Pyrroloquinoline quinone stimulates epithelial cell proliferation by activating epidermal growth factor receptor through redox cycling

Abstract

Pyrroloquinoline quinone (PQQ), a redox cofactor for bacterial dehydrogenases, has been implicated to be an important nutrient in mammals functioning as a potent growth factor. However, the underlying molecular mechanisms have not been elucidated. The present study revealed that PQQ induces the activation (tyrosine autophosphorylation) of epidermal growth factor receptor (EGFR) and its downstream signaling in a ligand-independent manner, leading to increased cellular proliferation in an epithelial cell line A431. PQQ inhibited protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the EGFR signaling by tyrosine dephosphorylation, to oxidatively modify the catalytic cysteine through its redox cycling activity to generate H2O2. PQQ-inducible intracellular ROS production and EGFR activation were significantly suppressed by the pre-treatment with antioxidants. The intracellular redox state regulates the EGFR signaling through the redox-sensitive catalytic cysteine of PTP1B and modulates cell proliferation. Our data suggest that PQQ may stimulate epithelial cell proliferation by activating EGFR by oxidation and subsequent inactivation of PTP1B via its redox cycling. Our results provide novel insight into the mechanisms by which PQQ may function as a growth factor to contribute to mammalian growth.