RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Abstract

Abstract. Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gα i/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target.

Identification of DEP domain-containing proteins by a machine learning method and experimental analysis of their expression in human HCC tissues

“…The DEPDC protein family includes seven members, which contain the DEP domain as their common characteristic; these proteins can mediate protein-to-protein interaction and membrane targeting of signal molecules5185960. Consequently, most DEPDCs are involved in signal transduction and closely related to several other signal molecules.…”

Regulator of G-protein signaling (RGS) proteins as drug targets: Progress and future potentials

“…2). To date, there are at least 20 distinct RGS proteins classified, made even greater by the many genetic variants of some RGS proteins that continue to be revealed, such as RGS6 that has multiple splice variants that vary in function and localization (17).…”

“…With nearly every new function revealed, the role of a small molecule that would be useful as a drug or probe molecule for further investigation can be inferred. There are a number of recent publications on RGS proteins in cancer (17), inflammation (18), cardiovascular processes (19 -21), neuroinflammation (22), and even pregnancy (23, 24) that describe the diverse role RGS proteins play in these processes. In this review we will present examples that help reinforce the rationale behind the search for RGS inhibitors, in particular, those focused on neurological disorders and cancer.…”

“…These mutant G␣ subunits create an uncoupled RGS-G␣ state that provides essential information about the physiological impact of disrupting this interaction. Subsequent RGS knockout or knockdown studies have also been used to mimic an environment where GPCR signaling goes unchecked by RGS proteins, and they have reinforced the important role of RGS proteins in signal transduction (17,27,28).…”

“…RGS6, RGS7, and RGS9, have been implicated in a multitude of disease states, which is likely a result of the multifunctional domains they possess. RGS6 has been the subject of intense study and is implicated in a number of neurological disease states (17). Studies with RGS6 have demonstrated its role as a critical mediator of alcohol-seeking behavior, anxiety, depression, and survival of aging dopaminergic neurons of the substantia nigra pars compacta, which are lost in Parkinson's disease (53)(54)(55).…”