The Tetraspan Molecule Cd151, a Novel Constituent of Hemidesmosomes, Associates with the Integrin α6β4 and May Regulate the Spatial Organization of Hemidesmosomes

Abstract

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 α3β1 and α6β4 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 α3β1 and α6β4. In β4-deficient pyloric atresia associated with junctional epidermolysis bullosa (PA-JEB) keratinocytes, CD151 and α3β1 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 α3β1. Transient transfection studies of PA-JEB cells with β4 revealed that the integrin α6β4 becomes incorporated into the α3β1-CD151 clusters where it induces the formation of hemidesmosomes. As a result, the amount of α3β1 in the clusters diminishes and the protein becomes restricted to the peripheral focal adhesions. Furthermore, CD151 becomes predominantly associated with α6β4 in hemidesmosomes, whereas its codistribution with α3β1 in focal adhesions becomes partial. The localization of α6β4 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 β4 chimeras containing the extracellular and transmembrane domain of the IL-2 receptor and the cytoplasmic domain of β4, we found that for recruitment of CD151 into hemidesmosomes, the β4 subunit must be associated with α6, confirming that integrins associate with tetraspans via their α 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 α6β4. 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.

Pericellular activation of proMMP-7 (promatrilysin-1) through interaction with CD151

“…They include epithelial cells migrating over injured airway, 5 rat corneal squamous epithelium during wound healing after excimer keratectomy 42 and carcinoma cells in human cancer tissues such as colon adenocarcinomas, 14 infiltrative basal cell carcinomas and squamous cell carcinomas of the skin. 43 CD151 is localized to basal cells of stratified squamous cell epithelium 22,24,44,45 and the basolateral layer of enterocytes on villi. 22 Although information about localization in carcinoma cells is limited, our immunohistochemical and in situ zymographical studies on the human lung adenocarcinoma tissues have demonstrated colocalization of CD151 and MMP-7 on the carcinoma cell membranes and MMP-7 activity at the carcinoma cell nests.…”

“…27 All these data support the notion that CD151 is a positive effecter of metastasis. As CD151 is able to bind with various integrin species, especially a3b1 and a6b4 integrins, it has been suggested that CD151-integrin protein complexes may play a role in cell motility probably through modulation of the interaction between integrin and ECM such as laminin-5 24 and also activation of focal adhesion kinase. 46 However, these studies have completely lacked information about proteinases, which are also essential to tumor cell invasion and metastasis.…”

“…20,21 Other integrins (a5b1, a6b1, a6b4 and aIIbb3) are also known to interact with CD151 depending on cell types, [22][23][24][25] although information about the binding sites is not available. Since CD151 is located at the periphery of the thin invasive protrusions (invadopodia) of cancer cells and treatment of the cells with anti-CD151 monoclonal antibody inhibits metastasis, 26 this molecule is considered to play an important role in invasion and metastasis.…”

Les tétraspanines dans la physiopathologie de la peau

“…Dans la décennie qui suivit, la fonction dans la régu-lation de ces processus cellulaires d'autres tétraspa-nines, en interaction avec les intégrines, a été étudiée. Ainsi, par des expériences d'immunofluorescence, il a été montré que les protéines CD9, CD81 et CD151 sont fortement exprimées dans les kératinocytes en culture α3β1, α6β1 et α4β1 [5][6][7] pour réguler leurs fonctions, comme l'attestent des expériences de mutagenèse dirigée visant à introduire des mutations dans les domaines fonctionnels de CD151 [8][9][10]. Les tétraspanines possèdent une structure commune comprenant quatre régions hydrophobes hautement conservées, transmembranaires, flanquées de courtes séquences intracytoplasmiques N-et C-terminales et de deux boucles extracellulaires de tailles inégales (les domaines EC1 et EC2) (Figure 1).…”

CD151 in cancer progression and metastasis: a complex scenario

“…Master Regulator of Laminin-Binding Integrins CD151 forms stable, lateral complexes with laminin-binding integrins, ie, a3b1, a6b1 and a6b4 crucial in cancer cell migration and invasion [36][37][38] (Figure 1). Integrin subunits a3 and a6 directly interact with CD151 through the QRD [194][195][196] site at the extracellular loop of the protein.…”