CELL MIGRATION ß Integrins Dictate Mode of Movement

Integrins are dimeric molecules consisting of one subunit and one ß subunit. The composition of integrins dictates ligand binding and cellular response (migration, attachment, and cell survival) to their interaction with the substrate or extracellular matrix. Danen et al. used cells engineered to express either ß1 or ß3 and showed that it is the presence of the ß1 or ß3 subunit that dictates whether cells move randomly or in a directed fashion. Epithelial GE11 cells engineered to express vß3 (GEß3) or 5ß1 (GEß1) cells were tested in a wounding assay, or motility was monitored in sparsely seeded cultures on fibronectin. Although both cells exhibited motile behavior that was greater than the ß1-deficient parent GE11 line, the GEß3 cells moved as a sheet in a directed fashion, and the GEß1 cells moved randomly in all directions. GEß3 cells, but not GEß1 cells, exhibited remodeling of the actin cytoskeleton and the formation of lamellipodia either during cell migration or in response to various treatments that trigger cell ruffling and actin cytoskeleton reorganization (epidermal growth factor, hepatocyte growth factor, or phorbol ester). In GEß1 cells, cofilin (an actin regulator required for directed movement) was inhibited (phosphorylated), and expression of a phosphomimetic mutant cofilin inhibited lamellipodia formation in the GEß3 cells. Use of mutants of the guanosine triphosphatases RhoA and Rac1 indicated that RhoA activity was responsible for the increased phosphorylation of cofilin in the GEß1 cells and the highly dynamic nature of cell adhesion sites in these cells. Furthermore, although expression of activated Rac1 allowed GEß1 cells to appear more GEß3-like in morphology, it did not decrease cofilin phosphorylation and did not allow the cells to undergo directed movement. Thus, it appears that the efficiency of coupling of ß integrins to RhoA and the degree of cofilin activation appear to generate different types of cell movement.

E. H. J. Danen, J. van Rheenen, W. Franken, S. Huveneers, P. Sonneveld, K. Jalink, A. Sonnenberg, Integrins control motile strategy through a Rho-cofilin pathway. J. Cell Biol. 169, 515-526 (2005). [Abstract] [Full Text]

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