Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a distinct open reading frame called K15 at a position equivalent to the gene encoding LMP2A of Epstein-Barr virus (EBV). K15 isolates from body cavity-based lymphoma (BCBL) cells exhibited a dramatic sequence variation and a complex splicing pattern. However, all K15 alleles are organized similarly with the potential SH2 and SH3 binding motifs in their cytoplasmic regions. Northern blot analysis showed that K15 was weakly expressed in latently infected BCBL-1 cells, and the level of its expression was significantly induced by tetradecanoyl phorbol acetate stimulation. K15 encoded 40-to 55-kDa proteins, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and was localized at the cytoplasm and plasma membrane. To demonstrate the signal-transducing activity of the K15 protein, we constructed a chimeric protein in which the cytoplasmic tail of the human CD8␣ polypeptide was replaced with that of KSHV K15. While the CD8-K15 chimera was not capable of eliciting cellular signal transduction upon stimulation with an anti-CD8 antibody, it significantly inhibited B-cell receptor signaling, as evidenced by a suppression of tyrosine phosphorylation and intracellular calcium mobilization. This inhibition required the putative SH2 or SH3 binding motif in the cytoplasmic region of K15. Biochemical study of CD8-K15 chimeras showed that the cytoplasmic region of K15 was constitutively tyrosine phosphorylated and that the tyrosine residue within the putative SH2 binding motif of K15 was a primary site of phosphorylation. These results demonstrate that KSHV K15 resembles LMP2A in genomic location, splicing pattern, and protein structure and by the presence of functional signal-transducing motifs in the cytoplasmic region. Thus, KSHV K15 is likely a distant evolutionary relative of EBV LMP2A.DNA sequences of a novel member of the herpesvirus group, called Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8, have been widely identified in Kaposi's sarcoma (KS) tumors from human immunodeficiency virus-positive and -negative patients (4,5,21,32,35). KSHV has also been identified in body cavity-based lymphoma (BCBL) and some forms of Castleman's disease (4, 5, 28). These are principally or exclusively of B-cell origin. Cell lines have been derived from some of the BCBL, and while some harbor both Epstein-Barr virus (EBV) and KSHV, others harbor KSHV only. The genomic sequence indicates that KSHV is a gammaherpesvirus that is closely related to herpesvirus saimiri (HVS) (25, 29) and the recently isolated rhesus monkey rhadinovirus (7,33).In primary lymphocytes, cross-linking the B-cell receptor (BCR) or T-cell receptor (TCR) leads to an intricate signal cascade including the recruitment and activation of the src family tyrosine kinases; the subsequent activation and recruitment of other kinases, phosphatases, or adapter proteins; the hydrolysis of phospholipids; the mobilization of intracellular calcium; the activation of protein kinase C; ...

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