St Jude Childrens Research Hospital, Department of Structural Biology, 262 Danny Thomas Place, Memphis, TN 38105, USA
Structure. The overall structure of the intact DVL1 protein remains unknown; however, each individual domain in DVL1 has been investigated. The 3D structure of the DIX domain of Dvl-1 has not been reported. The homology model of the DVL1 DIX domain was generated from the 3D structure of the Axin DIX domain (PDB code: 1WSP) and that of a mutant DIX(Y17D) was solved by using X-ray crystallography (PDB code: 3PZ8), which consists of 4 beta-sheets and 1 helix structures (Schwarz-Romond et al., 2007a; Liu et al., 2011). The structure of DVL1s PDZ domain comprises 6 beta-sheets (betaA~betaF) and 2 alpha-helices (alphaA and alphaB) (Wong et al., 2003). The DEP domain of DVL1 consists of a helix bundle with three a-helices (H1-H3), a beta-hairpin "arm" composed of two beta-strands (B1 and B2) between H1 and H2, and two short beta-strands (B3 and B4) (Wong et al., 2000).
- AXIN interacts with the DIX domain of DVLs, which leads to the activation of beta-catenin-mediated signaling (Li et al., 1999; Smalley et al., 1999; Cliffe et al., 2003; Kishida et al., 1999; Schwarz-Romond et al., 2007a; Schwarz-Romond et al., 2007b; Fiedler et al., 2011).
- BP75 (bromodomain-containing M(r) 75000 protein) binds to the DIX domain of mouse Dvl1 in mammalian cells and enhances Wnt signaling by inactivating GSK3beta (Kim et al., 2003).
- CK1epsilon (casein kinase Iepsilon) binds to the Dvl proteins and increases the phosphorylation of DVLs in a variety of tissue culture and in vitro assays (Peters et al., 1999; Sakanaka et al., 1999; Kishida et al., 2001). CK1epsilon phosphorylates two highly conserved residues, S139 and S142, of mouse Dvl1 protein, as confirmed by mass spectroscopy. Phosphoserines -139 and -142 are positive regulators of Dvl1-dependent Wnt signal transduction (Klimowski et al., 2006). In Drosophila, CK1epsilon phosphorylates the Ser236 residue in Dsh protein as confirmed by mutagenesis analysis (Klein et al., 2006). In Xenopus, CK1epsilon activates the Wnt/beta-catenin signaling pathway positively. The interaction between the kinase domain of CK1epsilon and the PDZ domain of Xenopus Dishevelled (Xdsh) was identified by a yeast two-hybrid assay (Peters et al., 1999). However, another study suggested that the entire DEP domain, but not the PDZ domain, is necessary for the binding of DVL1 to CK1epsilon in mammalian intact cell assays (Kishida et al., 2001). In Drosophila, studies suggested that CK1epsilon facilitates both Wnt/beta-catenin and Wnt/PCP signaling pathways (Strutt et al., 2006; Klein et al., 2006). Consistent with this finding, CK1epsilon activates Dvl proteins via non-canonical Wnt ligands in SN4741 cells, suggesting that CK1epsilon-mediated phosphorylation of Dvl proteins may be a common step in both canonical and non-canonical pathways (Bryja et al., 2007).
- CKII (casein kinase II) is a serine/threonine kinase that can phosphorylate and associate with the PDZ domain of Drosophila Dsh (or DVLs) (Willert et al., 1997; Lee et al., 1999).
- Diversin regulates heart formation and gastrulation movements during development. Diversins ankyrin repeats are necessary for interaction with the DVL DEP domain, for activation of the non-canonical Wnt signaling pathway, and for other biological responses (Moeller et al., 2006).
- Dapper (Dpr) binds to the PDZ domain of DVL1, which inhibits the Wnt/beta-catenin signaling (Wong et al., 2003). However,another study showed that human DPR1 can bind the DEP domain of DVL1 and inhibit Wnt signaling by promoting DVL1 degradation (Zhang et al., 2006).
- Daam1, a Formin-Homology (FH) protein, binds to both DVL and Rho proteins and mediates Wnt-induced Dvl1-Rho complex formation. Xenopus Daam1 regulates gastrulation (Habas et al., 2001).
- EphrinB1 interacts with the PDZ domain of Dishevelled. In Xenopus embryos, EphrinB1 plays a role in retinal progenitor cell movement into the eye field through an interaction with DVL (Tanaka et al., 2003; Lee et al., 2006; Lee HS et al., 2009). Phosphorylation of tyrosines 324 and 325 disrupts the EphrinB1/Dsh interaction, thus modulating retinal progenitor movement that is dependent on the planar cell polarity pathway (Lee HS et al., 2009).
- Frat protein was originally isolated on the basis of its tumor-promoting activity in human lymphocytes (Jonkers et al., 1997). It also binds to the basic region (aa 220-230) of DVL1 (Li et al., 1999; Hino et al., 2003), an interaction that is enhanced by CK1epsilon, which activates Wnt/beta-catenin signaling (Hino et al., 2003).
- Frizzled (Fz) protein, a key component of Wnt signaling, interacts with Dvl proteins (Wong et al., 2003; Shafer et al., 2011). NMR studies showed that a peptide derived from a conserved motif (KTxxxW) located two amino acids C-terminal to the seventh transmembrance domain of Fz directly binds to the PDZ domain of Dvl-1, implying that its interaction is necessary for activating the Wnt/beta-catenin signaling (Wong et al., 2003). Interestinly, Dvl-1 can inhibit PCP signaling by increasing hyperphosphorylation of Fz3 and preventing its internalization (Shafer et al., 2011).
- Idax (Inhibition of the Dvl and AXin complex) bound to the PDZ domain of DVL was identified in a rat brain cDNA library that was screened by the yeast two-hybrid method (Hino et al., 2001). Idax interacts with DVL in intact cells also. NMR spectroscopy identified the minimum region in rat Idax protein required for binding to mouse Dvl1 PDZ domain as the internal sequence of the KTxxxI motif (London et al., 2004). Idax suppresses the Wnt3a-dependent accumulation of beta-catenin and activation of Tcf in L cells (Hino et al., 2001). The levels of CXXC4 mRNA, which encodes the protein Idax, in renal cell carcinoma were significantly lower in patients with metastases than in patients without metastases (P=0.0016) (Kojima et al., 2009).
- Naked cuticle (Nkd) regulates early Wnt activity by acting as an inducible antagonist. The Nkd EFX domain interacts with the basic/PDZ domain of Drosophila Dsh or DVLs in the yeast two-hybrid assay (Wharton et al., 2001).
- MuSK kinase domain interacts with Dvl1 DEP domain in a mouse muscle cell line and in HEK293 cells transfected with the mouse constructs, which plays an important role in the agrin- and neuro-induced AChR (acethylcholine receptor) clustering (Luo et al., 2002). In Dvl1 mutant mice AchR clusters had a more disperse distribution at the endplate (Henriquez et al., 2008).
- PAR-1 is a serine/threonine kinase. In Drosophila, Par-1 binds to and phosphorylates Dsh/Dvl protein and promotes Wnt/beta-catenin signaling at the expense of JNK signaling (Sun et al., 2001). Par-1 target sites in Dsh are essential for proper Dsh translocation from the cytoplasmic vesicles to the cell cortex but not for Dsh activity in the canonical Wnt/beta-catenin pathway. Different PAR-1 isoforms mediate two distinct and essential roles in Xenopus axial development. PAR-1BY plays an essential role in the PCP branch and mediates Dsh membrane localization while PAR-1A and PAR-BX are essential for canonical Wnt signaling, possibly via targets other than Dishevelled (Ossipova et al., 2005). Mammalian Par-1b promotes cell-cell adhesion and inhibits Dvl-mediated transformation of Madin-Darby canine kidney cells.
- PIP5K1 (phosphatidylinositol-4-phosphate 5-kinase type I) and DVL co-immunoprecipitate when they are overexpressed in HEK293 cells. The N-terminal half of the PIP5K1beta kinase domain interacts with Dvl1 fragment that contains the DIX and PDZ domains; Wnt3a may regulate this interaction (Pan et al., 2008).
- Ror2 is a receptor tyrosin kinase (RTK) binds the Dvl C-terminus (Witte et al., 2010).
- Syndecan-4 (Syn4) interacts with Dvl protein and also functionally and biochemically with the Wnt receptor Fz7 in Xenopus embryos (Muñoz et al., 2006).
- Transmembrane 88 (TMEM88), a two-transmembrane-type protein, interacts with the PDZ domain of Dvl. Using NMR spectroscopy, the interaction between the C-terminal tail of TMEM88 and the PDZ domain of Dvl-1 was confirmed (Lee et al., 2010). In HEK293 cells, TMEM88 attenuated the Wnt/beta-catenin signaling induced by Wnt-1 ligand in a dose-dependent manner, and TMEM88 knockdown by RNAi increased Wnt activity. In Xenopus, TMEM88 protein is sublocalized at the cell membrane and inhibits Wnt signaling induced by Xdsh, but not beta-catenin (Lee et al., 2010).
Ho-Jin Lee ; Jie J Zheng
DVL1 (dishevelled, dsh homolog 1 (Drosophila))
Atlas Genet Cytogenet Oncol Haematol. 2011-06-01
Online version: http://atlasgeneticsoncology.org/gene/463/dvl1-(dishevelled-dsh-homolog-1-(drosophila))