Disease relevance of DVL1

• Prickle-1 Negatively Regulates Wnt/beta-Catenin Pathway by Promoting Dishevelled Ubiquitination/Degradation in Liver Cancer [1].
• Recently, we identified aberrant Wnt activation as a result of Dishevelled overexpression in malignant mesothelioma [2].
• Activation of tumor-specific splice variant Rac1b by dishevelled promotes canonical Wnt signaling and decreased adhesion of colorectal cancer cells [3].
• Activation of the Wnt pathway in non small cell lung cancer: evidence of dishevelled overexpression [4].
• To evaluate the biological significance of Wnt signaling and, in particular, Dvl function in lung cancer, we transfected siRNA (designed to inhibit selectively human Dvl-1, -2, and -3), to the NSCLC cell line H1703, which is known to have beta-catenin-mediated Tcf-dependent transcriptional activity [4].

Psychiatry related information on DVL1

• DVL-1 and DVL-3 are members of a human dsh-like gene family, which is probably involved in human development [5].
• Identification of genomic organisation, sequence variants and analysis of the role of the human dishevelled 1 gene in late onset Alzheimer's disease [6].
• Through its many signaling activities, Dishevelled plays important roles in the embryo and the adult, ranging from cell-fate specification and cell polarity to social behavior [7].

High impact information on DVL1

• In our analysis of signaling proteins containing DEP domains ( approximately 90 residue sequence motifs first recognized in fly Dishevelled, worm EGL-10, and mammalian Pleckstrin), we find that DEP domains are responsible for specific recognition of GPCRs [8].
• The DIX domain targets dishevelled to actin stress fibres and vesicular membranes [9].
• Here we describe the molecular characterization of members of the Wnt signalling pathway--Wnt, Dishevelled, GSK3, beta-Catenin and Tcf/Lef--in Hydra, a member of the evolutionarily old metazoan phylum Cnidaria [10].
• Dishevelled is a conserved protein that interprets signals received by Frizzled receptors [11].
• The KLHL12-Cullin-3 ubiquitin ligase negatively regulates the Wnt-beta-catenin pathway by targeting Dishevelled for degradation [11].

Biological context of DVL1

• Sequencing revealed the skipping of 3 exons in the smallest DVL1 fragment, thus leading to a frameshift and predicting a truncated DVL1 gene product [12].
• Human dishevelled genes constitute a DHR-containing multigene family [13].
• Ser523 and Ser529 around the DVL-binding motif of FZD5 orthologs were putative aPKC phosphorylation sites [14].
• The DIX domain protein coiled-coil-DIX1 inhibits c-Jun N-terminal kinase activation by Axin and dishevelled through distinct mechanisms [15].
• It has been suggested that these Dvl-2-containing structures correspond to intracellular vesicles and may be involved in the Wnt signal transduction process [16].

Anatomical context of DVL1

• Thus, our results suggest that an adverse interaction among misfolded SOD1, NEDL1, translocon-associated protein-delta, and Dishevelled-1 forms a ubiquitinated protein complex that is included in potentially cytotoxic protein aggregates and that mutually affects their functions, leading to motor neuron death in FALS [17].
• Furthermore, we have shown that Dpr1 induces Dvl degradation via a lysosome inhibitor-sensitive and proteasome inhibitor-insensitive mechanism [18].
• The structures do not localise with markers of the early or late endocytic pathway and time-lapse analysis demonstrates that Dvl-2 puncta move in a random fashion over short distances but do not originate from the plasma membrane [16].
• In order to elucidate Dvl's role in Wnt signaling, we attempted to overexpress Dvl in cells, but were unable to obtain stable cell lines [19].
• RESULTS: We report that Dsh protein accumulates in cell nuclei when Xenopus embryonic explants or mammalian cells are incubated with inhibitors of nuclear export or when a specific nuclear-export signal (NES) in Dsh is disrupted by mutagenesis [20].

Associations of DVL1 with chemical compounds

• Which event(s) occur in Wnt-responsive cells depends critically on the ability of Dishevelled (Dsh)/Dvl proteins to interpret distinct types of intracellular, receptor-generated stimuli and transmit them to at least two distinct sets of effector molecules, all while apparently ignoring a third type of Wnt-generated Ca(2+) signal [21].
• Redox-dependent activation of the Wnt-beta-catenin pathway occurs independently of extracellular Wnts and is impaired by RNAi of NRX . In addition, association between Dvl and NRX is inhibited by H(2)O(2) treatment [22].

Physical interactions of DVL1

• WNT signals, transduced through Frizzled (FZD) receptors with extracellular WNT-binding domain and cytoplasmic Dishevelled-binding domain, are implicated in carcinogenesis and embryogenesis [23].

Other interactions of DVL1

• Axin and Dishevelled are two downstream components of the Wnt signaling pathway [24].
• The beta-catenin oncoprotein depends upon the association of Dvl and Axin proteins through their DIX domains, and its accumulation directs the expression of specific developmental-related genes at the nucleus [25].
• Ectopically expressed mammalian Dishevelled 2 (Dvl-2) activates downstream signalling and localises to cytoplasmic puncta [16].
• Furthermore, the adenomatous polyposis coli (APC) gene product appears to be required for Dvl-mediated cell death [19].
• Association of dishevelled with the clathrin ap-2 adaptor is required for frizzled endocytosis and planar cell polarity signaling [26].

Analytical, diagnostic and therapeutic context of DVL1

• Two-hybrid screening for the physiological targets of NEDL1 has identified Dishevelled-1, one of the key transducers in the Wnt signaling pathway [17].
• Low-pass filtering of the ECG produced a better correlation between tidal volume and the change in the DVL, when the cutoff frequency was set at 20-45 Hz [27].

References