PAR-1 is a Dishevelled-associated kinase and a positive regulator of Wnt signalling

Abstract

Wnt signalling regulates β-catenin-dependent developmental processes through the Dishevelled protein (Dsh). Dsh regulates two distinct pathways, one mediated by β-catenin and the other by Jun kinase (JNK). We have purified a Dsh-associated kinase from Drosophila that encodes a homologue of Caenorhabditis elegans PAR-1, a known determinant of polarity during asymmetric cell divisions. Treating cells with Wnt increases endogenous PAR-1 activity coincident with Dsh phosphorylation. PAR-1 potentiates Wnt activation of the β-catenin pathway but blocks the JNK pathway. Suppressing endogenous PAR-1 function inhibits Wnt signalling through β-catenin in mammalian cells, and Xenopus and Drosophila embryos. PAR-1 seems to be a positive regulator of the β-catenin pathway and an inhibitor of the JNK pathway. These findings show that PAR-1, a regulator of polarity, is also a modulator of Wnt–β-catenin signalling, indicating a link between two important developmental pathways.

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Figure 1: Identification and cloning of Drosophila and human PAR-1 as encoding a Dishevelled-associated kinase.
Figure 2: Wnt stimulates PAR-1 activity and suppression of PAR-1 blocks Wnt signalling.
Figure 3: PAR-1 antisense oligonucleotides decrease the response to Wnt in human cells.
Figure 4: PAR-1 potentiates the canonical Wnt pathway at a step upstream of Axin and β-catenin, and inhibits the JNK pathway.
Figure 5: Suppression of PAR-1 inhibits Wnt signalling in Xenopus.
Figure 6: Effects of loss of function and overproduction of dPAR-1 during Drosophila development.

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Acknowledgements

We thank J. Fernandez at Rockefeller University for protein sequencing. We are grateful to R. Grosschedl, S. Cumberlege, P. Klein, D. Kessler, R. Zuckermann, M. Milner, R. Carthew and Developmental Studies Hybridoma Band for critical reagents. We appreciate helpful discussions with C. Mello, T. H. Shin, C. Sakanaka, K. Ramer, and D. Yan. We thank M. Wu for the Xenopus injection assay, S. Harrison for critical reading of the manuscript, C. Turk for technical assistance and B. Cheung for administrative assistance. This work was supported partially by funds from the National Institutes of Health-Program of Excellence in Molecular Biology (PO HL43821) and by an unrestricted award from the Howard Hughes Medical Institute.

Author information

Correspondence to Lewis T. Williams.

Supplementary information

Figure S1

Identification of a Dsh-associated kinase from Drosophila embryos and cultured cells. (PDF 252 kb)

Figure S2 Purification and cloning of Dsh-associated kinase from Drosophila embryos.

Figure S3 In vitro and in vivo phosphorylation of Dsh by dPAR-1.

Figure S4 RT-PCR analysis showing expression of three hPAR-1 genes in different human tissues.

Figure S5 Dvl phosphorylation induced by Wnt is sensitive to phosphatase treatment.

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