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Original Article |
6ß4 and May Regulate the Spatial Organization of Hemidesmosomes
Correspondence to: Arnoud Sonnenberg, The Netherlands Cancer Institute, Division of Cell Biology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Tel:(31) 20-5121942 Fax:(31) 20-5121944 E-mail:asonn{at}nki.nl.
CD151 is a cell surface protein that belongs to the tetraspan superfamily. It associates with other tetraspan molecules and certain integrins to form large complexes at the cell surface. CD151 is expressed by a variety of epithelia and mesenchymal cells. We demonstrate here that in human skin CD151 is codistributed with 3ß1 and 6ß4 at the basolateral surface of basal keratinocytes. Immunoelectron microscopy showed that CD151 is concentrated in hemidesmosomes. By immunoprecipitation from transfected K562 cells, we established that CD151 associates with 3ß1 and 6ß4. In ß4-deficient pyloric atresia associated with junctional epidermolysis bullosa (PA-JEB) keratinocytes, CD151 and 3ß1 are clustered together at the basal cell surface in association with patches of laminin-5. Focal adhesions are present at the periphery of these clusters, connected with actin filaments, and they contain both CD151 and 3ß1. Transient transfection studies of PA-JEB cells with ß4 revealed that the integrin 6ß4 becomes incorporated into the 3ß1-CD151 clusters where it induces the formation of hemidesmosomes. As a result, the amount of 3ß1 in the clusters diminishes and the protein becomes restricted to the peripheral focal adhesions. Furthermore, CD151 becomes predominantly associated with 6ß4 in hemidesmosomes, whereas its codistribution with 3ß1 in focal adhesions becomes partial. The localization of 6ß4 in the pre-hemidesmosomal clusters is accompanied by a strong upregulation of CD151, which is at least partly due to increased cell surface expression. Using ß4 chimeras containing the extracellular and transmembrane domain of the IL-2 receptor and the cytoplasmic domain of ß4, we found that for recruitment of CD151 into hemidesmosomes, the ß4 subunit must be associated with 6, confirming that integrins associate with tetraspans via their subunits. CD151 is the only tetraspan identified in hemidesmosomal structures. Others, such as CD9 and CD81, remain diffusely distributed at the cell surface.
In conclusion, we show that CD151 is a major component of (pre)-hemidesmosomal structures and that its recruitment into hemidesmosomes is regulated by the integrin 6ß4. We suggest that CD151 plays a role in the formation and stability of hemidesmosomes by providing a framework for the spatial organization of the different hemidesmosomal components.
Key Words:
integrin 6ß4, tetraspan CD151, hemidesmosome, focal adhesion, cross-talk
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