title: Expression of herpes simplex virus type 2 US3 affects the Cdc42/Rac pathway and attenuates c-Jun N-terminal kinase activation.
abstract: BACKGROUND
  Although the US3 gene product of herpes simplex virus (HSV) has been identified as a serine/threonine protein kinase (PK), the functions are poorly understood.
  
  
  RESULTS
  We found that US3 PK of HSV-2 induced disruption of actin filaments, cell rounding and accumulation of binucleate cells in HEp2 cells. Cell rounding was abrogated by expression of either kinase-dead forms of US3 PK or a mutant protein lacking the acidic cluster in the kinase regulatory domain. Co-expression of dominant active forms of Cdc42/Rac inhibited cell rounding, suggesting that a signal transduction pathway involving Cdc42/Rac may play a role in the morphological changes induced by the kinase. Cdc42 and Rac, members of the Rho family of small GTPases, function as molecular switches changing actin cytoskeletal organization, influencing transcription and controlling apoptotic cell death. By computed homology search, we noticed significant similarities between US3 PK and p21-activated kinase (PAK), which is activated by the Cdc42 or Rac. We also found that the expression of US3 suppressed the activation of c-Jun N-terminal kinase (JNK), a kinase that is downstream of PAK.
  
  
  CONCLUSIONS
  These observations suggest that the US3 PK affects the Cdc42/Rac pathway and can act as an upstream suppressor of JNK in the stress-activated signalling pathway.
authors.affiliation: Laboratory of Virology, Research Institute for Disease Mechanism and Control, Nagoya, University School of Medicine, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Murata
authors.forename: F
authors.initials: F
authors.lastname: Goshima
authors.forename: T
authors.initials: T
authors.lastname: Daikoku
authors.forename: H
authors.initials: H
authors.lastname: Takakuwa
authors.forename: Y
authors.initials: Y
authors.lastname: Nishiyama
mesh_terms: D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002449:Cell Aggregation / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000473:pathology; D048429:Cell Size / Q000235:genetics; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000235:genetics; D005822:Genetic Vectors / Q000096:biosynthesis / Q000138:chemical synthesis; D018258:Herpesvirus 2, Human / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D014709:Vero Cells; D014764:Viral Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000502:physiology*; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins / Q000502:physiology*
chemical_list: D000199:Actins; D014764:Viral Proteins; C515911:PAK3 protein, human; D017346:Protein Serine-Threonine Kinases; C084395:US3 protein, Human herpesvirus 2; D054462:p21-Activated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins