ReviewDishevelled: The hub of Wnt signaling
Introduction
Wnt signaling plays a critical role in a vast array of biological process, including cell proliferation, migration, polarity establishment and stem cell self-renewal. Deregulation of Wnt signaling is associated with cancer development [1], [2], [3]. Wnt ligands, which are secreted glycoproteins, initiate signaling by interacting with cell surface receptors Frizzled (Fz) and low density lipoprotein receptor-related protein 5/6 (LRP5/6). Subsequent recruitment of the downstream signal mediators Dishevelled (Dvl/Dsh) to Fz and Axin to LRP5/6 results in disassembly of the β-catenin destruction complex consisting of Axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β) and casein kinase 1 (CK1), ultimately leading to the nuclear accumulation of β-catenin. Binding of β-catenin with the transcription factors of the lymphoid enhancer-binding factor (LEF)/T-cell factor (TCF) family switches the inhibitory state of LEF/TCF to the activating state and turn on the transcription of Wnt target genes. In addition to the canonical Wnt pathway, Wnt can also signal via Dvl to activate Rho/JNK planar cell polarity and Ca2+-dependent pathways [1], [4].
Dsh was originally identified based on the phenotype of disorientation in body and wing hairs in Drosophila [5]. Three Dsh homologues (Dvl1, 2 and 3) have been identified in humans and mice, and the proteins consist of about 750 amino acids and display high sequence homology [6], [7], [8], [9], [10]. It has been demonstrated that Dvl can interact with a wide range of partner proteins (Table 1 and Fig. 1), while retain the ability to distinguish between suitable partners. The dynamic interaction works through sequestration or release of specific partners in a given cell or at a given time. This characteristic of Dvl provides an insight into the mechanism underlying how the convergence of extracellular signals and the divergence of intracellular outcomes are generated. The importance of Dvl in Wnt signaling and in embryogenesis has been greatly appreciated [11], [12], [13], [14]. This review attempts to summarize a current understanding of the molecular mechanisms of Dvl in Wnt signal transduction and the biological functions of Dvl during mouse development.
Section snippets
The structure of Dvl
Dvl proteins possess three conserved domains (Fig. 2), an amino-terminal DIX (Dishevelled, Axin) domain of 80 amino acids, a central PDZ (Postsynaptic density 95, Discs Large, Zonula occludens-1) domain of about 90 amino acids, and a carboxyl-terminal DEP (Dvl, Egl-10, Pleckstrin) domain of 80 amino acids [11]. In addition, another two conserved regions, the basic region and the proline-rich region, are also implicated to mediate protein–protein interaction and/or phosphorylation.
The function of Dvl in the canonical Wnt pathway
The canonical Wnt signaling pathway is deduced from genetic studies in Drosophila and is widely conserved in the animal kingdom. The binding of Wnt to its cell surface receptors recruits Dvl to the receptor complex (Fig. 3) and thereby prevent the constitutive proteolytic destruction of β-catenin. Recent studies shed new light on this pathway. It was shown that Wnt binding leads to a clustering of receptors Fz and LRP6 to form polymers with the aid of Dvl [41], [42]. The dynamic polymerization
Dvl in the non-canonical Wnt pathways
Non-canonical Wnt signaling is initiated by Fz and diverges downstream, however, it does not involve β-catenin-mediated gene expression. Here we focus on the roles of Dvl in regulation of cytoskeleton and cell adhesion.
The function of Dvl in receptor endocytosis
Wnt stimulation induces endocytosis of its receptors, although the significance of receptor endocytosis in Wnt signal transduction is still under debate. In contrast to the well documented roles of endocytic pathways in the β-catenin-independent Wnt signaling, the importance of endocytosis in the β-catenin-dependent pathway is still controversial [111], [112]. Dvl2 is important for Wnt5a-triggered Fz4 endocytosis by specifically recruiting β-arrestin2 to the plasma membrane [113]. This
Regulation of Dvl activity by phosphorylation
Although Wnt stimulation induces Dvl phosphorylation, the role of phosphorylation remains incompletely understood. Casein kinase 1 (CK1ε and CK1δ) binds to Dvl and is a positive regulator of Wnt signaling, possibly via phosphorylating Dvl [115], [116], [117], [118], [119], [120]. Two specific sites (Ser139 and Ser142) were identified to be phosphorylated by CK1ε in recombinant mouse Dvl1 protein [121]. However, mutation of these two sites did not completely abrogate Dvl activity, indicating
Regulation of Dvl protein stability
The stability of Dvl proteins is controlled by proteasomal or lysosomal degradation. Several Dvl-interacting proteins have been reported to facilitate Dvl poly-ubiquitination and degradation. First, Dvl1 interacts with the neuronal HECT-type ubiquitin ligase NEDL1 [130]. NEDL1 targets the C-terminal region containing three proline-rich clusters of Dvl1 and contributes to the ubiquitination and degradation of Dvl1. Second, the stability of Dvl is controlled by KLHL12, which serves as a
Biological functions of Dvl-knockout mouse model
All three murine Dvl genes (Dvl1, Dvl2, and Dvl3) are broadly expressed during embryonic development and in adult tissues, including brain, lung, kidney, skeletal muscle, and heart [6], [8], [139]. At E10.5, the mRNAs were expressed at a high level in neural organs including the brain and peripheral ganglia, and low in limb, tail buds and nasal epithelium, although Dvl2 mRNA was present almost equally in neural and non-neural organs [140]. To elucidate the specific functions of individual Dvl
Conclusion and outlook
Dvl plays a central role in propagating Wnt signaling to canonical and non-canonical pathways. Although the underlying mechanisms remain far from clear, the studies with mouse models have demonstrated the importance of Dvl in cardiac development, neural tube formation and cochlear polarity. Given its hub position and association with more than fifty binding partners, it is not surprising that Dvl mediates complex and versatile signal transduction. Identification and characterization of the
Acknowledgement
We thank Drs Wei Wu and Qinghua Tao for critical reading. The research in YGC's lab is supported by grants from the National Natural Science Foundation of China (30430360, 90713045), and the 973 Program (2006CB943401 and 2006CB910102).
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