title: Type XVII collagen regulates lamellipod stability, cell motility, and signaling to Rac1 by targeting bullous pemphigoid antigen 1e to alpha6beta4 integrin.
abstract: 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.
authors.affiliation: Department of Cell and Molecular Biology, The Feinberg School of Medicine at Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hamill
authors.forename: Susan B
authors.initials: SB
authors.lastname: Hopkinson
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Jonkman
authors.forename: Jonathan C R
authors.initials: JC
authors.lastname: Jones
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D043170:Collagen Type XVIII / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D000071821:Dystonin; D055785:Gene Knockdown Techniques; D006801:Humans; D039161:Integrin alpha6beta4 / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D043170:Collagen Type XVIII; D003598:Cytoskeletal Proteins; C486268:DST protein, human; D000071821:Dystonin; D039161:Integrin alpha6beta4; D009419:Nerve Tissue Proteins; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein