The cellular story of dishevelleds

Abstract

Dishevelled (DVL) proteins, three of which have been identified in humans, are highly conserved components of canonical and noncanonical Wnt signaling pathways. These multifunctional proteins, originally discovered in the fruit fly, through their different domains mediate complex signal transduction: DIX (dishevelled, axin) and PDZ (postsynaptic density 95, discs large, zonula occludens-1) domains serve for canonical beta-catenin signaling, while PDZ and DEP (dishevelled, Egl-10, pleckstrin) domains serve for non-canonical signaling. In canonical or beta-catenin signaling, DVL forms large molecular supercomplexes at the plasma membrane consisting of Wnt-Fz-LRP5/6-DVL-AXIN. This promotes the disassembly of the beta-catenin destruction machinery, beta-catenin accumulation, and consequent activation of Wnt signaling. Therefore, DVLs are considered to be key regulators that rescue cytoplasmic beta-catenin from degradation. The potential medical importance of DVLs is in both human degenerative disease and cancer. The overexpression of DVL has been shown to potentiate the activation of Wnt signaling and it is now apparent that up-regulation of DVLs is involved in several types of cancer.

Figure 1

Wnt signaling pathway and its key components. (A) In the absence of Wnt, beta-catenin destruction complex consisting of AXIN1, adenomatous polyposis coli (APC), casein kinase 1 (CK1), and glycogen synthase kinase 3 beta (GSK3β) is formed. This results in beta-catenin phosphorylation, ubiquitination, and degradation in the proteasome. (B) Binding of Wnt ligands to receptor complex consisting of Frizzled (Fz) and low density lipoprotein receptor-related protein 5 and 6 (LRP5/6) results in recruitment of DVL to the membrane by binding to Fz and AXIN. This disables the formation of beta-catenin destruction complex, allowing beta-catenin to accumulate in the nucleus where it activates Wnt target genes upon binding to lymphoid enhancer factor/ T cell factor (LEF/TCF).

Figure 2

Dishevelled protein structure with conserved domains and regions: DIX (dishevelled, axin) domain, DSV (dishevelled) domain, the basic region, PDZ (postsynaptic density 95, discs large, zonula occludens-1) domain, proline-rich region, and DEP (dishevelled, Egl-10, pleckstrin) domain.

Figure 3

(A) Brain metastasis immunohistochemically stained for detection of dishevelled 3 (DVL3) protein (monoclonal mouse anti-human DVL3, Santa Cruz Biotehnology, Dallas, TX, USA), showing membranous staining. (B) Glioblastoma sample immunohistochemically stained for detection of dishevelled 1 (DVL1) protein (monoclonal mouse anti-human DVL1, Santa Cruz Biotehnology). (C) Control staining.