title: Integrin beta4 regulates migratory behavior of keratinocytes by determining laminin-332 organization.
abstract: Whether alpha6beta4 integrin regulates migration remains controversial. beta4 integrin-deficient (JEB) keratinocytes display aberrant migration in that they move in circles, a behavior that mirrors the circular arrays of laminin (LM)-332 in their matrix. In contrast, wild-type keratinocytes and JEB keratinocytes, induced to express beta4 integrin, assemble laminin-332 in linear tracks over which they migrate. Moreover, laminin-332-dependent migration of JEB keratinocytes along linear tracks is restored when cells are plated on wild-type keratinocyte matrix, whereas wild-type keratinocytes show rotation over circular arrays of laminn-332 in JEB keratinocyte matrix. The activities of Rac1 and the actin cytoskeleton-severing protein cofilin are low in JEB keratinocytes compared with wild-type cells but are rescued following expression of wild-type beta4 integrin in JEB cells. Additionally, in wild-type keratinocytes Rac1 is complexed with alpha6beta4 integrin. Moreover, Rac1 or cofilin inactivation induces wild-type keratinocytes to move in circles over rings of laminin-332 in their matrix. Together these data indicate that laminin-332 matrix organization is determined by the alpha6beta4 integrin/actin cytoskeleton via Rac1/cofilin signaling. Furthermore, our results imply that the organizational state of laminin-332 is a key determinant of the motility behavior of keratinocytes, an essential element of skin wound healing and the successful invasion of epidermal-derived tumor cells.
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Bernd U
authors.initials: BU
authors.lastname: Sehgal
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: DeBiase
authors.forename: Sumio
authors.initials: S
authors.lastname: Matzno
authors.forename: Teng-Leong
authors.initials: TL
authors.lastname: Chew
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Claiborne
authors.forename: Susan B
authors.initials: SB
authors.lastname: Hopkinson
authors.forename: Alan
authors.initials: A
authors.lastname: Russell
authors.forename: M Peter
authors.initials: MP
authors.lastname: Marinkovich
authors.forename: Jonathan C R
authors.initials: JC
authors.lastname: Jones
mesh_terms: D002465:Cell Movement / Q000502:physiology*; D051338:Cofilin 1 / Q000378:metabolism; D016109:Epidermolysis Bullosa, Junctional; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D051338:Cofilin 1; D039161:Integrin alpha6beta4; D007797:Laminin; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein