The SARS-CoV-2 Spike Protein Activates the Epidermal Growth Factor Receptor-Mediated Signaling
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Culture, Chemicals and Antibodies
2.2. Whole Cell Extract and Western Blotting Analysis
3. Results
3.1. Spike and RBD Activate EGFR, AKT, and ERK1/2 in A549 Cells
3.2. Activation of AKT by Spike 1 and RBD Is EGFR-Dependent
3.3. The Activation of AKT and ERK1/2 by Spike 1 and RBD Occurs in ACE2-Expressing Cells
3.4. Effects of Spike 1 and RBD on the Cell Survival Marker, Survivin
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Wang, C.; Horby, P.W.; Hayden, F.G.; Gao, G.F. A novel coronavirus outbreak of global health concern. Lancet 2020, 395, 470–473. [Google Scholar] [CrossRef] [Green Version]
- Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; et al. China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382, 727–733. [Google Scholar] [CrossRef] [PubMed]
- Hu, B.; Guo, H.; Zhou, P.; Shi, Z.L. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol. 2021, 19, 141–154. [Google Scholar] [CrossRef] [PubMed]
- Li, W.; Moore, M.J.; Vasilieva, N.; Sui, J.; Wong, S.K.; Berne, M.A.; Somasundaran, M.; Sullivan, J.L.; Luzuriaga, K.; Greenough, T.C.; et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003, 426, 450–454. [Google Scholar] [CrossRef] [Green Version]
- Tolouian, R.; Zununi Vahed, S.; Ghiyasvand, S.; Tolouian, A.; Ardalan, M.R. COVID-19 interactions with angiotensin-converting enzyme 2 (ACE2) and the kinin system; looking at a potential treatment. J. Ren. Inj. Prev. 2020, 9, e19. [Google Scholar] [CrossRef]
- Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280.e8. [Google Scholar] [CrossRef] [PubMed]
- Yan, R.; Zhang, Y.; Li, Y.; Xia, L.; Guo, Y.; Zhou, Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020, 367, 1444–1448. [Google Scholar] [CrossRef] [Green Version]
- Tai, W.; He, L.; Zhang, X.; Pu, J.; Voronin, D.; Jiang, S.; Zhou, Y.; Du, L. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell. Mol. Immunol. 2020, 17, 613–620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sriram, K.; Loomba, R.; Insel, P.A. Targeting the renin-angiotensin signaling pathway in COVID-19: Unanswered questions, opportunities, and challenges. Proc. Natl Acad. Sci. USA 2020, 117, 29274–29282. [Google Scholar] [CrossRef]
- Lavoie, J.L.; Sigmund, C.D. Minireview: Overview of the renin-angiotensin system--an endocrine and paracrine system. Endocrinology 2003, 144, 2179–2183. [Google Scholar] [CrossRef] [Green Version]
- Krammer, F. SARS-CoV-2 vaccines in development. Nature 2020, 586, 516–527. [Google Scholar] [CrossRef] [PubMed]
- Mourad, J.J.; Levy, B.I. Interaction between RAAS inhibitors and ACE2 in the context of COVID-19. Nat. Rev. Cardiol. 2020, 17, 313. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guo, J.; Huang, Z.; Lin, L.; Lv, J. Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J. Am. Heart Assoc. 2020, 9, e016219. [Google Scholar] [CrossRef]
- Gurwitz, D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev. Res. 2020, 81, 537–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Oliveros, E.; Oni, E.T.; Shahzad, A.; Kluger, A.Y.; Lo, K.B.; Rangaswami, J.; McCullough, P.A. Benefits and Risks of Continuing Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Antagonists, and Mineralocorticoid Receptor Antagonists during Hospitalizations for Acute Heart Failure. Cardiorenal Med. 2020, 10, 69–84. [Google Scholar] [CrossRef]
- South, A.M.; Tomlinson, L.; Edmonston, D.; Hiremath, S.; Sparks, M.A. Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat. Rev. Nephrol. 2020, 16, 305–307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Patel, A.B.; Verma, A. COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence? JAMA 2020, 323, 1769–1770. [Google Scholar] [CrossRef] [PubMed]
- Sommerstein, R.; Kochen, M.M.; Messerli, F.H.; Gräni, C. Coronavirus Disease 2019 (COVID-19): Do Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers Have a Biphasic Effect? J. Am. Heart Assoc. 2020, 9, e016509. [Google Scholar] [CrossRef]
- Mascolo, A.; Scavone, C.; Rafaniello, C.; Ferrajolo, C.; Racagni, G.; Berrino, L.; Paolisso, G.; Rossi, F.; Capuano, A. Renin-Angiotensin System and Coronavirus Disease 2019: A Narrative Review. Front. Cardiovasc. Med. 2020, 7, 143. [Google Scholar] [CrossRef]
- Sriram, K.; Insel, P.A. Inflammation and thrombosis in COVID-19 pathophysiology: Proteinase-activated and purinergic receptors as drivers and candidate therapeutic targets. Physiol. Rev. 2020, 101, 545–567. [Google Scholar] [CrossRef]
- Lee, C.H. Role of specialized pro-resolving lipid mediators and their receptors in virus infection: A promising therapeutic strategy for SARS-CoV-2 cytokine storm. Arch. Pharm. Res. 2021, 44, 84–98. [Google Scholar] [CrossRef] [PubMed]
- Zamorano Cuervo, N.; Grandvaux, N. ACE2: Evidence of role as entry receptor for SARS-CoV-2 and implications in comorbidities. eLife 2020, 9, e61390. [Google Scholar] [CrossRef] [PubMed]
- Venkataraman, T.; Frieman, M.B. The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis. Antivir. Res. 2017, 143, 142–150. [Google Scholar] [CrossRef] [PubMed]
- Mitchell, H.D.; Eisfeld, A.J.; Stratton, K.G.; Heller, N.C.; Bramer, L.M.; Wen, J.; McDermott, J.E.; Gralinski, L.E.; Sims, A.C.; Le, M.Q.; et al. The Role of EGFR in Influenza Pathogenicity: Multiple Network-Based Approaches to Identify a Key Regulator of Non-lethal Infections. Front. Cell Dev. Biol. 2019, 7, 200. [Google Scholar] [CrossRef]
- Wiedemann, A.; Mijouin, L.; Ayoub, M.A.; Barilleau, E.; Canepa, S.; Teixeira-Gomes, A.P.; Le Vern, Y.; Rosselin, M.; Reiter, E.; Velge, P. Identification of the epidermal growth factor receptor as the receptor for Salmonella Rck-dependent invasion. FASEB J. 2016, 30, 4180–4191. [Google Scholar] [CrossRef] [Green Version]
- Albiges, L.; Foulon, S.; Bayle, A.; Gachot, B.; Pommeret, F.; Willekens, C.; Stoclin, A.; Merad, M.; Griscelli, F.; Lacroix, L.; et al. Determinants of the outcomes of patients with cancer infected with SARS-CoV-2: Results from the Gustave Roussy cohort. Nat. Cancer 2020, 1, 965–975. [Google Scholar] [CrossRef] [PubMed]
- Dai, M.; Liu, D.; Liu, M.; Zhou, F.; Li, G.; Chen, Z.; Zhang, Z.; You, H.; Wu, M.; Zheng, Q.; et al. Patients with Cancer Appear More Vulnerable to SARS-CoV-2: A Multicenter Study during the COVID-19 Outbreak. Cancer Discov. 2020, 10, 783–791. [Google Scholar] [CrossRef] [PubMed]
- Ranadheera, C.; Coombs, K.M.; Kobasa, D. Comprehending a Killer: The Akt/mTOR Signaling Pathways Are Temporally High-Jacked by the Highly Pathogenic 1918 Influenza Virus. EBioMedicine 2018, 32, 142–163. [Google Scholar] [CrossRef]
- Zhang, J.; Feng, H.; Xu, S.; Feng, P. Hijacking GPCRs by viral pathogens and tumor. Biochem. Pharmacol. 2016, 114, 69–81. [Google Scholar] [CrossRef] [Green Version]
- Sodhi, A.; Montaner, S.; Gutkind, J. Viral hijacking of G-protein-coupled-receptor signalling networks. Nat. Rev. Mol. Cell Biol. 2004, 5, 998–1012. [Google Scholar] [CrossRef]
- Coureuil, M.; Lécuyer, H.; Scott, M.G.; Boularan, C.; Enslen, H.; Soyer, M.; Mikaty, G.; Bourdoulous, S.; Nassif, X.; Marullo, S. Meningococcus Hijacks a β2-adrenoceptor/β-Arrestin pathway to cross brain microvasculature endothelium. Cell 2010, 143, 1149–1160. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Palakkott, A.R.; Alneyadi, A.; Muhammad, K.; Eid, A.H.; Amiri, K.M.A.; Akli Ayoub, M.; Iratni, R. The SARS-CoV-2 Spike Protein Activates the Epidermal Growth Factor Receptor-Mediated Signaling. Vaccines 2023, 11, 768. https://doi.org/10.3390/vaccines11040768
Palakkott AR, Alneyadi A, Muhammad K, Eid AH, Amiri KMA, Akli Ayoub M, Iratni R. The SARS-CoV-2 Spike Protein Activates the Epidermal Growth Factor Receptor-Mediated Signaling. Vaccines. 2023; 11(4):768. https://doi.org/10.3390/vaccines11040768
Chicago/Turabian StylePalakkott, Abdul Rasheed, Aysha Alneyadi, Khalid Muhammad, Ali Hussein Eid, Khaled M. A. Amiri, Mohammed Akli Ayoub, and Rabah Iratni. 2023. "The SARS-CoV-2 Spike Protein Activates the Epidermal Growth Factor Receptor-Mediated Signaling" Vaccines 11, no. 4: 768. https://doi.org/10.3390/vaccines11040768
APA StylePalakkott, A. R., Alneyadi, A., Muhammad, K., Eid, A. H., Amiri, K. M. A., Akli Ayoub, M., & Iratni, R. (2023). The SARS-CoV-2 Spike Protein Activates the Epidermal Growth Factor Receptor-Mediated Signaling. Vaccines, 11(4), 768. https://doi.org/10.3390/vaccines11040768