Co-expressing membrane-bound SP-STK and secreted SP-STP, and the low-molecular-weight SP-PTP play an important role in the complex multifactorial mechanism of GAS pathogenesis. However, the nature of early interactions of the secreted SP-STP and SP-PTP proteins with host cells is not fully understood. In the present study, the interaction of SP-STP and SP-PTP with the EGFR, a major surface tyrosine kinase receptor of human lung epithelial cells was examined to test the hypothesis that during early interaction SP-PTP, if not SP-STP dephosphorylates EGF-stimulated EGFR because of its ability to dephosphorylate phospho-Tyr residues. For this, the tyrosine kinase domain of EGFR was first subjected to dephosphorylation in the presence of increasing concentrations of SP-PTP and SP-STP using in vitro phosphorylation assays. None of these phosphatases dephosphorylated EGFR even at a high concentration. Instead, these phosphatases were, in fact, differentially phosphorylated in the presence of EGFR in a dose-dependent manner. Intriguingly, the innate phosphatase activities of both SP-STP and SP-PTP also increased substantially upon phosphorylation. LC-MS/MS-based proteomic analysis of EGFR-phosphorylated SP-STP and SP-PTP revealed several phosphosites. These sites included ten residues (5 Thr, 3 Ser, and 2 Tyr residues) within the SP-STP sequence and two Tyr residues within the SP-PTP sequence. The enzymatically-active secreted SP-STP enters the host cell nucleus by crossing two membrane barriers and causes host-cell apoptosis/pyroptosis. Thus, the enhanced de novo phosphatase activity of the secreted SP-STP and/or SP-PTP by the EGFR-mediated phosphorylation, occurring soon after the protein/GAS entry within the host cell provides a novel mechanism of GAS pathogenesis.