The RGS (regulator of G-protein signalling) and GoLoco domains of RGS14 co-operate to regulate Gi-mediated signalling

Traver, Sabine; Splingard, Anne; Gaudriault, Georges; Gunzburg, Jean de

doi:10.1042/bj20031889

Cited by 41 publications

(46 citation statements)

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“…It also blocks the association of Gα with Gβγ, potentially leading to prolonged Gβγ signalling. This enables dual regulation of Gα by RGS12 and RGS14 (Traver et al, 2004). RGS12 and RGS14 are two of the largest classical RGS proteins with additional domains apart from the RGS and GoLoco domains.…”

Section: Additional Domains and Non-canonical Functions Of Rgs Proteinsmentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.Abbreviations DEP, Disheveled Egl-10 Pleckstrin; GAP, GTPase-activating protein; GGL, G protein γ-like; PPI, protein-protein interaction; RGS, regulator of G protein signalling; R7BP, R7 binding protein; R9AP, RGS9 associated protein IntroductionG protein-mediated signalling pathways have played a pivotal role in drug discovery and development for many decades. The large family of GPCRs or their downstream effectors are the target of 40% of clinically used drugs and thus represent a multi-billion-dollar industry (Wise et al., 2002). Interestingly, of the more than 300 non-olfactory GPCRs known, only a fraction of them are targeted by drugs. Thus, there is a large untapped area of drug development still available. Moreover, many GPCR drugs are associated with low efficacy and/or side effects. More targeted therapies are therefore required, and as we learn more about the structure and function of GPCRs and their regulators, these goals will be achievable.All biological signals are tightly regulated and for every on-switch there is usually an off-switch. GPCRs are activated by ligands, transmitting signalling information to Gα subunits of heterotrimeric G proteins by enhancing the exchange of GDP for GTP in the Gα nucleotide binding site, which results in the dissociation of Gα from Gβγ dimers and activation of both G protein components. Deactivation of G proteins does not occur by simple reversal of nucleotide exchange, but rather by an independently regulated GTPase activity, hydrolyzing GTP to GDP. Although Gα proteins possess an intrinsic ability to hydrolyze GTP, this process is very slow and cannot account for the transient nature of intracellular signalling cascades in vivo. Hence, additional kinetic mechanisms are required for the physiological timing of signals. One of the most critical of these kinetic mechanisms is mediated through regulator of G protein signalling (RGS) proteins, which have received increasing interest as novel drug targets in the past two decades. As a result, RGS proteins have now been added as the most recent ad...

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Section: Additional Domains and Non-canonical Functions Of Rgs Proteinsmentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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“…The GoLoco motif of RGS14 has GDP dissociation inhibitor activity (GDI) for G i ␣. Although its physiological significance remains enigmatic, the GoLoco motif does enhance the inhibitory effect of RGS14 on G i ␣ signaling triggered through the muscarinic receptor (13). Three regions of RGS14 also show weak homologies to the DNA binding domains of high mobility group I and Y proteins (Alliance for Cellular Signaling RGS14 Molecular Page).…”

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confidence: 99%

RGS14 Is a Centrosomal and Nuclear Cytoplasmic Shuttling Protein That Traffics to Promyelocytic Leukemia Nuclear Bodies Following Heat Shock

Cho

Kim

Kehrl

2005

Journal of Biological Chemistry

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RGS14, a member of the regulator of G-protein signaling (RGS) protein family, possesses an N-terminal RGS domain, two Raf-like Ras-binding domains, and a GoLoco motif, which has GDP dissociation inhibitor activity. In this study we show that unique among the known mammalian RGS proteins, RGS14 localizes in centrosomes. Its first Ras-binding domain is sufficient to target RGS14 to centrosomes. RGS14 also shuttles between the cytoplasm and nucleus, and its nuclear export depends on the CRM-1 nuclear export receptor. Mutation of a nuclear export signal or treatment with leptomycin B causes nuclear accumulation of RGS14 and its association with promyelocytic leukemia protein nuclear bodies. Furthermore, a point mutant defective in nuclear export fails to target to centrosomes, suggesting that nuclear cytoplasmic shuttling is necessary for its proper localization. Mild heat stress, but not proteotoxic or transcription-linked stresses, re-localizes the RGS14 from the cytoplasm to promyelocytic leukemia nuclear bodies. Expression of RGS14, but not point mutants that disrupt the functional activity of its RGS domain or GoLoco motif, enhances the reporter gene activity. The multifunctional domains and the dynamic subcellular localization of RGS14 implicate it in a diverse set of cellular processes including centrosome and nuclear functions and stress-induced signaling pathways. Many of the members of the regulator of G protein signaling (RGS)1 family of over 30 proteins regulate signaling pathways initiated by receptors that couple to heterotrimeric G proteins. They do so by enhancing the rate of GTP hydrolysis of G␣ subunits, thus reducing the duration that the G␣ subunits are GTP-bound (1-4), by antagonizing the interactions between activated G␣ subunits and effectors (2), by directly inhibiting the activities of certain effectors (5, 6), and by inhibiting the dissociation of guanine nucleotides from the G␣ subunits (7). However, emerging evidence suggests that RGS proteins, particularly those that contain domains in addition to their signature RGS domain, have other cellular functions (for recent reviews see Refs. 8 and 9).RGS14 is a GTPase-activating protein (GAP) for the G i ␣ subfamily but not for the G q ␣, G s ␣, or G 12/13 ␣ subfamily (10). It possesses an N-terminal RGS domain that is necessary and sufficient for its GAP activity and several other domains, including two Raf-like Ras-binding domains (RBD) and a GoLoco motif (7, 11). A region overlapping the first RBD domain and portion of the second RBD has been designated as a Rapinteraction domain (RID) because it mediated the interaction of RGS14 with GTP-bound forms of Rap1 and Rap2 but not Ras (12). The functional importance of this binding and whether the RBD domains might interact with other small GTPases is unknown. The GoLoco motif of RGS14 has GDP dissociation inhibitor activity (GDI) for G i ␣. Although its physiological significance remains enigmatic, the GoLoco motif does enhance the inhibitory effect of RGS14 on G i ␣ signaling triggered through th...

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“…As an RGS protein, RGS14 engages activated forms (G␣-GTP) of the G␣ i/o subfamily to stimulate G␣-directed GTP hydrolysis (7,18,19,55). Through its GPR motif, RGS14 selectively binds either inactive G␣ i1 -GDP or G␣ i3 -GDP to inhibit GDP dissociation and target RGS14 to the plasma membrane (13,20,21).…”

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confidence: 99%

Integration of G Protein α (Gα) Signaling by the Regulator of G Protein Signaling 14 (RGS14)

Brown¹,

Goswami

Branch³

et al. 2015

Journal of Biological Chemistry

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Background: RGS14 binds distinct forms of active and inactive G␣ proteins through its RGS domain and GPR motif. Results: Inactive G␣ i1 -GDP binding of the GPR motif does not preclude RGS action on active G␣ o -GTP. Conclusion: RGS14 simultaneously binds active G␣ o and inactive G␣ i1 while retaining GAP activity. Significance: These findings clarify our understanding of how RGS14 integrates signaling by distinct G protein subunits.

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The RGS (regulator of G-protein signalling) and GoLoco domains of RGS14 co-operate to regulate Gi-mediated signalling

Cited by 41 publications

References 31 publications

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

RGS14 Is a Centrosomal and Nuclear Cytoplasmic Shuttling Protein That Traffics to Promyelocytic Leukemia Nuclear Bodies Following Heat Shock

Integration of G Protein α (Gα) Signaling by the Regulator of G Protein Signaling 14 (RGS14)

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