Affinage

RGS12

Regulator of G-protein signaling 12 · UniProt O14924

Length
1447 aa
Mass
156.4 kDa
Annotated
2026-06-10
38 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS12 is a large multi-domain scaffold protein that integrates heterotrimeric G-protein regulation with receptor tyrosine kinase and MAPK signaling across diverse cell types (PMID:9651375, PMID:17380122). Its catalytic RGS box acts as a GTPase-activating protein selective for Gi-class Gα subunits, while a separate C-terminal GoLoco motif binds GDP-bound Gαi1/2/3 and functions as a guanine-nucleotide dissociation inhibitor, giving RGS12 dual, opposing control over the Gαi nucleotide cycle (PMID:9651375, PMID:11387333). The protein also carries protein-interaction modules — an N-terminal PDZ domain and a PTB domain — that target it to specific partners: the PDZ domain recognizes C-terminal motifs of GPCRs such as CXCR2 (PMID:9651375), and the PTB domain binds tyrosine-phosphorylated effectors, including the Cav2.2 synprint region at phospho-Tyr-804 to set the kinetics of voltage-independent calcium-channel inhibition in DRG neurons (PMID:11130074, PMID:15536086) and cSrc-phosphorylated Gαi to accelerate its deactivation (PMID:24578342). Through its PTB domain RGS12 assembles activated Ras/B-Raf/MEK2 with TrkA to sustain ERK activation required for NGF-driven neurite outgrowth (PMID:17380122). In skeletal and immune tissues RGS12 drives osteoclast differentiation via RANKL-induced PLCγ/Ca²⁺/NFAT2 signaling and osteoblast differentiation via a Gαi–ERK axis (PMID:17042716, PMID:30489658), and it activates NF-κB by promoting IκB ubiquitination and p65 nuclear translocation in macrophages (PMID:32512384, PMID:35873013). RGS12 is essential for hearing, where it polarizes the GPSM2–GNAI(GDP) complex to organize stereocilia (PMID:36260679), and it supports mitochondrial oxidative phosphorylation in chondrocytes and trophoblasts by promoting tyrosine phosphorylation of ATP synthase subunits (PMID:32922858, PMID:41663754). The PDZ domain further engages PTEN, NHERF1/NPT2A, and YAP/TEAD signaling, and its disruption by a bipolar-disorder-associated R59Q variant weakens ligand binding (PMID:33198557, PMID:39518985, PMID:39293332, PMID:33686240).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1998 High

    Established RGS12's core biochemical identity — a Gi-selective GAP whose PDZ domain targets specific GPCRs — defining it as a receptor-coupled signal-termination scaffold rather than a simple GAP.

    Evidence In vitro GTPase assay and yeast two-hybrid/biochemical PDZ-binding mapping

    PMID:9651375

    Open questions at the time
    • Cellular context of CXCR2 desensitization not tested in vivo
    • Whether PDZ targeting couples GAP activity to receptor not resolved biochemically
  2. 2000 Medium

    Showed that distinct RGS12 isoforms localize to the nucleus and associate with mitotic chromosomes, raising a cell-cycle/nuclear role separate from G-protein signaling.

    Evidence Confocal microscopy, subcellular fractionation, and live-cell imaging in COS-7 cells

    PMID:10869340

    Open questions at the time
    • Nuclear molecular function unidentified
    • No partners defined for the nuclear isoform
    • Link between nuclear localization and abnormal nuclei mechanistically unexplained
  3. 2000 High

    Demonstrated that the PTB domain, not PDZ or RGS domains, recruits RGS12 to the N-type calcium channel to tune voltage-independent inhibition, defining a domain-specific effector-coupling mechanism in neurons.

    Evidence Co-IP from endogenous DRG neurons plus domain-specific fusion-protein microinjection with electrophysiology

    PMID:11130074

    Open questions at the time
    • Identity of the activating tyrosine kinase not established
    • Direct channel-binding site not yet mapped
  4. 2001 High

    Resolved that RGS12 has a second, independent G-protein activity — a GoLoco-motif GDI that stabilizes GDP-bound Gαi — making RGS12 bifunctional within a single polypeptide.

    Evidence In vitro GTPγS binding, intrinsic tryptophan fluorescence, and AlF4⁻ conformational assays

    PMID:11387333

    Open questions at the time
    • How GAP and GDI activities are coordinated in cells unclear
    • No structural picture of full-length domain arrangement
  5. 2004 High

    Mapped the PTB–channel interaction to phospho-Tyr-804 of the Cav2.2 synprint region, mechanistically grounding phosphorylation-dependent recruitment in signal-termination kinetics.

    Evidence Protein overlay, surface plasmon resonance, peptide pulldown, and phospho-peptide microinjection electrophysiology

    PMID:15536086

    Open questions at the time
    • Kinase responsible for Tyr-804 phosphorylation not identified
    • Stoichiometry within native channel complex unknown
  6. 2005 Medium

    Extended RGS12 scaffolding to receptor tyrosine kinases by showing its PDZ/PTB region binds the PDGFβ receptor and dampens MAPK activation, indicating broad RTK regulatory capacity.

    Evidence Co-IP, domain-overexpression ERK assays, and confocal co-localization in airway smooth muscle cells

    PMID:16214305

    Open questions at the time
    • Endogenous loss-of-function not tested
    • Phospho-dependence of PDGFβR binding not mapped
  7. 2007 High

    Defined RGS12 as a positive ERK scaffold downstream of TrkA, assembling Ras/B-Raf/MEK2 to drive NGF-specific neurite/axon outgrowth — a function opposite to its RTK-dampening role.

    Evidence Co-IP for complex assembly plus siRNA knockdown with receptor-selective outgrowth assays in PC12 and DRG neurons

    PMID:17380122

    Open questions at the time
    • Which RGS12 domain anchors each MAPK-cascade component not fully resolved
    • Reconciliation with negative PDGF regulation not addressed
  8. 2007 Medium

    Connected RGS12 to bone remodeling by showing it is required for RANKL-induced Ca²⁺ oscillations, PLCγ/NFAT2 signaling, and osteoclast differentiation.

    Evidence RNAi silencing, Co-IP with N-type channels, calcium imaging, and immunoblotting in osteoclast-like cells

    PMID:17042716

    Open questions at the time
    • In vivo requirement not yet established at this stage
    • Direct molecular link between RGS12 and PLCγ unmapped
  9. 2013 Medium

    Provided in vivo proof that RGS12 is required in monocyte/macrophage lineage for osteoclastogenesis and bone-mass control.

    Evidence Mx1-Cre conditional knockout mouse with microCT and histomorphometry

    PMID:23349096

    Open questions at the time
    • Molecular effectors in vivo not dissected
    • Osteoblast-autonomous role not addressed here
  10. 2014 High

    Showed RGS12 PTB binding to cSrc-tyrosine-phosphorylated Gαi accelerates Gαi deactivation, integrating PTB-effector recognition with the GAP function in smooth muscle physiology.

    Evidence Co-IP, Gαi2 Tyr→Phe mutants, siRNA knockdown, cAMP, and contractility assays

    PMID:24578342

    Open questions at the time
    • Structural basis of PTB–phospho-Gαi recognition not resolved
    • Generality across Gαi isoforms in vivo untested
  11. 2017 Medium

    Identified a tumor-suppressor role in prostate cancer via repression of MNX1 and AKT activity, broadening RGS12 function to growth control.

    Evidence Knockdown/overexpression in cell lines and xenografts with AKT/MNX1 immunoblotting

    PMID:28611045

    Open questions at the time
    • Mechanism linking RGS12 domains to MNX1/AKT undefined
    • Direct binding partners in this axis not identified
  12. 2019 Medium

    Established that RGS12 PTB drives NF-κB(p65) activation in a feed-forward loop and is required for inflammatory arthritis, linking the scaffold to innate immune transcription.

    Evidence Co-IP, domain mapping, NF-κB reporter, myeloid conditional KO, and siRNA

    PMID:32512384

    Open questions at the time
    • Direct p65 vs IκB target of PTB binding not fully separated
    • Role of COX2 enhancement mechanistically incomplete
  13. 2019 High

    Demonstrated osteoblast-autonomous RGS12 function through a Gαi-ERK axis, placing GTPase, cAMP, and L-type Ca²⁺ signaling within bone formation.

    Evidence Osx-Cre conditional KO with GTPase, cAMP, Ca²⁺ imaging, PTX rescue, and ERK assays

    PMID:30489658

    Open questions at the time
    • How RGS12 couples to L-type channels mechanistically unclear
    • Relationship to its osteoclast role in same animal not integrated
  14. 2019 High

    Showed RGS12 forms a KOR complex that biases opioid signaling — attenuating G protein output while augmenting β-arrestin output — modulating striatal neurotransmission and behavior.

    Evidence Co-IP, [35S]GTPγS binding, fast-scan cyclic voltammetry, and RGS12-null behavioral phenotyping

    PMID:31141817

    Open questions at the time
    • Domain mediating KOR binding not mapped
    • Mechanism of β-arrestin augmentation unknown
  15. 2019 Medium

    Extended RGS12's developmental roles to skeletal muscle by showing it is required for myoblast differentiation and injury repair.

    Evidence Pax7-Cre conditional KO with ex vivo differentiation and cardiotoxin regeneration model

    PMID:31408461

    Open questions at the time
    • Molecular signaling pathway in myoblasts undefined
    • Domain requirement untested
  16. 2020 Medium

    Revealed an unexpected mitochondrial role: RGS12 localizes to chondrocyte mitochondria and promotes ATP5A tyrosine phosphorylation to sustain oxidative phosphorylation and prevent apoptosis.

    Evidence Mitochondrial fractionation, Col2a1-Cre conditional KO, OXPHOS/membrane potential assays, and ATP5A phospho-immunoblotting

    PMID:32922858

    Open questions at the time
    • Whether RGS12 directly mediates phosphorylation or recruits a kinase unknown
    • How a G-protein scaffold reaches the mitochondrial matrix unexplained
  17. 2020 Medium

    Linked RGS12 to serotonergic neurotransmission by showing null mice have altered SERT and affective behaviors.

    Evidence Global Rgs12 KO with SERT uptake/immunoblotting and behavioral battery

    PMID:32842837

    Open questions at the time
    • Direct molecular interaction with SERT or upstream receptors not shown
    • Region-specific cell type not defined
  18. 2020 Medium

    Identified a PDZ-mediated RGS12–PTEN interaction that enhances PTEN phospho/SUMOylation and suppresses AKT/mTOR, providing a tumor-suppressor mechanism in oral squamous cell carcinoma.

    Evidence PDZ Co-IP, CMV-Cre KO with 4NQO OSCC model, knockdown/overexpression, and pathway immunoblotting

    PMID:33198557

    Open questions at the time
    • Whether PDZ binds PTEN directly or via adaptor unresolved
    • Reconciliation with growth-promoting roles elsewhere not addressed
  19. 2021 Medium

    Detailed how RGS12 drives IκB ubiquitination/degradation and NF-κB activation to promote osteoarthritis inflammation, deepening its pro-inflammatory mechanism.

    Evidence Ubiquitin–IκB Co-IP, MG132 rescue, RGS12 KO OA model, and immunoblotting

    PMID:35873013

    Open questions at the time
    • E3 ligase recruited by RGS12 not identified
    • Direct vs indirect MTAP regulation unclear
  20. 2021 Medium

    Showed RGS12 negatively regulates GNA12/13–RhoA–YAP/TEAD signaling through its PDZ domain to suppress osteosarcoma growth and metastasis, and that PDZ peptides are therapeutically active.

    Evidence siRNA, orthotopic xenograft, YAP/TEAD reporter, PDZ peptide treatment, and pathway immunoblotting

    PMID:33686240

    Open questions at the time
    • Direct PDZ ligand within the GNA12/13–YAP axis not identified
    • Selectivity of PDZ peptide effects unclear
  21. 2022 High

    Defined RGS12's essential role in hearing: it polarizes GPSM2–GNAI(GDP) to organize stereocilia, with RGS12 and GPSM2 sharing GoLoco competition and RGS12/DAPLE generating polarized GEF/GAP activity.

    Evidence Rgs12 mutant mice with deafness phenotype, immunofluorescence, scanning EM, ABR, and competitive binding

    PMID:36260679

    Open questions at the time
    • Quantitative balance of RGS12 GAP vs GDI at the apical membrane not resolved
    • Whether RGS box or GoLoco dominates in vivo unclear
  22. 2022 Medium

    Connected RGS12 to ciliogenesis and angiogenesis by showing it associates with MYCBP2 and requires IFT80 to promote endothelial cilia, with KO reducing angiogenesis and arthritis.

    Evidence LC-MS/IP for MYCBP2, overexpression/KO in endothelial cells, IFT80 KO, cilia imaging, tube formation, and in vivo arthritis model

    PMID:37193553

    Open questions at the time
    • How RGS12 enhances MYCBP2 phosphorylation unclear
    • Domain mediating MYCBP2 binding not mapped
  23. 2023 Medium

    Showed RGS12 promotes macrophage M1 polarization and ciliogenesis via MYCBP2–KIF2A in tumor-associated macrophages, integrating its cilia and immune functions.

    Evidence Macrophage-specific KO, Co-IP, overexpression, cilia imaging, and cytokine measurements

    PMID:36797232

    Open questions at the time
    • Direct enzymatic link between RGS12 and MYCBP2 activation unknown
    • Relationship to NF-κB-driven polarization unintegrated
  24. 2024 Medium

    Characterized PDZ-domain ligand specificity (SAPAP3) and showed a bipolar-disorder-associated R59Q variant weakens PDZ binding, linking RGS12 to a neuropsychiatric disease allele.

    Evidence SPR, Co-IP, molecular docking, AlphaFold2, and molecular dynamics

    PMID:39518985

    Open questions at the time
    • Cellular consequence of R59Q not tested
    • Causality in disease not established by family/rescue data
  25. 2024 Medium

    Extended PDZ-domain partnerships to renal phosphate handling, with RGS12 binding NHERF1/NPT2A and harboring transport-inhibitory activity comparable to RGS14.

    Evidence Co-pulldown, domain-fragment binding analysis, and phosphate uptake assay in opossum kidney cells

    PMID:39293332

    Open questions at the time
    • In vivo renal phosphate role untested
    • Domain responsible for inhibitory activity only coarsely localized
  26. 2025 Medium

    Revealed a sex-dependent role in female nociceptors, where RGS12 loss reduces pain sensitivity and neurite outgrowth and upregulates GPER–Ca²⁺ signaling.

    Evidence Trpv1-Cre conditional KO, behavioral pain assays, DRG Ca²⁺ imaging, and GPER expression analysis

    PMID:41352678

    Open questions at the time
    • Mechanism of sex specificity unexplained
    • Direct RGS12–GPER molecular relationship not shown
  27. 2026 Medium

    Generalized the mitochondrial mechanism to placenta, where RGS12 promotes ATP5B tyrosine phosphorylation to maintain OXPHOS and prevent trophoblast apoptosis, with deficiency causing preterm birth susceptibility.

    Evidence Mitochondrial fractionation, siRNA, conditional KO mouse, ATP5B phospho Co-IP, OXPHOS assays, and p38MAPK immunoblotting

    PMID:41663754

    Open questions at the time
    • Kinase mediating ATP5B phosphorylation unidentified
    • Mechanism of mitochondrial targeting unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how RGS12's multiple, biochemically opposing activities (GAP, GDI, PDZ/PTB scaffolding, mitochondrial phospho-regulation) are selected and coordinated within a single cell, and no full-length structural model integrates its domains.
  • No structure of full-length RGS12 or its multi-domain complexes
  • Rules governing GAP-vs-GDI and positive-vs-negative ERK scaffolding unknown
  • Mechanism of mitochondrial localization and ATP synthase phosphorylation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 2 GO:0005634 nucleus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
CACNA1BGNAI2GPSM2MYCBP2NHERF1OPRK1PTENTRKA

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RGS12 acts as a GTPase-activating protein (GAP) selectively for Gi class alpha subunits in vitro, and its N-terminal PDZ domain binds selectively to C-terminal (A/S)-T-X-(L/V) motifs found in CXCR2 and an alternatively spliced form of RGS12 itself, providing a mechanism for targeting specific GPCRs for desensitization. In vitro GTPase assay; biochemical and interaction trap (yeast two-hybrid) experiments The Journal of biological chemistry High 9651375
2001 The C-terminal GoLoco motif of RGS12 binds exclusively to GDP-bound Gαi1, Gαi2, and Gαi3 and acts as a guanine nucleotide dissociation inhibitor (GDI), inhibiting GDP→GTP exchange and stabilizing Gαi1 in its GDP-bound form, independent of the N-terminal RGS box GAP activity. In vitro GTPγS binding assay; intrinsic tryptophan fluorescence assay; AlF4⁻-stimulated conformational change assay The Journal of biological chemistry High 11387333
2000 RGS12 is recruited to the N-type (Cav2.2) calcium channel in DRG neurons via its PTB domain upon agonist-induced tyrosine kinase activation downstream of GABA-B receptor, forming an endogenous complex that alters the time course of voltage-independent inhibition of calcium current; the PDZ and RGS domains of RGS12 had no observable effect on this process. Co-immunoprecipitation from primary DRG neuron lysates; microinjection of domain-specific fusion proteins with electrophysiological recording Nature High 11130074
2000 Alternatively spliced RGS12 isoforms with distinct N-termini localize exclusively to the nucleus in COS-7 cells; the trans-spliced short isoform (RGS12TS-S) concentrates in discrete nuclear foci in a cell-cycle-dependent manner, associates with metaphase chromosomes during mitosis, and its ectopic expression induces abnormally shaped and multiple nuclei. Confocal microscopy; subcellular fractionation; live-cell imaging across cell cycle stages The Journal of biological chemistry Medium 10869340
2004 The PTB domain of RGS12 binds to the SNARE-binding (synprint) region (amino acids 726–985) of the Cav2.2 alpha1 subunit in a tyrosine-phosphorylation-dependent manner at Tyr-804 (not Tyr-815), as mapped by protein overlay, surface plasmon resonance, and peptide precipitation assays; microinjection of synprint peptides containing phospho-Tyr-804 altered the desensitization rate of GABA-mediated channel inhibition. Protein overlay assay; surface plasmon resonance; peptide pulldown from DRG lysates; electrophysiology (microinjection of peptides) The Journal of biological chemistry High 15536086
2007 RGS12 associates with TrkA, activated H-Ras, B-Raf, and MEK2, acting as a scaffold to facilitate coordinated signaling to prolonged ERK activation; siRNA-mediated knockdown of RGS12 inhibits NGF-mediated neurite outgrowth of PC12 cells and axonal growth of primary DRG neurons, but not bFGF-stimulated outgrowth. Co-immunoprecipitation; siRNA knockdown with neurite outgrowth assay in PC12 cells and primary DRG neurons The EMBO journal High 17380122
2007 RGS12 is required for RANKL-induced [Ca²⁺]i oscillations, PLCγ phosphorylation, NFAT2 expression, and terminal osteoclast differentiation; RGS12 directly interacts with N-type calcium channels in osteoclast-like cells stimulated by RANKL. Lentivirus/vector-based RNAi gene silencing; co-immunoprecipitation; calcium imaging; immunoblotting Journal of bone and mineral research Medium 17042716
2005 The PDZ/PTB N-terminal domain and PTB domain of RGS12 can form a complex with the PDGFβ receptor, and overexpression of these domains reduces PDGF-induced p42/p44 MAPK activation; RGS12 co-localizes with PDGFβ receptor in cytoplasmic vesicles in airway smooth muscle cells. Co-immunoprecipitation; overexpression/domain-deletion functional assays measuring ERK activation; confocal co-localization Cellular signalling Medium 16214305
2013 Conditional deletion of Rgs12 in Mx1+ hematopoietic (monocyte/macrophage) cells using inducible Mx1-Cre reduces osteoclast numbers and increases bone mass in vivo, establishing an in vivo requirement for RGS12 in osteoclastogenesis with no significant effect on osteoblast formation. Conditional knockout (Mx1-Cre; Rgs12fl/fl) mouse model; microCT; histomorphometry Genesis Medium 23349096
2014 Gβγ-dependent activation of PI3Kγ and cSrc leads to tyrosine phosphorylation of Gαi1/2/3, which recruits RGS12 (via its PTB domain) to form a Gαi–RGS12 complex that accelerates Gαi deactivation and facilitates smooth muscle relaxation; tyrosine-deficient Gαi2 mutants and RGS12 knockdown each blocked phosphorylation and Gαi2–RGS12 association, causing augmented Gαi signaling. Co-immunoprecipitation; expression of tyrosine-deficient Gαi2 mutants; RGS12 siRNA knockdown; cAMP assay; smooth muscle contraction assay American journal of physiology. Gastrointestinal and liver physiology High 24578342
2017 RGS12 exhibits tumor-suppressor activity in prostate cancer by decreasing total and activated AKT levels and negatively regulating MNX1 expression in vitro and in vivo; RGS12 expression negatively correlates with MNX1 and AKT activity in a functionally validated manner. Knockdown/overexpression in prostate cancer cell lines; in vivo xenograft; immunoblotting for AKT and MNX1 Cancer research Medium 28611045
2019 RGS12 associates with NF-κB(p65) via its PTB domain to activate p65 phosphorylation and nuclear translocation in macrophages; NF-κB(p65) in turn transcriptionally regulates RGS12 expression; COX2 enhances nuclear translocation of both proteins. Deletion of RGS12 in myeloid lineage inhibits collagen-induced arthritis. Co-immunoprecipitation; domain-deletion mapping; NF-κB reporter assay; conditional knockout mouse model; siRNA knockdown in vivo/in vitro iScience Medium 32512384
2019 Rgs12 conditional knockout in osteoblast precursors (Osx-Cre) reduces osteoblast number and bone mass in vivo. Mechanistically, Rgs12 deletion inhibits GTPase activity, reduces cAMP levels, impairs L-type Ca²⁺ channel–mediated Ca²⁺ oscillations, and suppresses ERK phosphorylation; pertussis toxin (PTX) treatment or Rgs12 overexpression rescues ERK activity and osteoblast differentiation, placing Rgs12 in a Gαi-ERK axis during osteogenesis. Conditional knockout (OsxCre; Rgs12fl/fl); GTPase activity assay; cAMP assay; Ca²⁺ imaging; PTX inhibitor rescue; ERK immunoblotting; in vitro differentiation assay Journal of bone and mineral research High 30489658
2019 RGS12 forms a protein complex with KOR (kappa opioid receptor) in ventral striatal tissue and transfected cells; RGS12-null mice show increased KOR levels and G protein activation in the ventral striatum, enhanced sensitivity to KOR agonist-induced G protein-dependent behaviors (hypolocomotion, analgesia), but attenuated KOR-mediated conditioned place aversion (β-arrestin-dependent). RGS12 simultaneously attenuates G protein signaling and augments β-arrestin signaling downstream of KOR. Co-immunoprecipitation; fast-scan cyclic voltammetry; RGS12-null mouse behavioral studies; [35S]GTPγS binding for G protein activation; ventral striatum-selective phenotyping Neuropsychopharmacology High 31141817
2019 RGS12 is expressed in myoblasts and its protein abundance decreases during differentiation into myotubes; myoblasts from Rgs12-null mice have impaired ability to differentiate into myotubes ex vivo, and Pax7-Cre conditional knockout mice show attenuated muscle fiber repair after cardiotoxin injury. Conditional knockout mouse (Pax7-Cre; Rgs12fl/fl); ex vivo myoblast differentiation assay; cardiotoxin injury/regeneration model PloS one Medium 31408461
2020 RGS12 is present in mitochondria of primary chondrocytes and cartilage tissues; deletion of Rgs12 in type II collagen-positive chondrocytes decreases mitochondrial number, membrane potential, and oxidative phosphorylation. Mechanistically, RGS12 promotes tyrosine phosphorylation of ATP5A (ATP synthase subunit), enhancing its function; Rgs12-deficient mice exhibit body retardation, decreased bone mass, and chondrocyte apoptosis. Subcellular fractionation/mitochondrial localization; conditional knockout (Col2a1-Cre; Rgs12fl/fl); mitochondrial functional assays (membrane potential, OXPHOS); Co-IP/immunoblotting for ATP5A phosphorylation Cell discovery Medium 32922858
2020 RGS12 associates with PTEN via its PDZ domain, upregulating PTEN phosphorylation and SUMOylation, which inactivates AKT/mTOR signaling; knockout of RGS12 in mice promotes aggressive oral squamous cell carcinoma in a 4NQO model, and RGS12 knockdown in OSCC cells increases proliferation and migration. Co-immunoprecipitation (PDZ domain); knockout mouse model (CMVCre; Rgs12fl/fl) with 4NQO-induced OSCC; knockdown/overexpression in cancer cell lines; immunoblotting for pPTEN, SUMOylated PTEN, pAKT, pmTOR; in vivo xenograft Journal of dental research Medium 33198557
2020 Genetic deletion of Rgs12 in mice causes brain region-specific alterations in serotonin transporter (SERT) expression and function, with no hyperlocomotion to MDMA; RGS12-null mice show increased anxiety-like and anti-depressive-like behaviors, establishing RGS12 as a modulator of serotonergic neurotransmission. Rgs12 global knockout mice; open-field and home-cage locomotor assays; SERT expression by immunoblotting; SERT functional uptake assays; behavioral assays (FST, TST, EPM, EZM, social interaction) Journal of psychopharmacology Medium 32842837
2021 RGS12 knockdown in osteosarcoma cells upregulates Ezrin expression through promoting the GNA12/13–RhoA–YAP pathway; RGS12 negatively regulates YAP/TEAD1 transcriptional activity through its PDZ domain, suppressing Ezrin expression; PDZ domain peptides of RGS12 inhibit intratibial tumor growth and lung metastasis in orthotopic xenograft models. siRNA knockdown; orthotopic xenograft mouse model; luciferase reporter for YAP/TEAD1 activity; PDZ domain peptide treatment; immunoblotting for GNA12/13, RhoA, YAP, Ezrin Oncogene Medium 33686240
2021 RGS12 promotes ubiquitination and proteasomal degradation of IκB in macrophages, thereby activating NF-κB nuclear translocation and cytokine expression; RGS12 also indirectly suppresses MTAP expression (which would otherwise promote pIκB), and RGS12 deficiency prevents IκB ubiquitination and inflammation in surgically or chemically induced osteoarthritis. Co-immunoprecipitation (ubiquitin–IκB association); MG132 proteasome inhibitor rescue; RGS12 KO in OA model; immunoblotting for IκB, pIκB, MTAP, NF-κB Genes & diseases Medium 35873013
2021 RGS12 overexpression in macrophages promotes M1 polarization (not M2) and enhances migration; RGS12 associates with and activates MYCBP2, which targets KIF2A for degradation to promote ciliogenesis in tumor-associated macrophages, and RGS12 KO in macrophages decreases M1 TAMs in oral cancer tissue. Macrophage-specific RGS12 knockout mouse; co-immunoprecipitation; overexpression in macrophages; cilia imaging; immunoblotting for MYCBP2, KIF2A; cytokine measurements International journal of oral science Medium 36797232
2022 RGS12 is required to polarize the GPSM2–GNAI complex to the hair cell apical membrane and to organize mechanosensory stereocilia into rows of graded heights; Rgs12 mouse mutants are deaf. RGS12 and GPSM2 share GoLoco motifs that stabilize GNAI(GDP), with GPSM2 outcompeting RGS12 for GNAI binding; RGS12 and the GEF DAPLE are asymmetrically co-enriched at hair cell apical junctions, suggesting that polarized GEF/GAP activity generates free GNAI(GDP) for GPSM2. Rgs12 mouse mutant (knockout); confocal immunofluorescence for GPSM2, GNAI, RGS12, DAPLE; scanning electron microscopy of stereocilia; auditory brainstem response (deafness phenotype); competitive binding analysis Science advances High 36260679
2022 RGS12 in endothelial cells promotes ciliogenesis (increased cilia number and length) by associating with MYCBP2 and enhancing its phosphorylation; IFT80 knockout blocks the cilia increase caused by RGS12 overexpression; RGS12 KO reduces angiogenesis and inflammatory arthritis development in vivo. LC-MS/immunoprecipitation for MYCBP2 interaction; RGS12 overexpression/knockout in endothelial cells; IFT80 knockout; cilia imaging; tube formation assay; in vivo arthritis model Cell insight Medium 37193553
2024 The RGS12 PDZ domain binds the C-terminus of SAPAP3 (validated by molecular docking, SPR, and co-immunoprecipitation); the familial bipolar disorder-associated R59Q missense variant significantly reduces PDZ domain binding affinity for three peptide targets tested by SPR, likely through allosteric changes that weaken ligand interactions. Surface plasmon resonance; co-immunoprecipitation; molecular docking; AlphaFold2 structural modeling; molecular dynamics simulation International journal of molecular sciences Medium 39518985
2024 RGS12 C-terminal PDZ ligand binds NHERF1; full-length RGS12 and its upstream PDZ-domain-containing fragment bind NPT2A; the downstream RGS12 portion (without PDZ domain) does not interact with NPT2A but contains the inhibitory activity for hormone-sensitive phosphate transport comparable to RGS14. Immunoblotting co-pulldown for NHERF1; structural fragment binding analysis for NPT2A; phosphate uptake assay in opossum kidney proximal tubule cells with RGS12/RGS14 transfection Biochemical and biophysical research communications Medium 39293332
2024 DLGAP3 forms a complex with RGS12 (by co-immunoprecipitation); DLGAP3 overexpression increases RGS12 expression and RGS12 inhibits BRAF transcription and translation, reducing MEK/ERK phosphorylation in glioma cells. Co-immunoprecipitation; overexpression/knockdown in glioma cells; immunoblotting for pMEK, pERK, BRAF; dual-luciferase reporter for BRAF transcription Brain research Low 39551229
2025 In female (but not male) DRG nociceptor-specific Rgs12-cKO mice, pain sensitivity to mechanical and thermal stimuli is decreased, neurite outgrowth is reduced, and GPER expression dramatically increases; GPER-mediated Ca²⁺ signaling in DRG neurons is sex-dependent, placing RGS12 upstream of estrogen/GPER–calcium signaling in female nociceptors. Conditional knockout (Trpv1-Cre; Rgs12fl/fl); von Frey, hot plate, and CPP behavioral assays; Ca²⁺ imaging in primary DRG neurons; immunofluorescence; qRT-PCR and immunoblotting for GPER The journal of pain Medium 41352678
2026 RGS12 localizes to the mitochondria of placental trophoblast cells and promotes tyrosine phosphorylation of ATP5B (mitochondrial ATP synthase subunit); RGS12 knockdown reduces mitochondrial abundance, impairs oxidative phosphorylation, and decreases antioxidant capacity; placental Rgs12 deficiency in mice leads to preterm birth susceptibility, reduced fetal weight, and trophoblast apoptosis linked to p38MAPK activation. Subcellular fractionation/mitochondrial localization; siRNA knockdown in placental cells; conditional knockout mouse; Co-IP/immunoblotting for ATP5B tyrosine phosphorylation; mitochondrial functional assays; p38MAPK immunoblotting Cellular and molecular life sciences Medium 41663754

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 RGS12 and RGS14 GoLoco motifs are G alpha(i) interaction sites with guanine nucleotide dissociation inhibitor Activity. The Journal of biological chemistry 193 11387333
1998 GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain. The Journal of biological chemistry 186 9651375
2000 Tyrosine-kinase-dependent recruitment of RGS12 to the N-type calcium channel. Nature 119 11130074
1997 Molecular cloning and expression analysis of rat Rgs12 and Rgs14. Biochemical and biophysical research communications 108 9168931
2007 Selective role for RGS12 as a Ras/Raf/MEK scaffold in nerve growth factor-mediated differentiation. The EMBO journal 68 17380122
2000 Novel alternative splicing and nuclear localization of human RGS12 gene products. The Journal of biological chemistry 61 10869340
2007 RGS12 is essential for RANKL-evoked signaling for terminal differentiation of osteoclasts in vitro. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 53 17042716
1999 Raf-like Ras/Rap-binding domains in RGS12- and still-life-like signalling proteins. Journal of molecular medicine (Berlin, Germany) 52 10606204
2004 RGS12 interacts with the SNARE-binding region of the Cav2.2 calcium channel. The Journal of biological chemistry 38 15536086
2021 MicroRNA-204-5p reduction in rat hippocampus contributes to stress-induced pathology via targeting RGS12 signaling pathway. Journal of neuroinflammation 37 34674723
2005 The effect of RGS12 on PDGFbeta receptor signalling to p42/p44 mitogen activated protein kinase in mammalian cells. Cellular signalling 35 16214305
2017 RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression. Cancer research 31 28611045
2021 RGS12 is a novel tumor suppressor in osteosarcoma that inhibits YAP-TEAD1-Ezrin signaling. Oncogene 25 33686240
2020 RGS12 Represses Oral Cancer via the Phosphorylation and SUMOylation of PTEN. Journal of dental research 24 33198557
2019 Regulator of G Protein Signaling Protein 12 (Rgs12) Controls Mouse Osteoblast Differentiation via Calcium Channel/Oscillation and Gαi-ERK Signaling. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 24 30489658
2013 Mx1-cre mediated Rgs12 conditional knockout mice exhibit increased bone mass phenotype. Genesis (New York, N.Y. : 2000) 21 23349096
2023 RGS12 represses oral squamous cell carcinoma by driving M1 polarization of tumor-associated macrophages via controlling ciliary MYCBP2/KIF2A signaling. International journal of oral science 19 36797232
2019 Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 19 31141817
2021 RGS12 Drives Macrophage Activation and Osteoclastogenesis in Periodontitis. Journal of dental research 18 34796776
2020 RGS12 Is a Novel Critical NF-κB Activator in Inflammatory Arthritis. iScience 18 32512384
2021 Macrophage RGS12 contributes to osteoarthritis pathogenesis through enhancing the ubiquitination. Genes & diseases 15 35873013
2014 Inhibition of Gαi activity by Gβγ is mediated by PI 3-kinase-γ- and cSrc-dependent tyrosine phosphorylation of Gαi and recruitment of RGS12. American journal of physiology. Gastrointestinal and liver physiology 13 24578342
2020 RGS12 is required for the maintenance of mitochondrial function during skeletal development. Cell discovery 12 32922858
2019 A role for Regulator of G protein Signaling-12 (RGS12) in the balance between myoblast proliferation and differentiation. PloS one 12 31408461
2004 Mapping of RGS12-Cav2.2 channel interaction. Methods in enzymology 11 15488181
2022 RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells. Science advances 10 36260679
2004 Purification and in vitro functional analyses of RGS12 and RGS14 GoLoco motif peptides. Methods in enzymology 9 15488192
2020 Genetic deletion of Rgs12 in mice affects serotonin transporter expression and function in vivo and ex vivo. Journal of psychopharmacology (Oxford, England) 7 32842837
2022 Endothelial RGS12 governs angiogenesis in inflammatory arthritis by controlling cilia formation and elongation via MYCBP2 signaling. Cell insight 6 37193553
2025 RGS12 is a target of penehyclidine hydrochloride that enhances oxidative stress and ferroptosis in a model of myocardial ischemia/reperfusion injury by inhibiting the Nrf2 pathway. International journal of molecular medicine 3 39930821
2024 Distinct and overlapping RGS14 and RGS12 actions regulate NPT2A-mediated phosphate transport. Biochemical and biophysical research communications 3 39293332
2024 DLGAP3 suppresses malignant behaviors of glioma cells via inhibiting RGS12-mediated MAPK/ERK signaling. Brain research 2 39551229
2024 Molecular Modeling and In Vitro Functional Analysis of the RGS12 PDZ Domain Variant Associated with High-Penetrance Familial Bipolar Disorder. International journal of molecular sciences 1 39518985
2026 Role of RGS12 in placental mitochondrial dysfunction and adverse pregnancy outcomes. Cellular and molecular life sciences : CMLS 0 41663754
2025 RGS12 controls pain/mechanical sensitivity in a sex-dependent manner via regulating the estrogen/GPER-calcium signaling pathway. The journal of pain 0 41352678
2025 Functional Variation in RGS12 Should Not Preclude Methylphenidate Use in Bipolar Disorder with Established Mood Stabilization: Preclinical Evidence. International journal of molecular sciences 0 41465420
2024 The role of RGS12 in tissue repair and human diseases. Genes & diseases 0 40271194
2023 Corrigendum to "Endothelial RGS12 governs angiogenesis in inflammatory arthritis by controlling cilia formation and elongation via MYCBP2 signaling" [Cell Insight 1 (2022) 100055]. Cell insight 0 37965246

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