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Letters to Nature

Nature 419, 726-729 (17 October 2002) | doi:10.1038/nature01056; Received 13 May 2002; Accepted 25 July 2002

The DIX domain targets dishevelled to actin stress fibres and vesicular membranes

Daniel G. S. Capelluto1, Tatiana G. Kutateladze1,2, Raymond Habas2,3, Carla V. Finkielstein2,4, Xi He5 & Michael Overduin1

  1. Department of Pharmacology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, Colorado 80262, USA
  2. Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, Colorado 80262, USA
  3. Division of Neuroscience, Children's Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, and Laboratory of Molecular Genetics, National Institutes of Child Health and Human Development, Bethesda, Maryland 20892, USA
  4. Division of Neuroscience, Children's Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA
  5. These authors contributed equally to this work.

Correspondence to: Michael Overduin1 Correspondence and requests for materials should be addressed to M.O. (e-mail: Email: michael.overduin@uchsc.edu).

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Colorectal cancer results from mutations in components of the Wnt pathway that regulate beta-catenin levels1. Dishevelled (Dvl or Dsh) signals downstream of Wnt receptors and stabilizes beta-catenin during cell proliferation1 and embryonic axis formation2. Moreover, Dvl contributes to cytoskeletal reorganization during gastrulation3, 4, 5 and mitotic spindle orientation during asymmetric cell division6. Dvl belongs to a family of eukaryotic signalling proteins that contain a conserved 85-residue module of unknown structure and biological function called the DIX domain7. Here we show that the DIX domain mediates targeting to actin stress fibres and cytoplasmic vesicles in vivo. Neighbouring interaction sites for actin and phospholipid are identified between two helices by nuclear magnetic resonance spectroscopy (NMR). Mutation of the actin-binding motif abolishes the cytoskeletal localization of Dvl, but enhances Wnt/beta-catenin signalling and axis induction in Xenopus. By contrast, mutation of the phospholipid interaction site disrupts vesicular association of Dvl, Dvl phosphorylation, and Wnt/beta-catenin pathway activation. We propose that partitioning of Dvl into cytoskeletal and vesicular pools by the DIX domain represents a point of divergence in Wnt signalling.