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

Abstract

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 investigate if other molecular targets and pathways may be used by SARS-CoV-2. We investigated the possibility of 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 were examined upon cell treatment with the recombinant full spike 1 S protein or RBD. We demonstrate for the first time the activation of EGFR by the Spike 1 protein associated with the phosphorylation of the canonical Extracellular signal-regulated kinase1/2 (ERK1/2) and AKT kinases and an increase in survivin expression controlling the survival pathway. 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.

Targeting epidermal growth factor receptor signalling pathway: A promising therapeutic option for COVID‐19

“…Phosphorylation of key proteins in the downstream signalling pathways of EGFR reveals that EGFR is an essential component of the GFR signalling pathway upon SARS‐CoV‐2 infection 51 . Additionally, the S1 and RBD domains of the S protein of SARS‐CoV‐2 promote phosphorylation of EGFR, Akt and ERK1/2, as shown in A549 cells 19 . The EGFR also pulled down S protein of SARS‐CoV‐2 in HEK293T cells 20 .…”

“…51 Additionally, the S1 and RBD domains of the S protein of SARS-CoV-2 promote phosphorylation of EGFR, Akt and ERK1/2, as shown in A549 cells. 19 The EGFR also pulled down S protein of SARS-CoV-2 in HEK293T cells. 20 Meanwhile, S protein of SARS-CoV-2 activates MAPK through the ACE2-EGFR axis, which may facilitate the SARS-CoV-2 infection.…”

“…It reversibly binds to intracellular catalytic domain of EGFR, thus reversibly inhibiting EGFR phosphorylation and blocking its activation 99 . The SARS‐CoV‐2 infection induces EGFR expression 55 and promotes its phosphorylation through the Spike RBD and S1 domains 19 . EGFR activation impairs the antiviral activity of IFN by (1) negatively regulating suppressor of cytokine signalling (SOCS), which releases SOCS3‐mediated STAT3 antagonism, thus promotes virus replication, 122 and (2) impairing dimerisation of phosphorylated STAT1, which inhibits downstream interferon‐stimulated gene (ISG) transcription 23 .…”

“…The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of Coronavirus Disease 2019 (COVID- 19), represents one of the most demoralising natural tragedies of the 21st century. To date, 6,954,336 deaths have been reported worldwide from SARS-CoV-2 infection (source: https://covid19.who.…”

ACE2-EGFR-MAPK signaling contributes to SARS-CoV-2 infection

“…Proteomic and bioinformatics studies in Caco-2 and A549 cells expressing ACE2 (A549-ACE2 cells) that were infected with SARS-CoV-2 suggested increased EGFR signaling ( Klann et al, 2020 ; Stukalov et al, 2021 ). In addition to several omic studies, a recently published study described an increased EGFR phosphorylation in response to the full-length spike protein using A549 cells that are characterized by low levels of endogenous ACE2 ( Palakkott et al, 2023 ). Therefore, EGFR could be a promising candidate of a co-receptor to ACE2 for SARS-CoV-2 infection.…”