Growth factors propel cell migration in vitro and metastasis in vivo, but the underlying mechanisms are incompletely understood. Employing EGF-stimulated mammary cells we linked the lipid phosphatase synaptojanin 2 (SYNJ2) to MAPK-dependent invasive phenotype, as well as demonstrate high SYNJ2 expression in aggressive human breast tumors and low survival rates. High expression of SYNJ2 in benign or tumorigenic mammary epithelial cells, results with stabilization of EGFR and sustained MAPK signaling.In addition, high expression in mammary and other tumors might relate to repression of microRNA-31, a metastasis suppressor able to restrain SYNJ2 expression.
Knockdown of SYNJ2 in mammary tumor cells attenuates MAPK signaling and almost abolished their intravasation into blood vessels, metastasis to lymph nodes and lung colonization. When tested in vitro, SYNJ2-depleted cells exhibited deformed focal adhesions and disappearance of invadopodia. These effects correlated with derailed trafficking of both EGFR and beta-1 integrin, as well as defective delivery of metalloproteinases to invadopodia. We conclude that recycling of active EGFRs promotes invadopodia formation by locally dephosphorylating phosphatidyl-inositol 3,4,5-trisphosphate, PI(3,4,5)P3, into PI(3,4)P2, thereby priming invadopodia formation. Because of their emerging roles in metastasis, dephosphorylation of phosphoinositides and vesicular trafficking might serve as targets for cancer therapy.