A model for how cortactin phosphorylation regulates invadopodium maturation and tumor cell invasion through a pH-dependent pathway. Cortactin tyrosine phosphorylation regulates the interaction between NHE1 and cortactin. NHE1 alkalinizes the local invadopodia pH and induces the release of cortactin-bound cofilin. Released cofilin activates barbed end generation at the invadopodia and is deactivated by either phosphorylation or by rebinding cortactin after a decrease in local pH.