L. T. WILLIAMS AND COLLEAGUES

Wnt/Wingless (Wg) signalling is critical for normal embryonic development, and deregulation of the Wnt pathway can lead to aberrant development or cancer. The Dishevelled (Dsh) protein is phosphorylated and activated as a result of Wnt-binding to its receptor Frizzled (Fz). This in turn is required for activation of the two possible effectors of Wnt signalling, β-catenin and c-Jun N-terminal kinase (JNK). Dsh activation of JNK is also involved in the control of cell polarity. Sun et al. now report in this issue (p. 628) on differential regulation by Wnt of Dsh activation of β-catenin and JNK through the PAR-1 kinase. This represents a new function for PAR-1, which also controls cell polarity in asymmetric cell division in Caenorhabditis elegans and in Drosophila.

Sun et al. purified PAR-1 as a Dsh-associated kinase. They showed that PAR-1 phosphorylates Dsh in vitro and in vivo, and that Wnt signalling results in increased PAR-1 activity. Overexpression of PAR-1 has differential effects on the Wnt/β-catenin and Wnt/JNK pathways as it enhances Wnt/β-catenin signalling while inhibiting Wnt/JNK signalling. Conversely, antisense par-1 oligonucleotides inhibit Wnt/β-catenin signalling in mammalian cells, and RNA interference with double-stranded par-1 RNA generates a wg loss-of-function-like phenotype. A kinase-dead mutant of PAR-1 and a peptide that corresponds to the Dsh-binding domain of PAR-1 dominantly inhibit endogenous PAR-1 activity and phosphorylation of Dsh and Wnt/β-catenin signalling induced by Wnt, although they fail to inhibit Wnt/JNK signalling. Hence, PAR-1 seems to act as a 'switch' between the Wnt/β-catenin and Wnt/JNK pathways. The dominant-negative PAR-1 constructs does not interfere with the transcriptional response to overexpression of β-catenin, which indicates that PAR-1 indeed acts upstream of β-catenin.

These results indicate that Wnt signalling and cell and embryo polarity might have overlapping molecular mechanisms, and that Dsh might be one of the relevant targets of PAR-1 in regulating polarity as well as in Wnt signalling.