Article: article from journal or magazin.
Growth transformation of human T cells by herpesvirus saimiri requires multiple Tip-Lck interaction motifs.
Journal of Virology
Lymphoma induction and T-cell transformation by herpesvirus saimiri strain C488 depends on two viral oncoproteins, StpC and Tip. The major interaction partner of Tip is the protein tyrosine kinase Lck, a key regulator of T-cell activation. The Lck binding domain (LBD) of Tip comprises two interaction motifs, a proline-rich SH3 domain-binding sequence (SH3B) and a region with homology to the C terminus of Src family kinase domains (CSKH). In addition, biophysical binding analyses with purified Lck-SH2 domain suggest the phosphorylated tyrosine residue 127 of Tip (pY127) as a potential third Lck interaction site. Here, we addressed the relevance of the individual binding motifs, SH3B, CSKH, and pY127, for Tip-Lck interaction and for human T-cell transformation. Both motifs within the LBD displayed Lck binding activities and cooperated to achieve a highly efficient interaction, while pY127, the major tyrosine phosphorylation site of Tip, did not enhance Lck binding in T cells. Herpesvirus saimiri strain C488 recombinants lacking one or both LBD motifs of Tip lost their transforming potential on human cord blood lymphocytes. Recombinant virus expressing Tip with a mutation at position Y127 was still able to transform human T lymphocytes but, in contrast to wild-type virus, was strictly dependent on exogenous interleukin-2. Thus, the strong Lck binding mediated by cooperation of both LBD motifs was essential for the transformation of human T cells by herpesvirus saimiri C488. The major tyrosine phosphorylation site Y127 of Tip was particularly required for transformation in the absence of exogenous interleukin-2, suggesting its involvement in cytokine signaling pathways.
Amino Acid Motifs, Cell Line, Cell Transformation, Viral, Cells, Cultured, Herpesvirus 2, Saimiriine/genetics, Herpesvirus 2, Saimiriine/physiology, Humans, Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/chemistry, Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism, Mutation, Phosphoproteins/chemistry, Phosphoproteins/genetics, Phosphorylation, Protein Binding, Recombination, Genetic, Sequence Deletion, T-Lymphocytes/cytology, T-Lymphocytes/virology, Tyrosine/metabolism, Viral Proteins/chemistry, Viral Proteins/genetics
Web of science
Last modification date