Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, adheres to and invades genital epithelial cells. This study investigates host components that are used by the bacteria for their entry into epithelial cells. I found that the interaction of gonococci with the surface of HEC-1-B, a human endometrial carcinoma, and ME180, a human cervical epidermoid carcinoma, caused redistribution of both epidermal growth factor receptor (EGFR) and ErbB2, a related family member. Both EGFR and ErbB2 were translocated from the basolateral to the apical membrane in polarized HEC-1-B cells and concentrated under the microcolonies. Gonococcal infection increased EGFR and ErbB2 phosphorylation, indicating activation of the receptors. Kinase inhibitors of EGFR and ErbB2 inhibited and enhanced bacterial invasion, respectively, but had no effect on gonococcal adherence or the recruitment of EGFR and ErbB2 to the microcolonies. Gonococcal inoculation upregulated the transcription levels and matrix metalloproteinases (MMP)-mediated surface shedding of ligands of EGFR. Inhibition of the surface shedding of EGFR ligands by an MMP inhibitor and by heparin wash reduced gonococcal invasion without altering their adherence. N. gonorrhoeae induced the activation of the MAP Kinase ERK, PI3K/AKT and PLCγ signaling pathways in an EGFR tyrosine kinase-dependent manner. Blocking Ca2+ flux, the downstream pathway of PLCγ but not ERK and PI3K by inhibitors reduced gonococcal invasion. These data indicate that N. gonorrhoeae utilizes host signaling pathways to drive its invasion. The bacteria modulates host signaling by recruiting and activating EGFR and ErbB2. N. gonorrhoeae induces EGFR activation by increasing the expression and MMP-mediated shedding of EGFR ligands.