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Dishevelled and Wnt Signaling: Is the Nucleus the Final Frontier?


Dishevelled and Wnt Signaling: Is the Nucleus the Final Frontier?

Raymond Habas et al. J Biol.


The phosphoprotein Dishevelled (Dsh) is an essential component of Wnt signaling pathways and transduces signals into three separate branches, the canonical, non-canonical and Ca2+ pathways. How Dsh focuses signaling into these branches remains mysterious, but a new study reveals the importance of nuclear localization of Dsh for pathway-specific activation.


Figure 1
Figure 1
A schematic representation of the Wnt signal transduction cascade. (a) For the canonical pathway, signaling through the Frizzled (Fz) and LRP5/6 receptor complex induces the stabilization of β-catenin via the DIX and PDZ domains of Dishevelled (Dsh) and a number of factors including Axin, glycogen synthase kinase 3 (GSK3) and casein kinase 1 (CK1). β-catenin translocates into the nucleus where it complexes with members of the LEF/TCF family of transcription factors to mediate transcriptional induction of target genes. β-catenin is then exported from the nucleus and degraded via the proteosomal machinery. (b) For non-canonical or planar cell polarity (PCP) signaling, Wnt signaling is transduced through Frizzled independent of LPR5/6. Utilizing the PDZ and DEP domains of Dsh, this pathway mediates cytoskeletal changes through activation of the small GTPases Rho and Rac. (c) For the Wnt-Ca2+ pathway, Wnt signaling via Frizzled mediates activation of heterotrimeric G-proteins, which engage Dsh, phospholipase C (PLC; not shown), calcium-calmodulin kinase 2 (CamK2) and protein kinase C (PKC). This pathway also uses the PDZ and DEP domains of Dsh to modulate cell adhesion and motility. Note that for the PCP and Ca2+ pathways Dsh is proposed to function at the membrane, whereas for canonical signaling Dsh has been proposed to function in the cytoplasm; a recent study [10] implicates nuclear localization of Dsh in this pathway. See text for further details.

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