Review
doi: 10.1016/j.cellsig.2018.03.004. Epub 2018 Mar 17.Dishevelled: A masterful conductor of complex Wnt signals
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- PMID:29559363
- PMCID: PMC6317740
- DOI: 10.1016/j.cellsig.2018.03.004
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Review
Dishevelled: A masterful conductor of complex Wnt signals
Monica Sharma et al. Cell Signal.2018 Jul.
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Abstract
The Dishevelled gene was first identified in Drosophila mutants with disoriented hair and bristle polarity [1-3]. The Dsh gene (Dsh/Dvl, in Drosophila and vertebrates respectively) gained popularity when it was discovered that it plays a key role in segment polarity during early embryonic development in Drosophila [4]. Subsequently, the vertebrate homolog of Dishevelled genes were identified in Xenopus (Xdsh), mice (Dvl1, Dvl2, Dvl3), and in humans (DVL1, DVL2, DVL3) [5-10]. Dishevelled functions as a principal component of Wnt signaling pathway and governs several cellular processes including cell proliferation, survival, migration, differentiation, polarity and stem cell renewal. This review will revisit seminal discoveries and also summarize recent advances in characterizing the role of Dishevelled in both normal and pathophysiological settings.
Keywords: Cancer; Development; Disease; Dishevelled; Wnt; β-catenin.
Copyright © 2018 Elsevier Inc. All rights reserved.
Figures
In canonical Wnt pathway, DVL promotes clustering of Wnt-LRP5/6-Frizzled to form signalosomes, which results in phosphorylation of LRP5/6 and recruitment of Axin to the plasma membrane, further stabilizing the β–catenin levels in the cytoplasm. DVL has also been found to shuttle between the cytoplasm and the nucleus, acting as a transcriptional activator of Wnt target genes. In non-canonical pathway, Wnt-Frizzled complex interacts with DVL which relays signal to downstream effectors. Multiple pathways downstream of DVL regulate gene transcription, polarity and actin cytoskeleton remodeling of a cell.
DVL is made up of three conserved motifs namely an amino-terminal DIX domain, a central PDZ, and a carboxyl-terminal DEP domain. In addition to these three domains, DVL harbors two regions with positively charged amino acid residues (basic and proline-rich domain) plus a nuclear import (NLS) and a nuclear export signal (NES). The DIX and PDZ domain relay signal to canonical pathway (marked in black arrows), whereas DEP domain mainly regulates membrane localization of DVL and propagates non-canonical pathway (marked in blue arrows).
The agonists (marked in green arrows) and the antagonist (marked in red arrows) bind to specific domains of DVL to regulate Wnt pathway.
DVL-1, DVL-2 and DVL-3 RNA-seq data were analyzed using TCGA downloaded from Xena tool of UCSC Cancer Genomics Browser (http://xena.ucsc.edu/ ). Normalized RNA expression is plotted as log2 (norm_count+1). Dysregulated DVL expression between tumor and normal tissue were identified using t-test (p value < 0.001, log2FC > 1 or < −1).
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