Herpesvirus saimiri STP-A oncoprotein utilizes Src family protein tyrosine kinase and tumor necrosis factor receptor-associated factors to elicit cellular signal transduction.
The saimiri transforming protein oncogene, called STP-A, of herpesvirus saimiri (HVS) subgroup A is not required for viral replication but is required for lymphoid cell immortalization in culture and lymphoma induction in primates. Here we report that STP-A interacts with cellular tumor necrosis factor receptor-associated factors (TRAF2 and TRAF6) and Src family protein tyrosine kinases (SF-PTKs) in a genetically and functionally separable manner and that each interaction constitutively elicits independent cellular signal transduction. The amino-terminal and central proline-rich motifs of STP-A were responsible for TRAF6 and TRAF2 interactions, respectively, and STP-A and TRAF6 interaction contributed to the majority of NF-kappaB activation, whereas STP-A and TRAF2 interaction played a minor role in NF-kappaB activation. On the other hand, interaction of STP-A with SF-PTKs through its SH2 binding motif effectively elicited AP-1 and NF-AT transcription factor activity. One cellular gene targeted by STP-A is intercellular adhesion molecule 1 (ICAM-1), which participates in a wide range of inflammatory and immune responses. Both TRAF and SF-PTK signal transductions induced by STP-A were required for the marked increase of ICAM-1 expression. These results demonstrate that the viral oncogene STP-A independently targets two vital cellular signaling molecules and that these activities likely contribute to HVS-mediated lymphoid cell immortalization in culture and lymphoma induction in primates.
Garcia
Maria I
MI
Tumor Virology Division, New England Primate Research Center, Harvard Medical School, P.O. Box 9102, 1 Pine Hill Drive, Southborough, MA 01772-9102, USA.
Kaserman
Joseph
J
Chung
Young-Hwa
YH
Jung
Jae U
JU
Lee
Sun-Hwa
SH
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002460:Cell Line; D018274:Electroporation; D017930:Genes, Reporter; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells; D008156:Luciferases / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism*
D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C064364:STP protein, Herpesvirus saimiri; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D018799:Intercellular Adhesion Molecule-1; D008156:Luciferases; D005982:Glutathione Transferase; D019061:src-Family Kinases