Deregulated signal transduction by the K1 gene product of Kaposi's sarcoma-associated herpesvirus

The Kaposi's sarcoma (KS)-associated herpesvirus is a lymphotropic virus st rongly implicated in the pathogenesis of KS and several lymphoproliferative disorders. The KS-associated herpesvirus Iii gene encodes a transmembrane protein bearing a functional immunoreceptor tyrosine-based activation motif (ITAM)-like sequence; it previously has been proposed to be important in v iral tumorigenesis because its expression can trigger cell proliferation in vitro and in vivo. Here we show that expression of the full-length K1 prot ein can initiate calcium-dependent signal transduction in B cells; however, unlike other ITAM-based signal transduction events, K1 signaling occurs co nstitutively, in the absence of exogenous crosslinking ligands, This proper ty is caused by its cysteine-rich ectodomain, which when transferred to oth er consensus ITAMs induces constitutive signaling. Although ITAM-based sign aling by gl involves classical syk and phospholipase C gamma 2 activation, both ITAM- and syk-independent signaling pathways are activated by K1 expre ssion. These studies indicate that K1 is a deregulated signaling molecule w ith pleitropic effects that may explain its known growth deregulatory prope rties.