Abstract
The hemidesmosomal transmembrane component collagen XVII (ColXVII) plays an important role in the anchorage of the epidermis to the underlying basement membrane. However, this adhesion protein seems to be also involved in the regulation of keratinocyte migration, since its expression in these cells is strongly elevated during reepithelialization of acute wounds and in the invasive front of squamous cell carcinoma, while its absence in ColXVII-deficient keratinocytes leads to altered cell motility. Using a genetic model of murine Col17a1− /− keratinocytes we elucidated ColXVII mediated signaling pathways in cell adhesion and migration. Col17a1− /− keratinocytes exhibited increased spreading on laminin 332 and accelerated, but less directed cell motility. These effects were accompanied by increased expression of the integrin subunits β4 and β1. The migratory phenotype, as evidenced by formation of multiple unstable lamellipodia, was associated with enhanced phosphoinositide 3-kinase (PI3K) activity. Dissection of the signaling pathway uncovered enhanced phosphorylation of the β4 integrin subunit and the focal adhesion kinase (FAK) as activators of PI3K. This resulted in elevated Rac1 activity as a downstream consequence. These results provide mechanistic evidence that ColXVII coordinates keratinocyte adhesion and directed motility by interfering integrin dependent PI3K activation and by stabilizing lamellipodia at the leading edge of reepithelializing wounds and in invasive squamous cell carcinoma.
Highlights
Classical type I hemidesmosomes (HDs) are cell-matrix junctions that provide tissue integrity by anchoring epithelial cells to the basement membrane. They contain a number of interacting components: the transmembrane proteins collagen XVII (ColXVII) and a6b4 integrin, which bind to laminin 332 (LN332) in the basement membrane, and the intracellular linker proteins bullous pemphigoid antigen 230 (BP230) and plectin, which bind to the intermediate filament cytoskeleton
The role of the epidermal adhesion molecule ColXVII in cell migration was initially described in primary keratinocytes derived from junctional epidermolysis bullosa (JEB) patients, demonstrating that low abundance or complete absence of ColXVII on the cell surface resulted in increased, but nondirected motility [6,7]
Viral knockdown of ColXVII in epithelial cell lines by siRNA or shRNA approaches disclosed a positive correlation between ColXVII expression and migration speed [33,34]
Summary
Classical type I hemidesmosomes (HDs) are cell-matrix junctions that provide tissue integrity by anchoring epithelial cells to the basement membrane. They contain a number of interacting components: the transmembrane proteins collagen XVII (ColXVII) and a6b4 integrin, which bind to laminin 332 (LN332) in the basement membrane, and the intracellular linker proteins bullous pemphigoid antigen 230 (BP230) and plectin, which bind to the intermediate filament cytoskeleton. Of HDs is required during biological and pathological processes such as tissue repair, tumor cell migration and invasion. These processes are characterized by a balanced combination of cell-matrix attachment and detachment, implicating that HD components are involved in the regulation of cell motility [2,3]. Efficient migration requires an optimum of adhesion strength; too weak adhesion is inadequate for cell traction, whereas too strong adhesion is incompatible with migration [4,5]
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