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

Abstract

ObjectivesThe 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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 .…”

“…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 .…”

Oncogenesis and autoimmunity as a result of mRNA COVID-19 vaccination

“…On top of this, the spike protein potentiates the signalling of the epidermal growth factor receptor (EGFR) [177]. Persistent activation of STAT3 is a common feature of the tumor microenvironment and a major contributor to the inflammatory state [178].…”

“…Persistent activation of STAT3 is a common feature of the tumor microenvironment and a major contributor to the inflammatory state [178]. An intense activation of STAT3 can result from 1) an aberrant expression of IL-6 and subsequent stimulation of the IL-6 receptor [179], and 2) an intense activation of EGFR signalling as imposed by the spike protein [177]. These molecular events, illustrated in Figure 4, when they are happening concurrently, have the potential to bypass the inhibitory checkpoint of negative regulator suppressor of cytokine signalling 3 (SOCS3).…”

“…Moreover, the abnormally elevated expression of IL-6 and JAK/STAT3 signalling are pro-tumorigenic and enhance the differentiation of Th17 cells [179,180]. [174,176] and (B) the direct stimulation of EGFR by spike protein and synergy with IL-6R [177]. The final effect between IL-6R, EGFR and IL-6 would be the continuous production of STAT3, although the SOCS3 will still be present [179].…”