The focal adhesion kinase (FAK) is one of the first intracellular proteins to be activated when cells reorganize their cytoskeleton during adhesion, and changes in FAK distribution and activity mediate the shift of cancer cells to a migratory phenotype. Working with cultured pancreatic cancer cells, Sumitomo and coworkers have now identified a dual pathway by which the cell surface transmembrane proteinase neutral endopeptidase (NEP) regulates FAK phosphorylation and cell migration. Neuropeptides such as bombesin, acting through their receptors on the surface of responsive cells, stimulate the kinase c-Src to phosphorylate FAK. NEP is known to cleave these neuropeptides, and Sumitomo et al. confirm that overexpressing NEP blocks this pathway. Surprisingly, however, a mutant form of NEP that is inactive as a proteinase still blocks FAK phosphorylation and cell migration. The authors suggest that this residual activity depends on interactions between the cytoplasmic tail of NEP and 2 other cytoplasmic factors that otherwise bind and phosphorylate FAK. This c-Src independent pathway may account for other recent data indicating that catalytically inactive NEP retains some biological activity.
Journal of Clinical Investigation