title: Kaposi's sarcoma-associated herpesvirus-encoded G protein-coupled receptor activation 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.
abstract: 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 gamma-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.
authors.affiliation: Division of Experimental Medicine, Robert Mapplethorpe Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: N
authors.initials: N
authors.lastname: Munshi
authors.forename: R K
authors.initials: RK
authors.lastname: Ganju
authors.forename: S
authors.initials: S
authors.lastname: Avraham
authors.forename: E A
authors.initials: EA
authors.lastname: Mesri
authors.forename: J E
authors.initials: JE
authors.lastname: Groopman
mesh_terms: D054357:Chemokine CXCL10 / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051418:Focal Adhesion Kinase 2; D019288:Herpesvirus 8, Human; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D054357:Chemokine CXCL10; D004791:Enzyme Inhibitors; C115448:G protein-coupled receptor, Human herpesvirus 8; D019707:Receptors, Chemokine; D014764:Viral Proteins; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases