Affinage

RGS17

Regulator of G-protein signaling 17 · UniProt Q9UGC6

Length
210 aa
Mass
24.4 kDa
Annotated
2026-06-10
33 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS17 (RGSZ2) is a GTPase-activating protein (GAP) that accelerates GTP hydrolysis on activated Gαi1-3, Gαo, and Gαz subunits and binds active Gαq, but not Gαs, thereby terminating G protein signaling downstream of dopamine-D2/Gαi and TRH/Gαq receptors (PMID:15096504). Its GAP activity is positively regulated by Ca2+ binding to conserved positions on the Gα-binding surface, which promotes Gα interaction and lowers the Km for GTP hydrolysis (PMID:30940727), and is negatively regulated by covalent SUMOylation within the RGS box (which abolishes GAP activity) and by non-covalent SUMO–SIM interactions (which block Gα-GTP binding) (PMID:22163035). At the C-terminus of mu-opioid and other GPCRs, RGS17 acts as an effector antagonist that sequesters morphine-activated Gα subunits to dampen receptor responsiveness, operating within a HINT1/PKCγ complex in which an nNOS/NO-dependent redox zinc switch releases zinc from the RGSZ2 zinc finger to recruit PKCγ and Raf-1 (PMID:15827571, PMID:18652891, PMID:22563771), while RGS17 binding to the nNOS PDZ domain restrains the nNOS/NO/NMDAR/CaMKII pathway and prevents morphine analgesic tolerance (PMID:21348811). In cancer, RGS17 drives tumor cell proliferation through a cAMP-PKA-CREB axis (PMID:19244110) and is targetable through its Gαo interaction surface by cysteine-reactive small-molecule inhibitors (PMID:28621943, PMID:21680864).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2004 High

    Established RGS17's core biochemical identity as a GAP with defined Gα selectivity, answering which heterotrimeric G proteins it regulates and how it shapes receptor signaling.

    Evidence Yeast two-hybrid, in vitro GAP assays, and cell-based cAMP/calcium signaling readouts

    PMID:15096504

    Open questions at the time
    • Did not resolve subcellular targeting or receptor-specific recruitment
    • No structural basis for Gα selectivity
  2. 2005 Medium

    Showed RGS17 functions as an effector antagonist at mu-opioid receptors by sequestering activated Gα, linking its GAP biochemistry to opioid antinociception in vivo.

    Evidence Co-IP from brain membranes and in vivo siRNA knockdown with antinociception behavior

    PMID:15827571

    Open questions at the time
    • Mechanism of sustained sequestration not defined
    • Single lab
  3. 2007 Medium

    Defined the temporal order of RGS17 action, showing Gα sequestration precedes MOR phosphorylation and internalization during morphine adaptation.

    Evidence In vivo icv administration, Co-IP from brain tissue, behavioral assay

    PMID:17634133

    Open questions at the time
    • Causal link to GRK recruitment correlative
    • Single lab
  4. 2008 Medium

    Placed RGS17 in a HINT1/PKCγ signaling complex and identified a zinc-dependent recruitment mechanism for PKCγ to the MOR.

    Evidence In vivo pharmacology (NMDAR/NOS inhibitors, zinc chelators), Co-IP, HINT1 knockdown

    PMID:18652891

    Open questions at the time
    • Stoichiometry and direct vs indirect binding within complex unresolved
    • Single lab
  5. 2009 Medium

    Identified an oncogenic role for RGS17 via the cAMP-PKA-CREB axis, distinct from its GAP-mediated signal termination.

    Evidence siRNA/overexpression in tumor cells, cAMP assays, PKA inhibition epistasis, xenografts

    PMID:19244110

    Open questions at the time
    • How a Gαi GAP raises cAMP not mechanistically reconciled
    • Single lab
  6. 2010 Medium

    Linked RGS17 to chemosensitivity by showing it blunts LPA-driven AKT survival signaling in ovarian cancer.

    Evidence siRNA knockdown/overexpression, viability and apoptosis assays, AKT phosphorylation in two cell lines

    PMID:21044322

    Open questions at the time
    • Direct connection between GAP activity and AKT modulation not established
    • Single lab
  7. 2011 Medium

    Resolved how RGS17 restrains nNOS, defining a PDZ-mediated interaction that prevents morphine analgesic tolerance.

    Evidence RGSZ2 knockout/knockdown mice, behavioral assays, pharmacological rescue, Co-IP

    PMID:21348811

    Open questions at the time
    • Direct PDZ binding affinity not quantified
    • Single lab
  8. 2011 Medium

    Uncovered SUMOylation and SUMO-SIM interactions as on/off switches for RGS17 GAP activity and Gα binding.

    Evidence SUMOylation assays, RGS-box/SIM mutagenesis, in vitro GAP and Gα-GTP binding assays

    PMID:22163035

    Open questions at the time
    • In vivo prevalence of SUMOylated RGS17 unknown
    • SUMO ligase machinery not identified
  9. 2011 Medium

    Connected RGS17 to dual Giα/Gqα engagement in hepatocellular carcinoma and showed its abundance is set by protein degradation.

    Evidence Co-IP, knockdown/overexpression with proliferation/migration assays, miRNA inhibition

    PMID:21620966

    Open questions at the time
    • Degradation pathway/E3 ligase not identified
    • Single lab
  10. 2011 Medium

    Reconstituted the RGS17-Gαo interaction in a high-throughput format, enabling small-molecule inhibitor discovery against an oncogenic target.

    Evidence AlphaScreen protein-protein interaction assay, HTS, IC50 determination

    PMID:21680864

    Open questions at the time
    • Cellular efficacy of hits not shown
    • Single in vitro method
  11. 2012 Medium

    Generalized the RGSZ2 redox zinc switch beyond opioids, showing diverse GPCRs trigger nNOS/NO-dependent zinc release that recruits PKCγ and Raf-1.

    Evidence Co-IP across multiple GPCR systems with zinc chelation and NOS inhibition

    PMID:22563771

    Open questions at the time
    • Identity of the relevant zinc finger residues not pinpointed
    • Single lab
  12. 2017 Medium

    Defined a cysteine-dependent inhibitor binding mechanism, providing a chemical strategy to disrupt the RGS17-Gαo interaction.

    Evidence AlphaScreen, site-directed mutagenesis, ITC, mass spectrometry

    PMID:28621943

    Open questions at the time
    • Cysteine reactivity raises selectivity concerns
    • Single lab
  13. 2019 High

    Provided a structural basis for Ca2+ as a positive regulator of GAP activity, refining how RGS17 catalysis is tuned by divalent cations.

    Evidence 1.5-Å crystal structure, NMR chemical shift perturbation, binding affinity and GTPase assays

    PMID:30940727

    Open questions at the time
    • Physiological Ca2+ concentration dependence in cells not tested
    • Interplay with SUMO regulation unaddressed
  14. 2025 Medium

    Placed RGS17 upstream of the inflammatory immune cascade in cisplatin ototoxicity using hair-cell-specific knockout.

    Evidence Hair-cell-specific RGS17 knockout mice, cisplatin, ABR thresholds, immunohistochemistry

    PMID:40061942

    Open questions at the time
    • Downstream signaling linking RGS17 to inflammation not defined
    • Single lab
  15. 2025 Low

    Suggested tumor-secreted RGS17 suppresses CD8+ T cell glycolysis and cytotoxicity via PI3K/AKT, extending its oncogenic role to immune evasion.

    Evidence Tumor knockdown, conditioned media transfer, T cell function/glycolysis assays, PI3K/AKT Western blot

    PMID:40627213

    Open questions at the time
    • Mechanism inferred without reconstitution or epistasis confirmation
    • How an intracellular GAP acts as a secreted factor unexplained
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RGS17's biochemical GAP activity is mechanistically reconciled with its opposing roles in cAMP-PKA-CREB proliferation, AKT modulation, and immune evasion remains unresolved.
  • No unifying model linking GAP activity to downstream cAMP/AKT phenotypes
  • Regulatory crosstalk between Ca2+, SUMO, and zinc-switch states untested in vivo
  • Endogenous degradation machinery controlling RGS17 abundance unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
GNAI1GNAO1GNAQGNAZHINT1NOS1OPRM1PRKCG
Complex memberships
RGSZ2-HINT1-nNOS complex at mu-opioid receptor C-terminus

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 RGS17 (RGSZ2) acts as a GTPase-activating protein (GAP) for Gαi1-3, Gαo, and Gαz subunits, and interacts with active forms of Gαi1-3, Gαo, Gαz, and Gαq but not Gαs. RGS17 exhibits limited selectivity for Gαo among Gi/Go proteins, unlike the highly Gz-selective RGSZ1. In cellular assays, RGS17 reduced dopamine-D2/Gαi-mediated inhibition of cAMP formation and abolished TRH receptor/Gαq-mediated calcium mobilization. Yeast two-hybrid screening, in vitro pull-down assay, co-immunoprecipitation, pre-steady-state and steady-state GTPase assays, cell-based cAMP and calcium signaling assays The Journal of biological chemistry High 15096504
2005 RGSZ2 (RGS17) co-precipitates with mu-opioid receptors (MORs) and Gαz (but not other Gα subunits) in periaqueductal gray matter membranes. Morphine challenge increases RGSZ2 association with MORs while Gi/o/z subunits dissociate from MORs. RGSZ2 influences MOR signaling by sequestering Gα subunits, functioning as an effector antagonist. Knockdown of RGSZ2 augmented antinociceptive responses to morphine and DAMGO via mu-opioid receptors. Co-immunoprecipitation from brain membrane fractions, in vivo siRNA knockdown with behavioral antinociception assay, Western blot Neuropsychopharmacology Medium 15827571
2007 Morphine induces long-lasting transfer of MOR-activated Gα subunits to RGSZ2 proteins in neurons, causing sustained sequestration that reduces receptor responsiveness and precedes MOR phosphorylation and internalization. This Gα sequestration by RGSZ2 is associated with increased free Gβγ, GRK-mediated phosphorylation, and MOR endocytosis. In vivo intracerebroventricular drug administration, co-immunoprecipitation from brain tissue, Western blot, behavioral antinociception assay Molecular pain Medium 17634133
2008 RGSZ2 (RGS17) is part of a complex at the C-terminus of the mu-opioid receptor (MOR) with HINT1/PKCI. Morphine-activated NMDAR/nNOS cascade generates free zinc ions that recruit inactive PKCγ to the MOR via the HINT1/RGSZ complex through PKC C1 cysteine-rich domains. PKCγ then phosphorylates the MOR to reduce signal strength. Intracerebroventricular drug administration in vivo, co-immunoprecipitation, HINT1 knockdown, pharmacological inhibitors of NMDAR (MK801), NOS (SNAP/TPEN), phorbol esters, Western blot Cellular signalling Medium 18652891
2009 RGS17 promotes tumor cell proliferation through the cAMP-PKA-CREB pathway: RGS17 increases cAMP levels, enhances forskolin-mediated cAMP production, promotes CREB phosphorylation, and enhances CREB-responsive gene expression. Inhibition of cAMP-dependent kinase (PKA) prevents tumor cell proliferation, which is partially rescued by RGS17 overexpression. siRNA knockdown and overexpression in tumor cells, exon microarray and transcript analysis, cAMP measurement assays, forskolin stimulation, PKA inhibition, colony formation, xenograft in nude mice Cancer research Medium 19244110
2011 RGSZ2 binds to the PDZ domain of neural nitric oxide synthase (nNOS) via PDZ-binding motifs upstream of and within the RGSZ2 RGS box, negatively regulating nNOS activity. In RGSZ2-deficient mice, morphine over-stimulates the nNOS/NO/NMDAR/CaMKII pathway, causing rapid analgesic tolerance. Recovery of RGSZ2 levels or inhibition of nNOS, PKC, NMDAR, or CaMKII restored MOR signaling. RGSZ2 knockout/knockdown mice, intracerebroventricular drug administration, behavioral antinociception assay, pharmacological inhibition of nNOS/NMDAR/CaMKII/PKC, co-immunoprecipitation, Western blot Antioxidants & redox signaling Medium 21348811
2011 RGSZ2 undergoes covalent SUMOylation within its RGS box (RH domain), which abolishes GAP activity without affecting binding to GPCR-activated GαGTP subunits. Non-covalent SUMO binding to SUMO-interacting motifs (SIMs) within the RH domain blocks RGSZ2 from interacting with GαGTP subunits. A third SIM upstream of the RH domain can mediate regulatory interactions with sumoylated proteins without affecting GαGTP binding or GAP activity. SUMOylation assays, mutagenesis of RGS box and SIM motifs, in vitro GAP assays, GαGTP binding assays, immunoprecipitation PloS one Medium 22163035
2011 RGS17 associates with both Giα and Gqα subunits in hepatocellular carcinoma (HCC) cells. Altering RGS17 expression profoundly affected HCC cell mitogenesis and migration. RGS17 protein levels are governed by protein degradation rather than by miRNAs in HCC cells. Co-immunoprecipitation in human and rat HCC cells, siRNA knockdown and overexpression, cell proliferation and migration assays, miRNA inhibition experiments Cellular signalling Medium 21620966
2012 RGSZ2 functions as a redox zinc switch in neurons: agonist activation of a broad panel of GPCRs stimulates the RGSZ2-nNOS complex to produce NO, which releases zinc ions from the RGSZ2 zinc finger in a nNOS/NO-dependent mechanism, subsequently recruiting PKCγ and Raf-1 to the C-terminus or third internal loop of the activated GPCR. Co-immunoprecipitation of RGSZ2-nNOS-GPCR complexes, zinc chelation (TPEN), NOS inhibition, pharmacological activation of multiple GPCRs, Western blot Antioxidants & redox signaling Medium 22563771
2010 RGS17 knockdown significantly reduces chemotherapy-induced cell toxicity (cisplatin, vincristine, docetaxel) in ovarian cancer cells. RGS17 overexpression blocked LPA-mediated AKT activation, suggesting RGS17 blunts AKT survival signaling. Loss of RGS17 expression contributes to chemoresistance through amplification of AKT signals. siRNA knockdown, RGS17 overexpression, cell viability assays, phosphatidylserine externalization (apoptosis) assay, AKT phosphorylation by Western blot in SKOV-3 and MDR-HeyA8 cells Molecular cancer Medium 21044322
2019 Crystal structure of RGS17 at 1.5-Å resolution reveals Ca2+ bound to conserved positions on the predicted Gα-binding surface. NMR chemical shift perturbations confirmed Ca2+ binds the same site in solution. RGS17 has >55-fold higher affinity for Ca2+ than Mg2+. Ca2+ promotes RGS17 interaction with activated Gα and decreases the Km for GTP hydrolysis, suggesting Ca2+ positively regulates RGS17 GAP activity. X-ray crystallography (1.5-Å), NMR chemical shift perturbation assay, binding affinity measurements (Ca2+ vs Mg2+), in vitro GTPase assay with Ca2+ The Journal of biological chemistry High 30940727
2017 Natural product inhibitors of RGS17 (sanguinarine and celastrol) bind RGS17 through a cysteine-dependent mechanism, verified by site-directed mutagenesis and cysteine reactivity assessment. These compounds inhibit the RGS17-Gαo protein-protein interaction with IC50 values in high nanomolar to low micromolar range, with dissociation constants confirmed by ITC. High-throughput AlphaScreen assay, site-directed mutagenesis, isothermal titration calorimetry (ITC), mass spectrometry, Western blot, confocal microscopy, cytotoxicity assays Journal of natural products Medium 28621943
2011 The RGS17-Gαo protein-protein interaction was reconstituted and quantified using AlphaScreen technology, enabling high-throughput screening. Small-molecule inhibitors of the Gαo-RGS17 interaction were identified with IC50 values <10 µM. AlphaScreen protein-protein interaction assay, high-throughput screening of NCI Diversity Set II, dose-response IC50 determination Journal of biomolecular screening Medium 21680864
2025 RGS17 knockout in cochlear hair cells protects against cisplatin-induced outer hair cell loss, elevation of auditory brainstem response thresholds, cochlear inflammation (reduced CXCL1, CD45+, and CD68+ immune cells), and inner hair cell synaptopathy, placing RGS17 upstream of the inflammatory immune cascade in cisplatin ototoxicity. Hair-cell-specific RGS17 knockout mice, cisplatin treatment protocol, auditory brainstem response (ABR) threshold measurement, immunohistochemistry for CXCL1/CD45/CD68, hair cell counting Frontiers in immunology Medium 40061942
2025 Tumor-secreted RGS17 impairs CD8+ T cell cytotoxicity in lung adenocarcinoma by reducing IFN-γ and Granzyme B secretion and inhibiting glycolysis (reduced glucose consumption, lactate production, and ECAR) via the PI3K/AKT pathway. RGS17 knockdown in tumor cells increased CD8+ T cell tumor infiltration. RGS17 knockdown in tumor cells, conditioned media transfer to CD8+ T cells, flow cytometry for T cell function (IFN-γ/Granzyme B), glycolysis measurement (ECAR, glucose consumption, lactate production), Western blot for PI3K/AKT pathway components Discover oncology Low 40627213

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Hsa-mir-182 suppresses lung tumorigenesis through down regulation of RGS17 expression in vitro. Biochemical and biophysical research communications 95 20420807
2009 RGS17, an overexpressed gene in human lung and prostate cancer, induces tumor cell proliferation through the cyclic AMP-PKA-CREB pathway. Cancer research 88 19244110
2004 RGS17/RGSZ2, a novel regulator of Gi/o, Gz, and Gq signaling. The Journal of biological chemistry 72 15096504
2010 Regulators of G-Protein signaling RGS10 and RGS17 regulate chemoresistance in ovarian cancer cells. Molecular cancer 67 21044322
2009 Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene. Clinical cancer research : an official journal of the American Association for Cancer Research 63 19351763
2017 miR-203 inhibits cell proliferation, invasion, and migration of non-small-cell lung cancer by downregulating RGS17. Cancer science 59 28921827
2005 The RGSZ2 protein exists in a complex with mu-opioid receptors and regulates the desensitizing capacity of Gz proteins. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 57 15827571
2008 NMDAR-nNOS generated zinc recruits PKCgamma to the HINT1-RGS17 complex bound to the C terminus of Mu-opioid receptors. Cellular signalling 53 18652891
2018 MicroRNA-199 suppresses cell proliferation, migration and invasion by downregulating RGS17 in hepatocellular carcinoma. Gene 37 29559347
2007 Morphine induces endocytosis of neuronal mu-opioid receptors through the sustained transfer of Galpha subunits to RGSZ2 proteins. Molecular pain 37 17634133
2006 RGS17/RGSZ2 and the RZ/A family of regulators of G-protein signaling. Seminars in cell & developmental biology 34 16765607
2011 RGSZ2 binds to the neural nitric oxide synthase PDZ domain to regulate mu-opioid receptor-mediated potentiation of the N-methyl-D-aspartate receptor-calmodulin-dependent protein kinase II pathway. Antioxidants & redox signaling 31 21348811
2013 RGS17: an emerging therapeutic target for lung and prostate cancers. Future medicinal chemistry 29 23734683
2012 GPCRs promote the release of zinc ions mediated by nNOS/NO and the redox transducer RGSZ2 protein. Antioxidants & redox signaling 29 22563771
2007 Ontogenetic quinpirole treatment produces long-lasting decreases in the expression of Rgs9, but increases Rgs17 in the striatum, nucleus accumbens and frontal cortex. The European journal of neuroscience 25 17970732
2019 MiRNA-199 inhibits malignant progression of lung cancer through mediating RGS17. European review for medical and pharmacological sciences 22 31081094
2017 Natural Products Discovered in a High-Throughput Screen Identified as Inhibitors of RGS17 and as Cytostatic and Cytotoxic Agents for Lung and Prostate Cancer Cell Lines. Journal of natural products 21 28621943
2019 Long non-coding RNA Linc00483 accelerated tumorigenesis of cervical cancer by regulating miR-508-3p/RGS17 axis. Life sciences 20 31454494
2011 Altered expression and function of regulator of G-protein signaling-17 (RGS17) in hepatocellular carcinoma. Cellular signalling 18 21620966
2021 Hsa-miR-149-5p Suppresses Prostate Carcinoma Malignancy by Suppressing RGS17. Cancer management and research 17 33790651
2015 Deregulation of RGS17 Expression Promotes Breast Cancer Progression. Journal of Cancer 16 26185539
2011 Development of a novel high-throughput screen and identification of small-molecule inhibitors of the Gα-RGS17 protein-protein interaction using AlphaScreen. Journal of biomolecular screening 16 21680864
2012 Variation in regulator of G-protein signaling 17 gene (RGS17) is associated with multiple substance dependence diagnoses. Behavioral and brain functions : BBF 14 22591552
2011 SUMO-SIM interactions regulate the activity of RGSZ2 proteins. PloS one 12 22163035
2019 MiR-203 inhibits the malignant behavior of prostate cancer cells by targeting RGS17. European review for medical and pharmacological sciences 8 31298318
2018 RGS17 inhibits tumorigenesis and improves 5-fluorouracil sensitivity in nasopharyngeal carcinoma. OncoTargets and therapy 8 30464507
2017 G-Protein Signaling Protein-17 (RGS17) Is Upregulated and Promotes Tumor Growth and Migration in Human Colorectal Carcinoma. Oncology research 8 28337960
2019 High-resolution structure of RGS17 suggests a role for Ca2+ in promoting the GTPase-activating protein activity by RZ subfamily members. The Journal of biological chemistry 4 30940727
2022 Circ_0006220 promotes non-small cell lung cancer progression via sponging miR-203-3p and regulating RGS17 expression. Human & experimental toxicology 3 35041543
2025 Role of RGS17 in cisplatin-induced cochlear inflammation and ototoxicity via caspase-3 activation. Frontiers in immunology 2 40061942
2018 Screen Targeting Lung and Prostate Cancer Oncogene Identifies Novel Inhibitors of RGS17 and Problematic Chemical Substructures. SLAS discovery : advancing life sciences R & D 2 29351497
2025 Tumor-secreted RGS17 impairs CD8 + T cell function in lung adenocarcinoma through affecting glucose metabolism mediated by PI3K/AKT pathway. Discover oncology 1 40627213
2023 Hsa_circ_0000285-Mediated miR-599/RGS17 Axis Participates in the Pathogenesis of Abdominal Aortic Aneurysm by Regulating the Functions of Vascular Smooth Muscle Cells. Annals of clinical and laboratory science 1 37094862

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