Introduction

Regulator of G protein signaling (RGS) proteins, which modulate G protein-coupled receptors (GPCRs, located in cellular membrane and transmit outer signals into the intra-cellular environment) function, facilitate various downstream cellular signaling through regulating kinds of heterotrimeric G proteins by the acceleration of the intrinsic guanosine triphosphatase (GTPase) activity of their Gα subunits [1, 2]. In most cases, regulation of RGS proteins gives rise to the inhibition of multiple downstream G protein signaling pathways [3], and RGS proteins are thereby recognized by many researchers as the important downstream nodes of those GPCRs [4]. Since the discovery of RGS proteins in different species including yeast, Caenorhabditis elegans as well as mammalian cells in the 1990s [5,6,7,8], their pivotal role in altering cell proliferation, survival and death via controlling downstream cellular signaling activities has provided with the evidence that RGS proteins are potentially involved in sustaining normal physiological functions and that dysregulation of RGS proteins is closely associated with pathologies of many diseases such as cancer. In this review, we summarize the history and structure of RGS, and its role in cancer, and further discuss the molecular mechanisms governing the expression of RGS proteins, offering implications of these new discoveries for novel targeted drug development and related cancer therapy in the future.

A brief description for history of RGS protein discovery

The discovery of RGS proteins is achieved through a series of studies by different experimental systems. In the period of 1995 to 1997, experiments in Saccharomyces cerevisiae revealed the novel factor Sst2 that modulates Gpa1 (a G subunit in yeast) is involved in the regulation of pheromone sensitivity [9, 10]. Additional work performed in 1996 using the nematode C. elegans detected the mutations in the gene egl-10, which reflected mutations in GOA1 that participates in other signalings and in mammals are analogous to G proteins [7]. Later in 1997, egl-10 and Sst2 were genes found to share similar sequences to each other, and then several groups proposed that they could be a potentially new class of GPCR regulators in mammals [1, 7, 8]. Subsequently, the importance of these novel findings were proved by various experiments in rapid publication of papers from several independent research groups, and the main results and conclusions are as follows (Fig. 1): (1) RGS proteins bound with the ∝ subunits of G-protein directly; (2) the interaction of RGS with these subunits potentiated the GTP hydrolysis rate by G∝ (referring to GAP activity); (3) different RGS proteins specifically recognized their targeted G subunits, respectively [2, 6, 11]. The mechanisms underlying RGS protein activity regulation was further deciphered by a report later, showing how those proteins catalytically promoted GTP hydrolysis by G∝ subunits through stabilizing the transition state for GTP hydrolysis, and this finding established the canonical functions of RGS proteins, including GTPase-activating or GAP activity [5].

Fig. 1
figure 1

The schematic graph showing canonical regulation of GPCR signaling by RGS proteins. Upon bound with some agonist, GPCRs undergo a conformation change that facilitates the exchange of GDP for GTP on the a subunit of the heterotrimeric complex. Both GTP-bound Ga in the active form and the released Gbg dimer can subsequently stimulate the corresponding downstream signaling. RGS proteins are GAPs for Ga, which function to terminate signalling through GPCRs by accelerating the intrinsic GTPase activity of Ga and promoting reassociation of the heterotrimeric complex with the receptor at the cell membrane

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RGS protein family and RGS protein structure

In mammals, members of the R4 family of RGS proteins were the first ones clarified and studied, which are now typified by RGS4. Among all the RGS proteins, the RGS4 family represents the least structurally and functionally complex. To date, members of RGS proteins have been divided into different families, based on their varied structures and functions. The different RGS proteins were established and were named after their prototypical members, including A/RZ family, B/R4 family, C/R7 family, D/R12 family, E/RA family, F/GEF family and G/GRK family, among which, the A/RZ, B/R4, C/R7 and D/R12 families constitute the canonical RGS proteins [12] (Fig. 2). All the canonical RGS proteins possess the conserved RGS domain with a length of approximately 120 amino acids (aa), which is consisted of nine α-helices structures that can be subdivided further into two subdomains [4]: (1) the first subdomain that forms a smaller helix bundle and is consisted of series of helices including αI, II, III, VIII and IX; and (2) the larger bundle subdomain comprises four helices including αIV, V, VI and VII [13]. Different from the B/R4 family, which is with RGS4 as its prototypical member, the other RGS proteins contain multiple domains that participate in the interaction with various proteins beyond the G∝ and possess more complex domains of cellular function, such as the domain from presence in proteins PSD-95, Dlg and ZO-1/2 domains (PDZ domains), G-protein ∝-like domains (GGL), domain present in disheveled and axin (DAX) domains, kinase domains, Dbl homology/pleckstrin homology domains (DH), G-protein regulatory motif (GoLoco) domains, ∝-catenin–binding domains as well as Ras-binding domains (RBD). To date, there have been at least 20 distinct RGS proteins classified, which play various regulatory roles and can be divided into seven families [14]: A/RZ family includes RGS17, RGS19 and RGS20; B/R4 family includes RGS1, RGS2, RGS3, RGS4, RGS5, RGS8, RGS13, RGS16, RGS18, RGS21; C/R7 family includes RGS6, RGS7, RGS9 and RGS11; D/R12 family includes RGS10, RGS12 and RGS14; E/RA family includes Axin and Axin2; F/GEF family includes P115-RhoGEF, GRK2 and RGS22; G/GRK family includes GRK1, GRK4, GRK5, GRK6 and GRK7. However, as some RGS proteins with a number of genetic variations continue to be revealed, the number of new RGS proteins discovered is still increasing, such as the RGS6 protein that possesses several splicing variants with varied functions and cellular localization [15], and the RGS14 protein with genetic variants that disrupt downstream signaling activation [16].

Fig. 2
figure 2

The schematic lists of the family of RGS proteins. The different RGS proteins were established and were named after their prototypical members, and the A/RZ, B/R4, C/R7 and D/R12 families constitute the canonical RGS proteins

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A previous study in 1997 has already identified the structure of RGS protein with the classification of RH (RGS homology) domain [13]. In that study, the crucial structural determinants of the interaction of RGS protein with G determinants of the interaction of RGS protein with G∝ have also been revealed, which has established the structural basis for its GAP activity. As their function of negative mediators in G-protein signaling, RGS proteins are found to mainly exert their effects on regulating GAP activity on α subunits of G-proteins, particularly the Gi/o and Gq families of G-proteins. Although there are yet no reports confirming the GAP activity of any RGS domain against Gαs, emerging evidence has come out that RGS proteins are able to indirectly regulate Gαs downstream signaling through their interaction with subtypes of adenylate cyclase (AC) [17]. Despite the functions of the non-RH domains in RGS proteins, the RH domain is still most studied today, which is attracting the attention of researchers around the world for identifying and develo** novel inhibitors to suppress RGS activity to control kinds of downstream cellular signaling and to further help provide interventions of related diseases.

Mechanisms regulating RGS expression

Previous studies have provided evidence that the levels of RGS proteins are initially associated with the mechanisms that mediate the local concentration of those proteins at the site of a cell signaling. In addition, RGSexpression is also affected by other factors, including its regulation of protein stability, regulation at transcriptional levels, epigenetic regulation, regulation of subcellular localization as well as the environmental conditions such as hypoxia [3, 18,19,20,21,22,23,24,25] (Fig. 3), which allow RGS protein levels to be altered at both an acute and a chronic manner.

Fig. 3
figure 3

Summary of mechanisms regulating RGS proteins expression. RGS protein expression is affected by different factors, including regulation of protein stability (degradation regulation and post-translational modification), transcriptional regulation, epigenetic regulation (DNA methylation and histone deacetylation), and other factors such as hypoxia

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Regulation of RGS protein stability

Protein degradation is a dynamic but essential process employed by all of the cells to efficiently and precisely modulate the levels of stable proteins, resulting in the proper functions of those proteins for cells [26, 27]. The degradation commonly undergoes through either of the two ways, including (1) lysosomal proteolysis pathway; and (2) ubiquitin proteasome pathway [28]. Among the two pathways, the lysosomal proteolysis is triggered by proteins such as the lysosomal engulf proteins and the associated digestive enzymes, while the ubiquitin proteasome pathway degrades proteins through regulating poly-ubiquitination of the targeted proteins. During this process, the proteins that complete poly-ubiquitination can be recognized by a large and complex molecular machine, the proteasome complex, which subsequently binds to and degrades the targeted proteins eventually. Evidence has emerged that multiple enzymes participate in regulating the ubiquitin proteasome-dependent protein degradation, including the ubiquitin-activating enzymes (E1), the ubiquitin-conjugating enzymes (E2) and the ubiquitin ligases (E3), and compared to the lysosomal degradation pathway, ubiquitin proteasome pathway requires more energy.

The expression of RGS proteins is affected by their protein stability. In the past decade, previous studies have demonstrated the potential role of RGS4 as a target for degradation by proteasome [29]. The mechanisms underlying RGS4 protein degradation is due the regulation by the N-end rule pathway, a subset of the ubiquitin-mediated proteolytic pathway. The N-end rule pathway potentiates the targeted protein degradation by its recognition of the certain amino acid residues at the N-termini of those proteins. Based on the N-termini residue, the N-end rule pathway can be further subdivided into three types in eukaryotes, including the Arg/N-end rule pathway, the Ac/N-end rule pathway and the Pro/N-end rule pathway, which correspondingly recognizes the basic, acidic, amidated, and bulky hydrophobic N-termini residues, the Nα-terminally acetylated N-termini residues, and the N-termini-Pro residue or a Pro residue at position 2 in the presence of adjoining sequence motifs [30, 31]. A previous report has indicated that blocking of the N-end rule pathway efficiently suppresses the degradation and ubiquitination of RGS4 proteins in the reticulocyte lysate system [29], while the existence of MG132, a kind of proteasome inhibitor, inhibits RGS4 protein degradation but concurrently increased the protein levels of RGS4 that were poly-ubiquitinated, which further provides with the evidence that RGS4 protein is degraded through the N-end rule pathway. Interestingly, RGS4 protein degradation is also observed to be regulated by nitric oxide, which oxidizes the N-termini-cysteine residue that is necessary for the subsequent arginylation [32]. In addition to RGS4 protein, some other RGS proteins are also involved in the regulation by the N-end rule pathway, including RGS16, RGS5 as well as RGS2 [32,33,34]. Particularly, unlike RGS4, the proteasomal degradation of RGS2 protein requires a protein complex that includes DNA damage binding protein 1 (DDB1), F-box only protein 44 (FBXO44) and cullin 4B (CUL4B) [35]. Recently, the expression of RGS proteins has also been found to be affected by their stability through other mechanisms, such as the RGS9-2 protein that is specifically expressed in striatal neurons and functions mainly in the brain [36]. It is reported that, different from many other RGS proteins, RGS9-2 protein is mainly mediated by the lysosomal degradation pathway, and the proteolytic stability of RGS9-2 protein is controlled by R7 family binding protein (R7BP), which is determined as a newly discovered partner for RGS9-2. Another example is the RGS7 protein that belongs to the R7 family of RGS proteins, whose stabilization is specifically modulated by the binding partner Gβ5 [37]. Post-translational modifications, such as protein phosphorylation, are also confirmed to be strongly associated with RGS protein stabilization. Phosphorylation plays a key role in regulating the activities of a variety of cellular signaling pathways by affecting the expression, localization and stabilization of the targeted proteins, which consequently leads to alterations in cell proliferation, apoptosis, survival, mobility and possible malignancy as well [38]. To date, multiple phosphorylating sites have been figured out in different RGS proteins, which give rise to alterations in stability and activity of the RGS proteins. One example is the RGS16 protein that is phosphorylated constitutively at serine 194 (Ser 194) site and undergoes dynamical phosphorylation at the Ser 53 site induced by the activation of α2A-adrenoceptor. The altered phosphorylation levels of RGS16 protein contribute to the inhibition of GAP activity in RGS16, whereas RG16 phosphorylation at Tyr 168 potentiates not only the GAP activity but also the stability of RGS16 protein [39, 40], suggesting RGS16 levels and functions are closely associated with its phosphorylation status. One phenomenon that attracts many researchers’ attention is that, during the phosphorylation regulation, different RGS proteins can be affected by one same kinase. One famous example is the protein kinase A (PKA), a cAMP-dependent protein kinase that is involved in affecting various diseases including cancers in human [41, 42]. PKA is demonstrated to enhance RGS13 activity to negatively regulate CREB-induced transcription of target genes by facilitating the nuclear localization of RGS13, and concurrently, PKA blocks the proteasome degradation of RGS13 protein by its induction in phosphorylation at Thr 41 of RGS13 [43]. Similarly, PKA activation is also involved in promoting the nuclear trans-location of RGS10 protein. In addition to phosphorylation, other post-translational modifications have also been shown to be associated with RGS protein stability, such as protein palmitoylation [

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This paper was funded by Starting Research Foundation of The Children’s Hospital, Zhejiang University School of Medicine (No. 481), Foundation for The Top-Notch Youth Talent Cultivation Project of Independent Design Project of National Clinical Research Center for Child Health (No. Q21A0006), and National Natural Science Foundation of China (No. 31801207) to C. T.

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  1. National Clinical Research Center for Child Health of the Children’s Hospital, Zhejiang University School of Medicine, No. 3333, Binsheng Rd., Hangzhou, 310052, People’s Republic of China

    Lin Li, Qiang Xu & Chao Tang

  2. Department of Urology, Third Affiliated Hospital of the Second Military Medical University, Shanghai, 201805, China

    Lin Li

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Li, L., Xu, Q. & Tang, C. RGS proteins and their roles in cancer: friend or foe?. Cancer Cell Int 23, 81 (2023). https://doi.org/10.1186/s12935-023-02932-8

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