The Phosphorylation and Distribution of Cortactin Downstream of Integrin α9ß1 Affects Cancer Cell Behaviour.

ABSTRACT

Integrins, a family of heterodimeric adhesion receptors are implicated in cell migration, development and cancer progression. They can adopt conformations that reflect their activation states and thereby impact adhesion strength and migration. Integrins in an intermediate activation state may be optimal for migration and we have shown previously that fully activated integrin α9ß1 corresponds with less migratory behaviour in melanoma cells. Here, we aimed to identify components associated with the activation status of α9ß1. Using cancer cell lines with naturally occuring high levels of this integrin, activation by α9ß1-specific ligands led to upregulation of fibronectin matrix assembly and tyrosine phosphorylation of cortactin on tyrosine 470 (Y470). Specifically, cortactin phosphorylated on Y470, but not Y421, redistributed together with α9ß1 to focal adhesions where active ß1 integrin also localises, upon integrin activation. This was commensurate with reduced migration. The localisation and phosphorylation of cortactin Y470 was regulated by Yes kinase and PTEN phosphatase. Cortactin levels influenced fibronectin matrix assembly and active ß1 integrin on the cell surface, being inversely correlated with migratory behaviour. This study underlines the complex interplay between cortactin and α9ß1 integrin that regulates cell-extracellular matrix interactions.