Recruitment of Dbl by Ezrin and Dystroglycan Drives Membrane Proximal Cdc42 Activation and Filopodia Formation

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2007-02, Vol.6 (3), p.353-363
• Main Authors: Batchelor, Clare L., Higginson, Jen R., Chen, Yun-Ju, Vanni, Cristina, Eva, Alessandra, Winder, Steve J.
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Animals; Binding; Binding Sites; Biology; Bioscience; Calcium; Cancer; cdc42 GTP-Binding Protein - genetics; cdc42 GTP-Binding Protein - metabolism; Cell; Cell Line; Cercopithecus aethiops; COS Cells; Cycle; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Dystroglycans - genetics; Dystroglycans - metabolism; Fluorescent Antibody Technique; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - metabolism; Immunoblotting; Immunoprecipitation; Landes; Mice; Mutation; Organogenesis; Protein Binding; Proteins; Pseudopodia - metabolism; Rats; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; rho GTP-Binding Proteins - metabolism; RNA Interference; Swiss 3T3 Cells
• ISSN: 1538-4101; 1551-4005
• DOI: 10.4161/cc.6.3.3819

Dystroglycan is an essential laminin binding cell adhesion molecule which is also an adaptor for several SH2 domain-containing signalling 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 filopodial. 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-localisation of Cdc42 and dystroglycan at the tips of dynamic filopodia.