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J Biol Chem, Vol. 274, Issue 45, 31863-31867, November 5, 1999
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From the The Kaposi's sarcoma-associated herpesvirus
(KSHV) (also known as human herpesvirus 8) has been implicated in the
pathogenesis of Kaposi's sarcoma and B cell primary effusion
lymphomas. KSHV encodes a G protein-coupled receptor (GPCR) that acts
as an oncogene and constitutively activates two protein kinases, c-Jun
amino-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and
p38 mitogen-activated protein kinase. It also induces the production 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
model in which the related adhesion focal tyrosine kinase (RAFTK) was ectopically expressed. RAFTK has been shown to play an important role
in growth factor signaling in endothelium and in B cell antigen receptor signaling in B lymphocytes. KSHV-GPCR induced the tyrosine phosphorylation of RAFTK. Expression of wild-type RAFTK enhanced GPCR-mediated JNK/SAPK activation, whereas dominant-negative mutant constructs of RAFTK, such as K457A (which lacks kinase activity) and
Y402F (a Src-binding mutant), inhibited KSHV-GPCR-mediated activation
of JNK/SAPK. RAFTK also mediated the KSHV-GPCR-induced activation of
Lyn, a Src family kinase. However, RAFTK did not mediate the activation
of p38 mitogen-activated protein kinase induced by KSHV-GPCR. Human
interferon
Division of Experimental Medicine and
Hematology/Oncology, Robert Mapplethorpe Laboratory, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston,
Massachusetts 02115 and the ¶ Laboratory of Viral Oncogenesis,
Division of Hematology-Oncology, Cornell University Medical College,
New York, New York 10021
-inducible protein-10, which is known to inhibit
KSHV-GPCR activity, 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-GPCR-mediated downstream signaling to
transcriptional regulators such as JNK/SAPK.
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