Metastasis-associated kinase modulates Wnt signaling to regulate brain patterning and morphogenesis.

Wnt signaling is a major pathway regulating cell fate determination, cell proliferation and cell movements in vertebrate embryos. Distinct branches of this pathway activate beta-catenin/TCF target genes and modulate morphogenetic movements in embryonic tissues by reorganizing the cytoskeleton. The selection of different molecular targets in the pathway is driven by multiple phosphorylation events. Here, we report that metastasis-associated kinase (MAK) is a novel regulator of Wnt signaling during morphogenetic movements, and eye and brain development in Xenopus embryos. Injected MAK RNA suppressed Wnt transcriptional reporters and activated Jun N-terminal kinase. Furthermore, MAK was recruited to the cell membrane by Frizzled 3, formed a complex with Dishevelled and phosphorylated Dsh in vitro. The regional brain markers Otx2, En2 and Gbx2 were affected in embryos with modulated MAK activity in a manner consistent with a role for MAK in midbrain-hindbrain boundary formation. Confirming the inhibitory role for this kinase in Wnt/beta-catenin signaling, the midbrain patterning defects in embryos depleted of MAK were rescued by the simultaneous depletion of beta-catenin. These findings indicate that MAK may function in different developmental processes as a switch between the canonical and non-canonical branches of Wnt signaling.