Rac1 activity, polarity, lamellipodial dynamics, and directed motility are defective in keratinocytes exhibiting deficiency in β4
integrin or knockdown of the plakin
protein Bullous Pemphigoid Antigen 1e (BPAG1e). The activity of Rac, formation of stable lamellipodia, and directed migration are restored in β4
integrin-deficient cells by inducing expression of a truncated form of β4
integrin, which lacks binding sites for BPAG1e and
plectin. In these same cells, BPAG1e, the truncated β4
integrin, and
type XVII collagen (Col XVII), a transmembrane BPAG1e-binding
protein, but not
plectin, colocalize along the substratum-attached surface. This finding suggested to us that Col XVII mediates the association of BPAG1e and α6β4
integrin containing the truncated β4 subunit and supports directed migration. To test these possibilities, we knocked down Col XVII expression in keratinocytes expressing both full-length and truncated β4
integrin proteins. Col XVII-knockdown keratinocytes exhibit a loss in BPAG1e-α6β4
integrin interaction, a reduction in lamellipodial stability, an impairment in directional motility, and a decrease in Rac1 activity. These defects are rescued by a mutant Col XVII
protein truncated at its carboxyl terminus. In summary, our results suggest that in motile cells Col XVII recruits BPAG1e to α6β4
integrin and is necessary for activation of signaling pathways, motile behavior, and lamellipodial stability.