G protein-coupled receptors (GPCRs) constitute a large family of cell surface receptors, and play an important role in regulating cell survival and proliferation. They transduce environmental signals across the cytoplasm membrane through their ability to stimulate guanine nucleotide exchange by heterotrimeric G proteins, which induce multiple signaling cascades composed of scaffold/adaptor molecules and effector enzymes, leading to activation of many transcription factors including NF-kB. NF-kB is a family of transcription factors that play pivotal roles in regulating the expression of pro-inflammatory cytokines and pro-survival factors. Lysophosphatidic acid (LPA) is a potent bioactive lipid that elicits a wide variety of biological actions, particularly as an inducer of cell proliferation, migration, and survival, thereby, regulating wound healing, vascular remodeling, and tumor progression and metastasis. Binding LPA to its receptor, a GPCR family member, initiates multiple signaling pathways, leading to induction of pro-inflammatory and pro-angiogenic cytokines. It has also been shown that NF-kB is the key transcription factor mediating LPA- induced cytokine production. However, how GPCRs, such as LPA receptors, induce NF-kB activation remains largely unknown. In this application, we propose to investigate the molecular mechanism by which GPCRs induce NF-kB activation. Our preliminary studies indicate that NF-kB activation induced by several GPCR ligands, including LPA, endothelin-1, and serotonin, is dependent on two adaptor/scaffold molecules, CARMA3 and BcMO. Based on our preliminary studies, we hypothesize that CARMA3 and BcMO mediate a novel GPCR signal transduction pathway, leading to activation of NF-kB. In this application, we propose three specific aims to elucidate this novel signal transduction pathway. They are 1) to determine how the GPCR leads to activation of CARMA3;2) to determine the molecular mechanism by which CARMA3 activates downstream signaling cascades;3) to determine whether the CARMA3 is required for KSHV GPCR-induced NF-kB activation and malignancy. Elucidating this novel signal transduction pathway not only will reveal a general mechanism by which GPCRs induce NF-kB activation, but also provide therapeutic targets for modulating inflammation, wound healing, angiogenesis, and cancer.
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