Invasive
carcinoma cells use specialized actin polymerization-driven protrusions called invadopodia to degrade and possibly invade through the extracellular matrix (ECM) during
metastasis. Phosphorylation of the invadopodium
protein cortactin is a master switch that activates invadopodium maturation and function.
Cortactin was originally identified as a hyperphosphorylated
protein in v-Src-transformed cells, but the
kinase or
kinases that are directly responsible for
cortactin phosphorylation in invadopodia remain unknown. In this study, we provide evidence that the Abl-related nonreceptor
tyrosine kinase Arg mediates
epidermal growth factor (
EGF)-induced
cortactin phosphorylation, triggering actin polymerization in invadopodia, ECM degradation, and matrix proteolysis-dependent
tumor cell invasion. Both Src and Arg localize to invadopodia and are required for
EGF-induced actin polymerization. Notably, Arg overexpression in Src knockdown cells can partially rescue actin polymerization in invadopodia while Src overexpression cannot compensate for loss of Arg, arguing that Src indirectly regulates invadopodium maturation through Arg activation. Our findings suggest a novel mechanism by which an EGFR-Src-Arg-
cortactin pathway mediates functional maturation of invadopodia and
breast cancer cell invasion. Furthermore, they identify Arg as a novel mediator of invadopodia function and a candidate therapeutic target to inhibit
tumor invasion in vivo.