Laminin-5 inhibits human keratinocyte migration.
Laminin-5 (previously known as kalinin, epiligrin, and nicein) is an adhesive protein localized to the anchoring filaments within the lamina lucida space of the basement membrane zone lying between the epidermis and dermis of human skin. Anchoring filaments are structures within the lamina lucida and lie immediately beneath the hemidesmosomes of the overlying basal keratinocytes apposed to the basement membrane zone. Human keratinocytes synthesize and deposit laminin-5. Laminin-5 is present at the wound edge during reepithelialization. In this study, we demonstrate that laminin-5, a powerful matrix attachment factor for keratinocytes, inhibits human keratinocyte migration. We found that the inhibitory effect of laminin-5 on keratinocyte motility can be reversed by blocking the alpha3 integrin receptor. Laminin-5 inhibits keratinocyte motility driven by a collagen matrix in a concentration-dependent fashion. Using antisense oligonucleotides to the alpha3 chain of laminin-5 and an antibody that inhibits the cell binding function of secreted laminin-5, we demonstrated that the endogenous laminin-5 secreted by the keratinocyte also inhibits the keratinocyte's own migration on matrix. These findings explain the hypermotility that characterizes keratinocytes from patients who have forms of junctional epidermolysis bullosa associated with defects in one of the genes encoding for laminin-5 chains, resulting in low expression and/or functional inadequacy of laminin-5 in these patients. These studies also suggest that during reepithelialization of human skin wounds, the secreted laminin-5 stabilizes the migrating keratinocyte to establish the new basement membrane zone.
O'Toole
E A
EA
Department of Dermatology, Northwestern University, Chicago, Illinois 60611, USA.
Marinkovich
M P
MP
Hoeffler
W K
WK
Furthmayr
H
H
Woodley
D T
DT
D015703:Antigens, CD / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D003094:Collagen / Q000502:physiology; D003598:Cytoskeletal Proteins; D006801:Humans; D007158:Immunologic Techniques; D039422:Integrin alpha3; D016023:Integrins / Q000502:physiology; D015603:Keratinocytes / Q000166:cytology*; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D000097794:Kalinin; D000099149:Ezrin
D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D003094:Collagen; D003598:Cytoskeletal Proteins; D039422:Integrin alpha3; D016023:Integrins; D016376:Oligonucleotides, Antisense; D010750:Phosphoproteins; D000097794:Kalinin; D000099149:Ezrin