Activation of ErbB2 receptor tyrosine kinase supports invasion of endothelial cells by Neisseria meningitidis

ErbB2 is a receptor tyrosine kinase belonging to the family of epidermal gr owth factor (EGF) receptors which is generally involved in cell differentia tion, proliferation, and tumor growth, and activated by heterodimerization with the other members of the family. We show here that type IV pilus-media ted adhesion of Neisseria meningitidis onto endothelial cells induces tyros yl phosphorylation and massive recruitment of ErbB2 underneath the bacteria l colonies. However, neither the phosphorylation status nor the cellular lo calization of the EGF receptors, ErbB3 or ErbB4, were affected in infected cells. ErbB2 phosphorylation induced by N. meningitidis provides docking si tes for the kinase src and leads to its subsequent activation. Specific inh ibition of either ErbB2 and/or src activity reduces bacterial internalizati on into endothelial cells without affecting bacteria-induced actin cytoskel eton reorganization or ErbB2 recruitment. Moreover, inhibition of both acti n polymerization and the ErbB2/src pathway totally prevents bacterial entry . Altogether, our results provide new insight into ErbB2 function by bringi ng evidence of a bacteria-induced ErbB2 clustering leading to src kinase ph osphorylation and activation. This pathway, in cooperation with the bacteri a-induced reorganization of the actin cytoskeleton, is required for the eff icient internalization of N. meningitidis into endothelial cells, an essent ial process enabling this-pathogen to cross host cell barriers.