ACKnoWLEdgEmEntSWe are grateful to the following for supplies of antisera or plasmids, Art Alberts, P. Aspenstrom, Louise Anderson, Francis Barr and Sam Crouch, and to Kathryn Ayscough for comments on the manuscript. The work was funded by an MRC Career Establishment Grant to S.J.W., J.R.H. was in receipt of a BBSRC studentship and A.E. was supported by grants from the Italian Association for Cancer Research, Compagnia S. Paolo, and Ministero della Salute. ABStRACtDystroglycan is an essential laminin binding cell adhesion molecule, which is also an adaptor for several SH2 domain-containing signaling molecules and as a scaffold for the ERK-MAP kinase cascade. Loss of dystroglycan function is implicated in muscular dystrophies and the aetiology of epithelial cancers. We have previously demonstrated a role for dystroglycan and ezrin in the formation of filopodia structures. Here we demonstrate the existence of a dystroglycan:ezrin:Dbl complex that is targeted to the membrane by dystroglycan where it drives local Cdc42 activation and the formation of filopodia. Deletion of an ezrin binding site in dystroglycan prevented the association with ezrin and Dbl and the formation of filopodia. Furthermore, expression of the dystroglycan cytoplasmic domain alone had a dominant-negative effect on filopodia formation and Cdc42 activation by sequestering ezrin and Dbl away from the membrane. Depletion of dystroglycan inhibited Cdc42-induced filopodia formation. For the first time we also demonstrate co-localization of Cdc42 and dystroglycan at the tips of dynamic filopodia.

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Dystroglycan, a ubiquitous membrane-spanning cell adhesion molecule, is a crucial link between the actin cytoskeleton and the extracellular matrix. With a wide expression pattern and multiple interacting proteins, not only is dystroglycan now thought to be important as a structural molecule but also new research has suggested that it has a role in cell signalling, cytoskeleton reorganization and as a potential tumour suppressor.

Dystroglycan, a ubiquitous membrane-spanning cell adhesion molecule, is a crucial link between the actin cytoskeleton and the extracellular matrix. With a wide expression pattern and multiple interacting proteins, not only is dystroglycan now thought to be important as a structural molecule but also new research has suggested that it has a role in cell signalling, cytoskeleton reorganization and as a potential tumour suppressor.