Dishevelled-3 C-terminal His single amino acid repeats are obligate for Wnt5a activation of non-canonical signalingReport as inadecuate




Dishevelled-3 C-terminal His single amino acid repeats are obligate for Wnt5a activation of non-canonical signaling - Download this document for free, or read online. Document in PDF available to download.

Journal of Molecular Signaling

, 5:19

First Online: 23 November 2010Received: 24 September 2010Accepted: 23 November 2010

Abstract

BackgroundThe Wnt non-canonical pathway Wnt5a > Frizzled-2 > cyclic GMP phosphodiesterase-Ca-mobilization pathway regulates the activation of NF-AT is mediated by three mammalian Dishevelleds Dvl1, Dvl2, and Dvl3 and the role of the C-terminal region unique to Dvl3 was interrogated.

ResultsDvl1, Dvl2, and Dvl3 are expressed at varying levels in mouse totipotent F9 embryonal teratocarcinoma cells. The expression of each endogenous Dvl isoform, as defined by knock-down with siRNA, was obligate for Wnt5a to activate NF-AT-sensitive transcription. Elements upstream of effectors, e.g., cGMP phosphodiesterase and Ca-mobilization, were blocked by knock-down of any one of the Dvls; thus, with respect to Wnt5a activation of NF-AT Dvls are not redundant. Among the three Dvl isoforms, the C-terminal sequence of Dvl3 is the most divergent. Deletion of region of Dvl3 abolishes Wnt5a-stimulated signaling. Alanine Ala-substitution of histidine His single amino acid repeats at 637,638 and-or 647,648 in Dvl3, like C-terminal deletion, abolishes Wnt 5a signal propagation. Phenylalanine Phe-substitution of the same His-repeats in Dvl3 mimics Wnt5a stimulated NF-AT-sensitive transcription.

ConclusionsThe C-terminal third of Dvl3 and His single amino acid repeats 637,638 and 647,648 which are unique to and conserved in Dvl3 are essential for Wnt5a activation of the non-canonical pathway, but not the Wnt3a activation of the canonical pathway.

AbbreviationscGMPcyclic GMP

DMEMDulbecco-s modified Eagle-s medium

DshFly Dishevelled

Dvl1Dishevelled-1

Dvl2Dishevelled-2

Dvl3Dishevelled-3

KDknock-down

NF-ATNuclear Factor of Activated-T cells

rFzrat Frizzled

Electronic supplementary materialThe online version of this article doi:10.1186-1750-2187-5-19 contains supplementary material, which is available to authorized users.

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Author: Li Ma - Ying Wang - Craig C Malbon - Hsien-yu Wang

Source: https://link.springer.com/







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