PKC phosphorylates VASP to mediate chemotaxis in breast cancer cells

Breast carcinoma (BC) is one of the most common malignant cancers in females, and metastasis remains the leading cause of death in these patients. Chemotaxis plays an important role in cancer cell metastasis and the mechanism of breast cancer chemotaxis has become a central issue in contemporary research. PKC zeta, a member of the atypical PKC family, has been reported to be an essential component of the EGF-stimulated chemotactic signaling pathway. However, the molecular mechanism through which PKC zeta regulates chemotaxis remains unclear. Here, we used a proteomic approach to identify PKC zeta-interacting proteins in breast cancer cells and identified VASP as a potential binding partner. Intriguingly, stimulation with EGF enhanced this interaction and induced the translocalization of PKC zeta and VASP to the cell membrane. Further experiments showed that PKC zeta catalyzes the phosphorylation of VASP at Ser157, which is critical for the biological function of VASP in regulating chemotaxis and actin polymerization in breast cancer cells. Furthermore, in PKC zeta knockdown BC cells, the enrichment of VASP at the leading edge was reduced, and its interaction with profilin1 was attenuated, thereby reducing the chemotaxis and overall motility of breast cancer cells after EGF treatment. In functional assays, PKC zeta promoted chemotaxis and motility of BC cells through VASP. Our findings demonstrate that PKC zeta, a new kinase of VASP, plays an important role in promoting breast cancer metastasis and provides a theoretical basis for expanding new approaches to tumor biotherapy.