The KSHV G protein-coupled receptor signals via multiple pathways to induce transcription factor activation in primary effusion lymphoma cells.
Kaposi's sarcoma-associated virus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The KSHV G protein-couple receptor (vGPCR) is a homologue of the human IL-8 receptor that signals constitutively, activates mitogen- and stress-activated kinases, and induces transcription via multiple transcription factors including AP-1 and NFkappaB. Furthermore, vGPCR causes cellular transformation in vitro and leads to KS-like tumors in transgenic mouse models. vGPCR has therefore become an exciting potential therapeutic target for KSHV-mediated disease, but its signaling properties need to be better understood in the context of KSHV-infected hematopoietic cells. We recently described a PEL cell line that expresses vGPCR via an inducible promoter and have shown that vGPCR has broad capabilities of affecting cellular and viral transcription patterns in this highly relevant cell type. To elucidate the predominant signaling pathways used by vGPCR in PEL cells, we have used reporter gene assays to measure vGPCR activity in the presence of various pharmacologic enzyme inhibitors and plasmid constructs. We show that vGPCR-induced activation of AP-1 and CREB is mediated cooperatively by a Gq-ERK-1/2 and a Gi-PI3K-Src axis. Furthermore, unlike in other cell types, NFkappaB activation by vGPCR seems not to be substantially mediated by Gi or PI3K/Akt in PEL cells.
Cannon
Mark L
ML
Division of International Medicine and Infectious Disease, Department of Medicine, Weill Medical College of Cornell University, 1300 York Ave., Room A-421, New York, NY 10021, USA. mlcannon@med.cornell.edu
Cesarman
Ethels
E
D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D019288:Herpesvirus 8, Human; D006801:Humans; D008223:Lymphoma / Q000201:enzymology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019707:Receptors, Chemokine; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014764:Viral Proteins; D019061:src-Family Kinases; C115448:G protein-coupled receptor, Human herpesvirus 8; C060902:lyn protein-tyrosine kinase; C494918:AKT1 protein, human