Kaposi's sarcoma-associated herpesvirus-encoded G protein-coupled receptoractivation of c-jun amino-terminal kinase/stress-activated protein kinase and lyn kinase is mediated by related adhesion focal tyrosine kinase/proline-rich tyrosine kinase 2

The Kaposi's sarcoma-associated herpesvirus (KSHV) (also known as human her pesvirus 8) has been implicated in the pathogenesis of Kaposi's sarcoma and B cell primary effusion lymphomas, KSHV encodes a Gr protein-coupled recep tor (GPCR) that acts as an oncogene and constitutively activates two protei n kinases, c-Jun amino-terminal kinase (JNK)/stress-activated protein kinas e (SAPK) and p38 mitogen-activated protein kinase, It also induces the prod uction of vascular endothelial growth factor. These processes are believed to be important in KSHV-GPCR-related oncogenesis. We have characterized the signaling pathways mediated by KSHV-GPCR in a reconstituted 293T cell mode l in which the related adhesion focal tyrosine kinase (RAFTK) was ectopical ly expressed. RAFTK has been shown to play an important role in growth fact or signaling in endothelium and in B cell antigen receptor signaling in B l ymphocytes. KSHV-GPCR induced the tyrosine phosphorylation of RAFTK, Expres sion of wild-type RAFTK enhanced GPCR-mediated JNK/SAPK activation, whereas dominant negative mutant constructs of RAFTK, such as K457A (which lacks k inase activity) and Y402F (a Src-binding mutant), inhibited KSHV-GPCR-media ted activation of JNK/SAPK. RAFTK also mediated the KSHV-GPCR-induced activ ation of Lyn, a Src family kinase. However, RAFTK did not mediate the activ ation of p38 mitogen-activated protein kinase induced by KSHV-GPCR, Human i nterferon gamma-inducible protein-10, which is known to inhibit KSHV-GPCR a ctivity, was found to reduce RAFTK phosphorylation and JNK/SAPK activation. These results suggest that in cells expressing RAFTK/proline-rich tyrosine kinase 2, such as endothelial and B cells, RAFTK can act to enhance KSHV-G PCR-mediated downstream signaling to transcriptional regulators such as JNK /SAPK.