The vaccinia virus-stimulated mitogen-activated protein kinase (MAPK) pathway is required for virus multiplication

Biochem J. 2004 Jul 15;381(Pt 2):437-46. doi: 10.1042/BJ20031375.


Early events play a decisive role in virus multiplication. We have shown previously that activation of MAPK/ERK1/2 (mitogen-activated protein kinase/extracellular-signal-regulated kinase 1/2) and protein kinase A are pivotal for vaccinia virus (VV) multiplication [de Magalhães, Andrade, Silva, Sousa, Ropert, Ferreira, Kroon, Gazzinelli and Bonjardim (2001) J. Biol. Chem. 276, 38353-38360]. In the present study, we show that VV infection provoked a sustained activation of both ERK1/2 and RSK2 (ribosomal S6 kinase 2). Our results also provide evidence that this pattern of kinase activation depends on virus multiplication and ongoing protein synthesis and is maintained independently of virus DNA synthesis. It is noteworthy that the VGF (VV growth factor), although involved, is not essential for prolonged ERK1/2 activation. Furthermore, our findings suggest that the VV-stimulated ERK1/2 activation also seems to require actin dynamics, microtubule polymerization and tyrosine kinase phosphorylation. The VV-stimulated pathway MEK/ERK1/2/RSK2 (where MEK stands for MAPK/ERK kinase) leads to phosphorylation of the ternary complex factor Elk-1 and expression of the early growth response (egr-1) gene, which kinetically paralleled the kinase activation. The recruitment of this pathway is biologically relevant, since its disruption caused a profound effect on viral thymidine kinase gene expression, viral DNA replication and VV multiplication. This pattern of sustained kinase activation after VV infection is unique. In addition, by connecting upstream signals generated at the cytoskeleton and by tyrosine kinase, the MEK/ERK1/2/RSK2 cascade seems to play a decisive role not only at early stages of the infection, i.e. post-penetration, but is also crucial to define the fate of virus progeny.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells / enzymology
  • 3T3 Cells / virology
  • Actins / metabolism
  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • DNA Replication / genetics
  • DNA, Viral / genetics
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / metabolism
  • Early Growth Response Protein 1
  • Enzyme Activation / physiology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Viral / genetics
  • Genes, Immediate-Early / genetics
  • Immediate-Early Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins
  • MAP Kinase Signaling System / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinases / physiology*
  • Peptides / physiology
  • Phosphorylation
  • Protein Biosynthesis / physiology
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Ribosomal Protein S6 Kinases / metabolism
  • Transcription Factors / biosynthesis
  • Transcription Factors / metabolism
  • Vaccinia virus / enzymology*
  • Vero Cells / virology
  • Virus Replication / physiology*
  • ets-Domain Protein Elk-1


  • Actins
  • DNA, Viral
  • DNA-Binding Proteins
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Elk1 protein, mouse
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • Proto-Oncogene Proteins
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • vaccinia growth factor
  • Protein-Tyrosine Kinases
  • Ribosomal Protein S6 Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases