Novel G protein‐ and GPCR‐Regulated Oncogenic Signaling Circuitries

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The family of G protein‐coupled receptors (GPCRs) constitutes the largest group of cell surface proteins involved in signal transduction. GPCRs participate in a wide variety of physiological and pathophysiological functions, and are the target of 50–60% of all current therapeutic agents. This large receptor family plays important roles in normal and tumor cell growth. For example, the Kaposi's sarcoma (KS) associated herpesvirus (KSHV), the infectious cause of KS, expresses an oncogenic constitutively active GPCR, vGPCR, thus providing a direct link between G protein‐linked receptors and viral‐associated malignancies. Recent large cancer sequencing initiatives have revealed an unexpected and surprisingly high incidence of GPCR mutations, ranging from 5% to nearly 30%, in some of the most prevalent human malignancies. Activating mutations in Gαs have been observed in multiple tumors, while genes for both Gαq family members, Gαq (GNAQ) and Gα11 (GNA11), have been recently identified in approximately 80% of uveal melanomas, where they represent the driving uveal melanoma oncogene. How Gαq and its coupled receptors transduce mitogenic signals is still unclear, due to the complexity of signaling events perturbed upon Gq activation. Using a synthetic biology approach and a genome‐wide RNAi screen in drosophila cells, we have found that a highly conserved guanine nucleotide exchange factor, Trio, is essential to activate Rho‐ and Rac‐regulated signaling pathways acting on JNK and p38, and to transduce proliferative signals from Gαq to the nucleus independently of PLC‐β. Evidence will be presented that while many biological responses elicited by Gq depend on the transient activation of second messenger system, Gq utilizes a hardwired protein‐protein interaction‐based signaling circuitry to achieve the sustained stimulation of proliferative pathways, thereby controlling normal and aberrant cell growth. This knowledge may provide opportunities for the development of new G protein‐ and GPCR‐targeted treatment options in cancer.