{ "abstract": "Epidermal growth factor receptor (EGFR) signaling is a major pathway that controls cellular growth, survival, proliferation, and differentiation. Viruses often hijack this pathway to create a favorable environment to support their replication. Vaccinia virus (the prototype member of poxviridae) encodes its own viral growth factor (VGF). VGF is a secreted viral polypeptide with sequence and structural homology to the cellular EGF, which binds to and activates EGFR signaling. Studies from our lab and others have shown that VGF promotes metabolic reprogramming, cell motility, virulence, and spread during VACV infection. However, it remains unclear whether VGF fully mimics EGF signaling or selectively rewires downstream pathways to meet the specific demands of viral replication. To address this question, we used quantitative global phosphoproteomics to systematically compare signaling programs induced by EGF and VGF in primary human foreskin fibroblasts. By analyzing global phosphorylation patterns, kinase activity inference, and motif enrichment, we found that although both peptides engage the same EGFR receptor, EGF and VGF induce distinct downstream phosphorylation and bias downstream kinase activities. Transcriptomic analysis provided a complementary view of the cellular responses to the ligand treatment. Moreover, we found that VGF is more effective at promoting VACV plaque formation than EGF, thereby providing functional support to the VGF-biased EGFR signaling nodes important for viral spread. These findings highlight differences in how viral and cellular growth factors activate EGFR signaling and position poxviral growth factors as powerful tools for examining the fundamental principles of cellular signaling. Author summary: Viruses often manipulate cell signaling pathways to create environments that promote viral replication and spread. One critical pathway is EGFR signaling, which controls how cells grow, move, and survive. Vaccinia virus, the prototype member of the poxvirus family, produces its own mimic of cellular epidermal growth factor called VGF. Although VGF resembles the EGF peptide, it is unclear whether it activates cells in the same way or rewires the pathway to benefit the virus. We compared the response of human primary fibroblasts to EGF and VGF using quantitative global phosphoproteomics. We found that although both ligands engage the same receptor, EGFR, they trigger distinct patterns of protein phosphorylation and downstream kinase engagement. RNA sequencing further identified complementary transcriptional changes that were consistent with the ligand-specific pathway differences observed in the phosphoproteomic analysis. Functionally, we found that these differences enable VGF to be more effective than EGF at promoting vaccinia virus spread. Our work reveals how a virus‑encoded growth factor reshapes a major cellular pathway and highlights poxviruses as valuable tools for understanding the basic principles of cell signaling.", "abstract_shown": true, "affiliations": [ "Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 3, "authors": [ { "affs": [ 0 ], "name": "Anil Pant" }, { "name": "Lara Dsouza" }, { "name": "Zhilong Yang" } ], "bibtex": "https://research.draconitic.com/paper/bhd3y0rrkavmp.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014725", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014725", "id": "bhd3y0rrkavmp", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014725", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "lcc", "QH301-705.5" ], [ "lcc", "RC581-607" ], [ "openalex", "2406|Poxvirus research and outbreaks" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Post-translational modification/Phosphorylation" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/EGFR signaling" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/GTPase signaling" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/Signaling cascades/Stress signaling cascade" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Poxviruses/Vaccinia virus" ], [ "plos", "/Biology and life sciences/Microbiology/Virology/Viral replication" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/DNA viruses/Poxviruses/Vaccinia virus" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Poxviruses/Vaccinia virus" ], [ "plos", "/Biology and life sciences/Physiology/Endocrine physiology/Growth factors" ], [ "plos", "/Medicine and health sciences/Endocrinology/Endocrine physiology/Growth factors" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Poxviruses/Vaccinia virus" ], [ "plos", "/Research and analysis methods/Database and informatics methods/Bioinformatics/Sequence analysis/Sequence motif analysis" ] ], "openalex": "W7223676395", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014725&type=printable", "pmcid": "PMC13705586", "pmid": null, "published": "2026-10-01", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/bhd3y0rrkavmp.ris", "sources": [ { "first_seen": "2026-10-30T12:17:17Z", "native_id": "10.1371/journal.ppat.1014725", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014725" }, { "first_seen": "2026-10-30T12:21:48Z", "native_id": "PMC:PMC13705586", "source": "europepmc", "url": "https://europepmc.org/article/PMC/PMC13705586" }, { "first_seen": "2026-10-31T14:22:58Z", "native_id": "0bdb5298e5124dcca9642e33c21ee53e", "source": "doaj", "url": "https://doi.org/10.1371/journal.ppat.1014725" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "biology", "origin": "plos:microbiology", "subfield": "microbiology" } ], "title": "Vaccinia virus growth factor induces divergent signaling programs and biological outcomes from cellular epidermal growth factor", "title_text": "Vaccinia virus growth factor induces divergent signaling programs and biological outcomes from cellular epidermal growth factor", "type": "peer-reviewed", "updated_at": "2026-11-02T14:20:23Z", "url": "https://research.draconitic.com/paper/bhd3y0rrkavmp", "venue": "PLOS Pathogens", "versions": [] }