Viral growth factor rewires EGFR signaling differently from cellular EGF

Vaccinia virus, the prototype member of the poxvirus family, carries its own growth factor gene, and new research shows that this viral molecule does not simply imitate its cellular counterpart. In a study led by Anil Pant, Lara Dsouza and Zhilong Yang, quantitative global phosphoproteomics was used to compare the signaling programs triggered by the vaccinia virus growth factor (VGF) and by cellular epidermal growth factor (EGF) in primary human foreskin fibroblasts. Both peptides bind and activate the same receptor, the epidermal growth factor receptor (EGFR), a central pathway controlling cellular growth, survival, proliferation and differentiation that viruses often hijack to support their replication.

The comparison revealed that, despite engaging an identical receptor, EGF and VGF induce distinct downstream phosphorylation patterns and bias downstream kinase activities in different directions. The researchers analyzed global phosphorylation changes, inferred kinase activity and examined motif enrichment to reach this conclusion. A complementary transcriptomic analysis of the ligand-treated cells provided a matching view of how the cellular response differs depending on which growth factor is present.

VGF is a secreted viral polypeptide with sequence and structural homology to cellular EGF, and earlier work from the authors’ laboratory and others had already linked it to metabolic reprogramming, cell motility, virulence and spread during vaccinia virus infection. What remained unclear was whether VGF fully mimics EGF signaling or selectively rewires downstream pathways to meet the specific demands of viral replication. The new findings support the selective rewiring interpretation.

Functional experiments added weight to the phosphoproteomic results: VGF proved more effective than EGF at promoting vaccinia virus plaque formation, providing evidence that the VGF-biased EGFR signaling nodes are important for viral spread. The authors note that these results highlight differences in how viral and cellular growth factors activate EGFR signaling, and they position poxviral growth factors as powerful tools for examining fundamental principles of cellular signaling. Because the work was conducted in primary human fibroblasts, its conclusions describe signaling and plaque-formation outcomes in that experimental system rather than effects in a living host.

Subject of Research: Divergent EGFR signaling programs induced by vaccinia virus growth factor versus cellular epidermal growth factor

Article Title: Vaccinia virus growth factor induces divergent signaling programs and biological outcomes from cellular epidermal growth factor

Article References: Pant, A., Dsouza, L., & Yang, Z. (2026). Vaccinia virus growth factor induces divergent signaling programs and biological outcomes from cellular epidermal growth factor. PLOS Pathogens, 22(10), e1014725. https://doi.org/10.1371/journal.ppat.1014725

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DOI: 10.1371/journal.ppat.1014725

Keywords: vaccinia virus, poxvirus, viral growth factor, EGFR signaling, phosphoproteomics, epidermal growth factor, kinase activity, human fibroblasts, viral replication, cell signaling, Vaccinia, virus