Nemo kinase phosphorylates β-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin–β-catenin


Frizzled planar cell polarity (PCP) signaling regulates cell motility in several tissues, including ommatidial rotation in Drosophila melanogaster. The Nemo kinase (Nlk in vertebrates) has also been linked to cell-motility regulation and ommatidial rotation but its mechanistic role(s) during rotation remain obscure. We show that nemo functions throughout the entire rotation movement, increasing the rotation rate. Genetic and molecular studies indicate that Nemo binds both the core PCP factor complex of Strabismus–Prickle, as well as the E-cadherin–β-catenin (E-cadherin–Armadillo in Drosophila) complex. These two complexes colocalize and, like Nemo, also promote rotation. Strabismus (also called Vang) binds and stabilizes Nemo asymmetrically within the ommatidial precluster; Nemo and β-catenin then act synergistically to promote rotation, which is mediated in vivo by Nemo's phosphorylation of β-catenin. Our data suggest that Nemo serves as a conserved molecular link between core PCP factors and E-cadherin–β-catenin complexes, promoting cell motility.

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Figure 1: nmo is required throughout ommatidial rotation.
Figure 2: nmo is required in a cluster-autonomous manner for rotation.
Figure 3: Increased Nmo levels raise the rotation rate.
Figure 4: Nmo interacts physically and genetically with Stbm and Pk.
Figure 5: Nmo binds and phosphorylates β-cat and cadherin.
Figure 6: The activity of β-cat is modulated by Nmo in vivo.


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We thank Z. Chen (Baylor College of Medicine), T. Clandinin (Stanford School of Medicine), H. Oda and S. Tsukita (Japan Science and Technology Corporation, Kyoto), P. Rørth (Institute of Molecular and Cell Biology, Singapore), K. Saigo (University of Tokyo), U. Tepass (University of Toronto), N. Tolwinski (Sloan-Kettering Institute), T. Uemura (Kyoto University), W. Weis (Stanford University), T. Wolff (Howard Hughes Medical Institute, Janelia Farm), B. Mollereau (Rockefeller University) and the Bloomington stock center for flies and reagents, S. Okello and Y.A. Zeng for technical assistance, N. Maj for help in generating the rose diagrams, J. Delaney and U. Weber for comments on the manuscript, and all members of the Mlodzik laboratory for helpful discussions. This work was supported by US National Institutes of Health, National Eye Institute grant RO1 EY14597 to M.M., by Natural Sciences and Engineering Research Council of Canada grant RGPIN/203545 and Canadian Institutes of Health Research grant MOP 62895 to E.V., and US National Institutes of Health grant GM076561 to C.J.G.

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I.M. and M.M. designed experiments; I.M., W.J.G., M.R., A.J. and K.G. conducted experiments and analyzed data; A.J., W.J.G. and C.J.G. edited the manuscript; D.B. generated the nmoDB allele; C.J.G. conducted biochemical experiments with β-cat and Nmo; I.M., E.M.V. and M.M. analyzed data and prepared the manuscript.

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Correspondence to Esther M Verheyen or Marek Mlodzik.

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The authors declare no competing financial interests.

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Mirkovic, I., Gault, W., Rahnama, M. et al. Nemo kinase phosphorylates β-catenin to promote ommatidial rotation and connects core PCP factors to E-cadherin–β-catenin. Nat Struct Mol Biol 18, 665–672 (2011).

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