β4 INTEGRIN REGULATES THE MIGRATION OF ALVEOLAR EPITHELIAL CELLS

Zachary Tyler Colburn

Cell migration regulates crucial biological processes including development, wound healing, and metastasis. It requires the coordination of signaling and cytoskeletal rearrangements as well as the interactions between extracellular matrix ligands and matrix receptor proteins. Integrins are transmembrane matrix receptor proteins that link the extracellular matrix to the cytoskeleton. They form heterodimers composed of one α and one β integrin subunit and cluster together to form large adhesion complexes. Most integrins are found in matrix adhesion structures termed focal adhesions. However, the integrin heterodimer α6β4 assembles into distinct adhesion structures. These include hemidesmosomes, which mediate attachment of the epidermis to the dermis, as well as punctate arrays found in some epithelial and endothelial cells. Interestingly, the role of β4 integrin in cell migration is controversial, with studies reporting contradictory functions, which may be the result of cell or tissue specific differences. We investigated the functions and regulatory mechanisms of β4 integrin in the migration of lung epithelial cells. In the lung epithelial cell line A549 α6β4 integrin localizes in punctate arrays predominantly in lamellipodia. Surprisingly, in β4 integrin knockdown cells the distribution of α6 integrin is unperturbed. In such cells, α6 integrin instead pairs with β1 integrin. Since β1 integrin typically localizes to focal adhesions this represents a possible method of cross talk between distinct types of adhesion structures. In addition, β4 integrin knockdown cells exhibit reductions in Rac1 activity and directed migration, which can be restored following infection with adenoviruses encoding either β4 integrin or constitutively active Rac1. Interestingly, we have found that β4 integrin promotes the leader cell phenotype since its expression in the leading edge of wounded epithelial sheets is sufficient to drive wound closure We have also determined that β4 integrin associates with vimentin filaments in these cells. Moreover, vimentin knockdown cells exhibit reduced Rac1 activity and cell migration. In summary, these results indicate that β4 integrin is a positive regulator of both directed single cell migration and collective cell migration in lung epithelial cells. It does so by regulating signaling which depends on its association with vimentin intermediate filaments.

β4 INTEGRIN REGULATES THE MIGRATION OF ALVEOLAR EPITHELIAL CELLS

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