Type XVII Collagen Regulates Lamellipod Stability, Cell Motility, and Signaling to Rac1 by Targeting Bullous Pemphigoid Antigen 1e to alpha 6 beta 4 Integrin

Rac1 activity, polarity, lamellipodial dynamics, and directed motility are defective in keratinocytes exhibiting deficiency in beta 4 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 beta 4 integrin-deficient cells by inducing expression of a truncated form of beta 4 integrin, which lacks binding sites for BPAG1e and plectin. In these same cells, BPAG1e, the truncated beta 4 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 alpha 6 beta 4 integrin containing the truncated beta 4 subunit and supports directed migration. To test these possibilities, we knocked down Col XVII expression in keratinocytes expressing both full-length and truncated beta 4 integrin proteins. Col XVII-knockdown keratinocytes exhibit a loss in BPAG1e-alpha 6 beta 4 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 alpha 6 beta 4 integrin and is necessary for activation of signaling pathways, motile behavior, and lamellipodial stability.