquitin-proteasome pathway. We show that ubiquitination of beta-catenin is greatly reduced in Wnt-expressing cells, providing the first evidence that the ubiquitin-proteasome degradation pathway may act downstream of GSK3beta in the regulation of beta-catenin.The EMBO Journal 08/1997; 16(13):3797-804. DOI:10.1093/emboj/16.13.3797 · 10.75 Impact Factor
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ABSTRACT: The Wnt/β-catenin signaling pathway is crucial for proper embryonic development and tissue homeostasis. The phosphoprotein dishevelled (Dvl) is an integral part of Wnt signaling and has recently been shown to interact with the multifunctional scaffolding protein β-arrestin. Using Dvl deletion constructs, we found that β-arrestin binds a region N-terminal of the PDZ domain of Dvl, which contains casein kinase 1 (CK1) phosphorylation sites. Inhibition of Wnt signaling by CK1 inhibitors reduced the binding of β-arrestin to Dvl. Moreover, mouse embryonic fibroblasts lacking β-arrestins were able to phosphorylate LRP6 in response to Wnt-3a but decreased the activation of Dvl and blocked β-catenin signaling. In addition, we found that β-arrestin can bind axin and forms a trimeric complex with axin and Dvl. Furthermore, treatment of Xenopus laevis embryos with β-arrestin morpholinos reduced the activation of endogenous β-catenin, decreased the expression of the β-catenin target gene, Xnr3, and blocked axis duplication induced by X-Wnt-8, CK1ε, or DshΔDEP, but not by β-catenin. Thus, our results identify β-arrestin as a necessary component for Wnt/β-catenin signaling, linking Dvl and axin, and open a vast array of signaling avenues and possibilities for cross-talk with other β-arrestin-dependent signaling pathways.Proceedings of the National Academy of Sciences 04/2007; 104(16):6690-6695. DOI:10.1073/pnas.0611356104 · 9.81 Impact Factor
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ABSTRACT: Recent advances in understanding beta-catenin-independent WNT (non-canonical) signalling suggest an increasing complexity, raising the question of how individual non-canonical pathways are induced and regulated. Here, we examine whether intracellular signalling components such as beta-arrestin (beta-arr) and casein kinases 1 and 2 (CK1 and CK2) can contribute to determining signalling specificity in beta-catenin-independent WNT signalling to the small GTPase RAC-1. Our findings indicate that beta-arr is sufficient and required for WNT/RAC-1 signalling, and that casein kinases act as a switch that prevents the activation of RAC-1 and promotes other non-canonical WNT pathways through the phosphorylation of dishevelled (DVL, xDSH in Xenopus). Thus, our results indicate that the balance between beta-arr and CK1/2 determines whether WNT/RAC-1 or other non-canonical WNT pathways are activated.EMBO Reports 11/2008; 9(12):1244-50. DOI:10.1038/embor.2008.193 · 7.86 Impact Factor