The SARS-CoV-2 Spike Protein Activates the Epidermal Growth Factor Receptor-Mediated Signaling

Objectives The coronavirus disease-19 (COVID-19) pandemic is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the molecular and cellular levels, the SARS-Cov-2 uses its envelope glycoprotein, the spike S protein, to infect the target cells in the lungs via binding with their transmembrane receptor, the angiotensin-converting enzyme 2 (ACE2). Here, we wanted to invesitgate if other molecular targets and pathways may be used by SARS-Cov-2. Methods We investigated the possibility for the spike 1 S protein and its receptor-binding domain (RBD) to target the epidermal growth factor receptor (EGFR) and its downstream signaling pathway in vitro using the lung cancer cell line (A549 cells). Protein expression and phosphorylation was examined upon cell treatment with the recombinant full spike 1 S protein or RBD. Results We demonstrate for the first time the activation of EGFR by the Spike 1 protein associated with the phosphorylation of the canonical ERK1/2 and AKT kinases and an increase of survivin expression controlling the survival pathway. Conclusions Our study suggests the putative implication of EGFR and its related signaling pathways in SARS-CoV-2 infectivity and Covid-19 pathology. This may open new perspectives in the treatment of Covid-19 patients by targeting EGFR. ### Competing Interest Statement The authors have declared no competing interest.