Caswell et al. report how the altered behavior of integrins can prompt metastatic movement in tumor cells.
On 2D surfaces, cells may migrate randomly, or be strongly unidirectional. Integrins, which link the cell to the extracellular matrix, are known to influence the mode of migration, but exactly how has been unclear. Recent work has suggested that an integrin called α5β1 drives random movement, while an integrin called αvβ3 has been associated with unidirectional migration—the balance of activity between the two determining the type of movement. To further explore the contribution of α5β1 to random migration, the authors thus blocked αvβ3.
The treated cells changed their mode of migration from unidirectional to random, and their ability to invade 3D gels increased. The changed behavior correlated with an increase in trafficking of α5β1 from intracellular compartments to anterior membrane protrusions. But this increase in trafficking did not significantly alter α5β1's contribution to cell adhesion—the ease with which cells were dislodged from a spinning disk increased as the amount of αvβ3 was reduced, but was not correlated with any change in α5β1. This suggested that the cells' increased invasive ability was due to alteration in some other property. That property turned out to be activation of a proinvasive pathway headed by a kinase called Akt.
In αvβ3-blocked cells, α5β1 became associated with epidermal growth factor receptor 1 (EGFR1), which increased EGFR1's abundance at the membrane protrusions, as well as its autophosphorylation. Because EGFR1 is an activator of the Akt pathway, hey presto, the cells took on some new moves.