J. Cell Biol., Volume 141, Number 1, April 6, 1998 209-225

Linking Integrin ₆₄-based Cell Adhesion to the Intermediate Filament Cytoskeleton: Direct Interaction between the ₄ Subunit and Plectin at Multiple Molecular Sites

Günther A. Rezniczek, José M. de Pereda, Siegfried Reipert, and Gerhard Wiche

Institute of Biochemistry and Molecular Cell Biology, Vienna Biocenter, 1030 Vienna, Austria

Recent studies with patients suffering from epidermolysis bullosa simplex associated with muscular dystrophy and the targeted gene disruption in mice suggested that plectin, a versatile cytoskeletal linker and intermediate filament-binding protein, may play an essential role in hemidesmosome integrity and stabilization. To define plectin's interactions with hemidesmosomal proteins on the molecular level, we studied its interaction with the uniquely long cytoplasmic tail domain of the ₄ subunit of the basement membrane laminin receptor integrin ₆₄ that has been implicated in connecting the transmembrane integrin complex with hemidesmosome-anchored cytokeratin filaments. In vitro binding and in vivo cotransfection assays, using recombinant mutant forms of both proteins, revealed their direct interaction via multiple molecular domains. Furthermore, we show in vitro self-interaction of integrin ₄ cytoplasmic domains, as well as disruption of intermediate filament network arrays and dislocation of hemidesmosome-associated endogenous plectin upon ectopic overexpression of this domain in PtK2 and/or 804G cells. The close association of plectin molecules with hemidesmosomal structures and their apparent random orientation was indicated by gold immunoelectron microscopy using domain-specific antibodies. Our data support a model in which plectin stabilizes hemidesmosomes, via directly interlinking integrin ₄ subunits and cytokeratin filaments.

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