Hemidesmosome Formation Is Initiated by the {beta}4 Integrin Subunit, Requires Complex Formation of {beta}4 and HD1/Plectin, and Involves a Direct Interaction between {beta}4 and the Bullous Pemphigoid Antigen 180

doi:10.1083/jcb.142.1.271

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© The Rockefeller University Press, 0021-9525/1998//271 $5.00
The Journal of Cell Biology, Volume 142, Number 1, , 1998 271-284

Articles

Hemidesmosome Formation Is Initiated by the β4 Integrin Subunit, Requires Complex Formation of β4 and HD1/Plectin, and Involves a Direct Interaction between β4 and the Bullous Pemphigoid Antigen 180

Roel Q.J. Schaapveld^*, Luca Borradori^*^,, Dirk Geerts^*, Manuel R. van Leusden^*, Ingrid Kuikman^*, Mirjam G. Nievers^*, Carien M. Niessen^*, Renske D.M. Steenbergen, Peter J.F. Snijders, and Arnoud Sonnenberg^*

^* Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; Department of Dermatology, University of Geneva, CH-1211 Geneva, Switzerland; and Department of Pathology, University Hospital Vrije Universiteit, 1081 HV Amsterdam, The Netherlands

Hemidesmosomes (HDs) are stable anchoring structures that mediatethe link between the intermediate filament cytoskeleton andthe cell substratum. We investigated the contribution of varioussegments of the β4 integrin cytoplasmic domain in the formationof HDs in transient transfection studies using immortalizedkeratinocytes derived from an epidermolysis bullosa patient deficient in β4 expression. We found that the expression of wild-type β4 restored the ability of the β4-deficient cells to form HDs and that distinct domains in the NH₂- andCOOH-terminal regions of the β4 cytoplasmic domain arerequired for the localization of HD1/plectin and the bullouspemphigoid antigens 180 (BP180) and 230 (BP230) in these HDs.The tyrosine activation motif located in the connecting segment(CS) of the β4 cytoplasmic domain was dispensable for HDformation, although it may be involved in the efficient localizationof BP180. Using the yeast two-hybrid system, we could demonstrate a direct interaction between β4 and BP180 which involves sequences within the COOH-terminal part of the CS and thethird fibronectin type III (FNIII) repeat. Immunoprecipitationstudies using COS-7 cells transfected with cDNAs for ${alpha}$ 6 andβ4 and a mutant BP180 which lacks the collagenous extracellulardomain confirmed the interaction of β4 with BP180. Nevertheless,β4 mutants which contained the BP180-binding region, butlacked sequences required for the localization of HD1/plectin, failed to localize BP180 in HDs. Additional yeast two- hybridassays indicated that the 85 COOH-terminal residues of β4can interact with the first NH₂-terminal pair of FNIII repeatsand the CS, suggesting that the cytoplasmic domain of β4is folded back upon itself. Unfolding of the cytoplasmic domainmay be part of a mechanism by which the interaction of β4with other hemidesmosomal components, e.g., BP180, is regulated.

Key Words: hemidesmosome assembly • PA-JEB keratinocytes • protein–protein interaction • bullous pemphigoid antigens • ${alpha}$ 6β4 integrin

Abbreviations used in this paper: AD, activation domain; BD, binding domain; BP180, bullous pemphigoid antigen 180; BP230, bullous pemphigoid antigen 230; CS, connecting segment; FNIII, type III fibronectin repeat; GAL4, galactose metabolism regulatory gene 4; HDs, hemidesmosomes; IF, intermediate filament; NHK, normal human foreskin keratinocytes; PA-JEB, junctional epidermolysis bullosa associated with pyloric atresia; SC, synthetic complete medium; TAM, tyrosine activation motif.

R.Q.J. Schaapveld, Luca Borradori, and D. Geerts contributedequally to this work.

Carien M. Niessen's present address is Cellular Biochemistry& Biophysics Program, Memorial Sloan-Kettering Cancer Center,1275 York Avenue, New York 10021.

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