Skin cells stick to the basement membrane through hemidesmosome (HD)-localized integrin α6β4. Santoro et al. show that the MSP growth factor releases α6β4 from HDs and activates a migratory integrin, α3β1, instead. Binding of MSP to its tyrosine kinase receptor, Ron, led to phosphorylation of both Ron and α6β4, which introduced binding sites for 14-3-3 scaffolding proteins into both proteins. Through typical 14-3-3 dimerization, the phosphorylation thus creates a complex containing Ron and α6β4.
MSP-induced Ron/integrin complexes were seen at the leading edge of migrating cells and corresponded with loss of α6β4 from HDs. At the lamellipodia, phosphorylated α6β4 switched to a signaling role. Along with Ron, α6β4 activated transcription pathways that promote migration via production of matrix metalloproteases and additional MSP.
The venue change for α6β4 had a ripple effect on another integrin. Before MSP stimulation, α3β1, was stuck at cell–cell contacts, apparently in an inactive complex with Ron. But Ron exchanged partners upon phosphorylation, thus allowing α3β1 to move to focal contacts, where it interacts with actin fibers to promote migration. This may explain why application of MSP to open wounds shortened the healing time for mice. ▪