Affinage

RGS14

Regulator of G-protein signaling 14 · UniProt O43566

Length
566 aa
Mass
61.4 kDa
Annotated
2026-06-10
52 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RGS14 is a multidomain scaffolding protein that integrates heterotrimeric G protein signaling with Ras/Raf/ERK MAPK signaling and microtubule-based mitotic functions (PMID:11387333, PMID:19319189). Its N-terminal RGS domain accelerates GTP hydrolysis on Gαi/o subunits, while a C-terminal GoLoco/GPR motif binds Gαi1 and Gαi3 (but not Gαi2) selectively in their GDP-bound state and acts as a guanine nucleotide dissociation inhibitor, establishing two independent, biochemically distinct Gα interaction sites (PMID:11387333, PMID:11739605, PMID:15337739). These activities are regulated post-translationally: PKA phosphorylation at Thr494 adjacent to the GoLoco motif enhances GDI activity ~3-fold, and an intramolecular interaction mediated by the Ras-binding region enhances GAP activity while inhibiting GDI activity (PMID:12534294, PMID:23255434). Through its tandem Ras-binding domains RGS14 selectively binds activated H-Ras-GTP in cells and assembles an H-Ras-dependent Raf–MEK–ERK complex to promote sustained ERK activation and Ras-dependent neuronal differentiation, with inactive Gαi1-GDP markedly enhancing H-Ras affinity and Gαi1 binding being mutually exclusive with Raf binding, allowing GPCRs to dynamically tune the complex (PMID:19319189, PMID:19878719, PMID:23250758). RGS14 shuttles between cytoplasm and nucleus via CRM1/XPO1-dependent export and localizes to centrosomes, the mitotic spindle, and microtubules, binding polymerized microtubules directly to promote spindle/aster assembly and being required for the first embryonic mitotic division (PMID:15525537, PMID:15520006, PMID:15917656). In hippocampal CA2 pyramidal neurons RGS14 suppresses long-term potentiation and spatial learning by restricting dendritic spine Ca2+ elevations and downstream NMDA-receptor/CaMK/PKA/ERK signaling (PMID:20837545, PMID:29911178). RGS14 also regulates hormone-sensitive renal phosphate transport through a C-terminal PDZ ligand that binds NHERF1 to stabilize the NPT2A–NHERF1 complex against PTH/FGF23-induced dissociation, an activity controlled by phosphorylation of linker serines Ser266/Ser269 (PMID:35307350, PMID:39792018). Human variants in the RGS14 nuclear export sequence (L505R, R507Q) disrupt Gαi1 and XPO1 binding, trap the protein in the nucleus, and abolish its capacity to inhibit LTP (PMID:33410399).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Established that RGS14 acts on G protein signaling through a GAP activity selective for the Gαi/o subfamily and through a domain binding activated Rap1/Rap2, defining it as more than a simple GTPase regulator.

    Evidence GTPase assays with brain membranes, yeast two-hybrid, and cell-based SRE reporter assays

    PMID:10926822 PMID:10953050

    Open questions at the time
    • Did not resolve whether Rap binding is functional in cells
    • Mechanism linking RGS14 to MAPK attenuation unclear
  2. 2001 High

    Resolved that RGS14 carries two independent Gα interaction sites with opposite biochemical activities — an RGS-box GAP and a GoLoco-motif GDI selective for GDP-bound Gαi1/2/3 — defining its bifunctional regulation of the Gαi cycle.

    Evidence GTPγS binding and intrinsic tryptophan fluorescence assays with purified proteins, plus reconstitution GTPase assays and domain mapping

    PMID:11387333 PMID:11739605

    Open questions at the time
    • Cellular consequences of dual GAP/GDI activity not addressed
    • No structural model of the two binding modes
  3. 2003 High

    Showed that PKA phosphorylation at Thr494 adjacent to the GoLoco motif selectively potentiates GDI activity, providing a mechanism by which cAMP signaling tunes RGS14's effect on Gαi.

    Evidence In vitro PKA kinase assays, phosphomimetic mutagenesis with GDI/GAP readouts, cAMP stimulation in cells

    PMID:12534294

    Open questions at the time
    • Identity of second PKA site not functionally defined
    • In vivo relevance of Thr494 phosphorylation untested
  4. 2004 High

    Linked RGS14 to cell division and subcellular trafficking, showing it is essential for the first embryonic mitosis, localizes to centrosomes/spindle via its RBD, and shuttles between nucleus and cytoplasm via CRM1-dependent export.

    Evidence Loss-of-function in mouse zygotes, colocalization imaging, NES mutagenesis with leptomycin B, domain deletion constructs

    PMID:15520006 PMID:15525537

    Open questions at the time
    • Molecular role of RGS14 at the spindle not defined
    • Link between G protein activities and mitotic function unclear
  5. 2005 High

    Identified RGS14 as a direct microtubule-associated protein that binds polymerized microtubules and promotes tubulin polymerization and aster formation, providing a biochemical basis for its spindle role.

    Evidence Microtubule co-sedimentation, direct Kd measurement with pure tubulin, brain extract co-purification, in vitro aster formation with RGS14 depletion

    PMID:15917656

    Open questions at the time
    • How Gαi1-GDP inhibition of tubulin polymerization is regulated in vivo unknown
    • Mitotic phenotype mechanism not connected to MT binding directly
  6. 2006 Medium

    Mapped the domain logic of RGS14 localization, showing nuclear targeting requires RGS+RBD, nuclear exit requires GoLoco, and centrosome targeting requires the RBD, while inactive Gαi1/3 binding at the membrane sequesters RGS14 away from nucleus/centrosome.

    Evidence Confocal imaging of GFP-tagged domain mutants and co-IP with Gαi isoforms

    PMID:16246175 PMID:16870394

    Open questions at the time
    • Single-lab imaging not independently confirmed
    • Whether RGS14 dissociates intact heterotrimers in cells unresolved
  7. 2009 Medium

    Established RGS14 as a scaffold for the Ras–Raf–MEK–ERK pathway, showing it selectively binds H-Ras-GTP in cells, assembles an ERK-pathway complex, and is required for Ras-dependent neuronal differentiation.

    Evidence Co-IP, siRNA knockdown, PC12 neurite outgrowth and ERK phosphorylation assays

    PMID:19319189

    Open questions at the time
    • Direct vs. indirect Raf/MEK/ERK binding not fully dissected
    • Single cellular system
  8. 2010 High

    Defined the architecture and regulation of the RGS14–H-Ras–Raf complex, showing H-Ras binds the R1 RBD, H-Ras and Raf cooperatively bind RGS14, and Gαi1 binding is mutually exclusive with Raf, letting Gαi1 reverse RGS14's ERK inhibition by membrane recruitment; in parallel, in vivo work revealed RGS14 suppresses CA2 LTP and learning via ERK.

    Evidence Co-IP, localization imaging, ERK assays with domain mutants; and RGS14 KO mice with LTP electrophysiology, MEK inhibitor rescue, and behavioral testing

    PMID:19878719 PMID:20837545

    Open questions at the time
    • How GPCR input switches the complex in neurons not directly shown
    • CA2-specific molecular targets of RGS14 not fully defined
  9. 2011 Medium

    Demonstrated that RGS14 forms a Gαi/o-dependent complex with the α2A-adrenergic receptor that is disrupted by agonist and by the GEF Ric-8A, placing RGS14 in a receptor-coupled signaling module.

    Evidence BRET in live cells with pharmacological receptor stimulation and Ric-8A co-expression

    PMID:21880739

    Open questions at the time
    • Direct vs. Gα-bridged receptor contact not distinguished
    • Single primary method
  10. 2012 High

    Showed that inactive Gαi1-GDP allosterically enhances RGS14 affinity for H-Ras-GTP and that a native Gαi1·RGS14·H-Ras ternary complex exists in brain and is conformationally responsive to α2A-AR stimulation, unifying G protein and Ras inputs on one scaffold.

    Evidence BRET in live cells, co-IP from brain lysates, PC12 neurite outgrowth assays

    PMID:23250758

    Open questions at the time
    • Structural basis of Gαi-enhanced H-Ras binding unknown
    • Downstream output of the ternary complex in neurons not measured
  11. 2013 Medium

    Revealed an intramolecular RBD-mediated regulation that reciprocally enhances RGS-domain GAP activity while inhibiting GoLoco GDI activity, and showed RGS14 binds and potentiates B/R4 RGS proteins, adding autoregulatory and cooperative layers.

    Evidence In vitro GTPase/GDI assays with isolated and full-length constructs and protein-protein binding assays; and macrophage integrin/phagocytosis assays

    PMID:23255434 PMID:23805333

    Open questions at the time
    • In vivo significance of intramolecular regulation untested
    • Phagocytosis role from single lab
  12. 2015 High

    Captured the conformational logic of G protein engagement, showing GPR-bound Gαi1-GDP induces allosteric changes and that RGS14 can simultaneously bind Gαi1-GDP (GPR) and Gαo (RGS) while retaining GAP activity, establishing functional independence of the two Gα sites.

    Evidence Size exclusion chromatography, HDX-MS, BRET, biochemical reconstitution of the ternary complex with GTPase assay

    PMID:25666614

    Open questions at the time
    • No high-resolution crystal/cryo-EM structure
    • How allostery couples to Ras/ERK scaffolding not shown
  13. 2017 Medium

    Localized endogenous RGS14 to juxtanuclear ER/Golgi-derived membranes, nuclear pore complexes, and intranuclear channels, and showed it can traffic to the plasma membrane upon G protein activation, refining its dynamic localization in neuronal cells.

    Evidence Confocal and 3D-SIM super-resolution imaging of endogenous protein with AlF4⁻ activation and fractionation

    PMID:28934222

    Open questions at the time
    • Functional role at nuclear pores undefined
    • Single-lab imaging
  14. 2018 High

    Connected RGS14 to Ca2+/CaMKII signaling and 14-3-3γ regulation, showing RGS14 binds CaM, is a CaMKII substrate, and is regulated by dual 14-3-3γ sites that separately control Gαi binding and nuclear shuttling, while its CA2 LTP suppression operates by limiting spine Ca2+.

    Evidence IP-mass spectrometry from brain, in vitro binding and CaMKII phosphorylation, BRET, Ser-218 mutagenesis; and two-photon spine Ca2+ imaging with KO/OE and pharmacology

    PMID:29518331 PMID:29911178 PMID:30093406

    Open questions at the time
    • How CaMKII phosphorylation feeds back on RGS14 function not resolved
    • Link between 14-3-3γ regulation and spine Ca2+ control untested
  15. 2020 High

    Demonstrated that human RGS14 NES variants (L505R, R507Q) disrupt Gαi1 and XPO1 binding, trap RGS14 in the nucleus, and abolish LTP inhibition, while leaving spatial learning intact, dissociating RGS14's nuclear from dendritic-spine functions.

    Evidence Site-directed mutagenesis, co-IP, LTP electrophysiology, CRISPR/Cas9 knock-in mice, imaging, behavior

    PMID:33410399

    Open questions at the time
    • Nuclear function of RGS14 not mechanistically defined
    • Disease association of variants not established
  16. 2022 High

    Established a non-canonical, post-receptor renal function in which RGS14's C-terminal PDZ ligand binds NHERF1 to stabilize the NPT2A–NHERF1 complex and suppress PTH/FGF23-sensitive phosphate uptake, independent of G protein/cAMP signaling.

    Evidence Isotope phosphate uptake, BRET, siRNA, pull-down/overlay assays, mutagenesis in proximal tubule cells

    PMID:35307350

    Open questions at the time
    • In vivo whole-animal phosphate phenotype not shown
    • Whether other RGS14 domains modulate this axis unclear
  17. 2023 Medium

    Identified a mitochondrial role for RGS14 in CA2 neurons, where it reduces respiration and limits oxidative stress, with KO mice showing accelerated seizures and increased mortality, linking RGS14 to neuronal metabolic and neuroprotective functions.

    Evidence Mitochondrial localization imaging, respiration assays, kainic acid seizure model in KO mice, proteomics, oxidative stress immunostaining

    PMID:37075948

    Open questions at the time
    • Molecular mechanism of respiration control unknown
    • Whether mitochondrial role depends on G protein/Ras activities unclear
  18. 2025 Medium

    Refined the renal mechanism and extended RGS14 into spermatogonial stem cell biology and pharmacology: linker serines Ser266/Ser269 are PTH/FGF23-phosphorylated and required for phosphate-transport regulation; RGS14 binds GNAI3 to drive an SSC proliferation/MAPK/PLPP2 axis; and selective small-molecule RGS-box inhibitors were developed.

    Evidence Truncation/alanine mutagenesis with phosphate transport and phosphorylation assays; co-IP, siRNA, RNA-seq and PLPP2 rescue in SSCs; structure-guided GAP-inhibitor screening (one preprint)

    PMID:39792018 PMID:40352663 PMID:bio_10.1101_2025.06.11.659181

    Open questions at the time
    • Kinase responsible for Ser266/Ser269 phosphorylation not identified
    • Inhibitors lack structural validation and in vivo efficacy data
    • SSC axis from single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RGS14's distinct activities — Gαi/o GAP/GDI, H-Ras/ERK scaffolding, microtubule binding, mitochondrial regulation, nuclear shuttling, and renal NHERF1/NPT2A control — are coordinately switched within a single cell, and what defines the nuclear function, remains unresolved.
  • No integrated structural model coupling the multiple domains
  • Nuclear function of RGS14 undefined
  • Physiological switch governing which activity dominates in a given cell type unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 9 GO:0060090 molecular adaptor activity 4 GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005634 nucleus 5 GO:0005886 plasma membrane 4 GO:0005815 microtubule organizing center 3 GO:0005829 cytosol 3 GO:0005635 nuclear envelope 1 GO:0005739 mitochondrion 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-112316 Neuronal System 2 R-HSA-1640170 Cell Cycle 2 R-HSA-382551 Transport of small molecules 2
Partners
CAMK2GNAI1GNAI3HRASNHERF1RAF1XPO1YWHAG
Complex memberships
NPT2A–NHERF1 complex (regulated by RGS14)RGS14·Gαi1·H-Ras ternary complexRGS14·H-Ras·Raf·MEK·ERK complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 The GoLoco motif of RGS14 interacts exclusively with Gαi1, Gαi2, and Gαi3 in their GDP-bound forms and exhibits guanine nucleotide dissociation inhibitor (GDI) activity, inhibiting the rate of GDP-to-GTP exchange on Gαi1 and stabilizing the GDP-bound state. This is distinct from the N-terminal RGS box, which confers GTPase-accelerating protein (GAP) activity on Gαi/o subunits, establishing that RGS14 has two independent Gα interaction sites with different biochemical activities. GTPγS binding assays, intrinsic tryptophan fluorescence assays, in vitro binding experiments with purified proteins The Journal of biological chemistry High 11387333
2000 RGS14 binds activated Rap1 and Rap2 (but not Ras) through a domain distinct from the RGS domain that shares sequence identity with the Ras/Rap binding domain of B-Raf and Raf-1 kinases. RGS14 preferentially stimulates GTPase activity of Gαo over Gαi1 in brain membranes and in reconstitution assays. Yeast two-hybrid, in vitro binding with Rap2 mutants, GTPase assays with brain membranes, deletion analysis The Biochemical journal High 10926822
2000 RGS14 acts as a GAP for Gαi subfamily members and attenuates IL-8 receptor-mediated MAPK activation. RGS14 does not exhibit GAP activity toward Gαs or Gαq. Although not a GAP for G12/13α, RGS14 impairs G13α-mediated c-fos SRE activation. An RGS14 mutant (EN92/93AA) defective in Gαi signaling inhibition still blocks SRE activation. RGS14 localizes predominantly to the cytosol but is recruited to membranes by constitutively active G13αQ226L. GTPase assays, cell-based signaling reporter assays, subcellular fractionation, dominant-negative mutant analysis Molecular pharmacology Medium 10953050
2001 Full-length RGS14 in brain exists in two immunoreactive forms (~60 kDa and ~55 kDa) in cytosol and two membrane subpopulations. Recombinant RGS14 is a non-selective GAP for Gαi1 and Gαo, with full-length RGS14 approximately 10-fold more potent than the isolated RGS domain alone. GDI activity toward Gαi (but not Gαo) is restricted to the C-terminus containing the GoLoco domain, and the isolated RBD domain does not act as a GAP for Rap1. Immunoblotting with affinity-purified antisera, reconstitution GTPase assays, pulldown from brain membranes Journal of neurochemistry High 11739605
2003 PKA phosphorylates RGS14 at two specific sites in response to cAMP elevation; one site, threonine 494 (Thr494), is immediately adjacent to the GoLoco motif. Mimicking phosphorylation at Thr494 enhanced GDI activity of RGS14 toward Gαi nearly 3-fold without affecting GAP activity toward Gαi or Gαo. Radiolabeled phosphate incorporation, PKA inhibitor experiments, phosphomimetic mutant biochemical assays, cAMP stimulation in cells Biochemistry High 12534294
2004 The RGS14 GoLoco domain discriminates among Gαi isoforms: it inhibits guanine nucleotide exchange on Gαi1 and Gαi3, but not Gαi2. Gαi2 could be rendered sensitive to RGS14 GDI activity by replacing residues within the αA/αB and αB/αC loops of the α-helical domain, identifying these loops as key selectivity determinants. In vitro GTPγS binding assays, Gαi2 chimeric mutant analysis The Journal of biological chemistry High 15337739
2004 RGS14 is expressed in mouse embryos immediately prior to the first mitosis, colocalizes with the anastral mitotic apparatus of the mouse zygote, and is essential for completion of the first mitotic division. Loss of Rgs14 in the zygote causes cytofragmentation and failure to progress to the 2-cell stage. During interphase in proliferating cells RGS14 segregates to the nucleus, and during mitosis it localizes to the mitotic spindle and centrioles. Altering RGS14 levels in proliferating cells causes growth arrest. Loss-of-function in mouse embryos, colocalization imaging, overexpression/knockdown in proliferating cells Developmental cell High 15525537
2004 The RGS and GoLoco domains of RGS14 are independently able to inhibit signaling downstream of Gi via the βγ pathway. Targeting the isolated GoLoco domain to membranes (by myristoylation/palmitoylation or Rap binding) enhances its inhibitory activity. In the context of full-length RGS14, the RGS and GoLoco domains cooperate to confer maximal inhibition of Gi signaling. Cell-based signaling assays in HEK-m2 cells with domain mutants and truncation constructs, myristoylation targeting constructs The Biochemical journal Medium 15112653
2004 RGS14 localizes to centrosomes via its first Ras-binding domain, and shuttles between cytoplasm and nucleus via CRM-1-dependent nuclear export. Mutation of the nuclear export signal or leptomycin B treatment causes nuclear accumulation and association with PML nuclear bodies. A mutant defective in nuclear export also fails to target to centrosomes, indicating that nucleocytoplasmic shuttling is required for centrosomal localization. Immunofluorescence, leptomycin B treatment, NES mutant analysis, domain deletion constructs The Journal of biological chemistry Medium 15520006
2005 RGS14 is a microtubule-associated protein that binds directly to polymerized (but not depolymerized) microtubules with Kd ~1.3 μM. RGS14 copurifies with tubulin through multiple polymerization/depolymerization cycles from brain. Both RGS14 and Gαi1-GTP promote tubulin polymerization in the presence of microtubule-associated proteins, but preincubation of RGS14 with Gαi1-GDP abolishes this activity. Depletion of RGS14 from cell extracts blocks mitotic aster formation in vitro. Microtubule co-sedimentation, direct binding to pure tubulin with Kd measurement, brain extract purification, in vitro aster formation assay, RGS14 depletion Cell cycle (Georgetown, Tex.) High 15917656
2005 The RBD/GoLoco region of RGS14 (lacking the RGS domain) binds Gαo-GDP, Gαi-GDP, and Gβγ in brain pull-down assays. In reconstituted receptor-G protein systems, this region potentiates RGS4 GAP activity by increasing the apparent affinity of RGS4 for Gαi and Gαo, an activity requiring membranes and/or receptors. Brain pull-down assays, reconstituted M2 receptor/G-protein GTPase assays, steady-state GTPase measurements Biochemistry Medium 15807543
2006 RGS14 subcellular localization in HeLa cells is controlled by distinct domains: localization to the nucleus requires the RGS and RBD domains; translocation out of the nucleus depends on the GoLoco/GPR domain; localization to centrosomes depends on the RBD domain. RGS14 binds directly to both inactive (GDP) and active (GTP) forms of Gαi1 and Gαi3, but not Gαi2, and binding to inactive Gαi1/3 at the plasma membrane prevents nuclear or centrosomal association. Confocal imaging of GFP-tagged constructs with domain mutations, co-immunoprecipitation with Gαi isoforms from cells Cellular signalling Medium 16870394
2006 RGS14 GAP activity and GDI activity toward heterotrimeric G proteins are unaffected by Rap1/Rap2 binding. A heterotrimer composed of N-myristoylated Gαi1 and prenylated Gβγ is resistant to the GDI activity of the RGS14 GoLoco domain, suggesting RGS14 alone cannot dissociate intact heterotrimers. In vitro GTPase assays, GDI assays with assembled heterotrimer, Rap-binding competition experiments The Biochemical journal Medium 16246175
2009 In cellular contexts, RGS14 selectively binds activated H-Ras-GTP (not Rap isoforms), assembles a multiprotein complex with components of the ERK MAPK pathway (Raf, MEK, ERK) in an H-Ras-GTP-dependent manner, and promotes sustained ERK activation. siRNA knockdown of RGS14 inhibited NGF- and bFGF-mediated neuronal differentiation of PC12 cells, a process dependent on Ras-ERK signaling. Co-immunoprecipitation, siRNA knockdown, PC12 neurite outgrowth assays, ERK phosphorylation assays PloS one Medium 19319189
2010 RGS14 is highly enriched in CA2 pyramidal neurons and suppresses long-term potentiation (LTP) at Schaffer collateral synapses. Deletion of RGS14 (exons 2–7 knockout) enables robust LTP at CA2 synapses without affecting CA1 plasticity. MEK inhibition blocks LTP in RGS14-deficient CA2 neurons, implicating ERK/MAP kinase signaling. RGS14 KO mice show enhanced spatial learning and object recognition memory without deficits in non-hippocampal tasks. Genetic knockout mice, electrophysiology (LTP recordings), MEK inhibitor pharmacology, behavioral testing Proceedings of the National Academy of Sciences of the United States of America High 20837545
2010 Activated H-Ras binds RGS14 at the R1 Ras-binding domain (RBD) to form a stable complex at cell membranes. RGS14 co-localizes with and forms a complex with Raf kinases in cells, and the regulatory region of Raf-1 binds the RBD region of RGS14. H-Ras and Raf facilitate one another's binding to RGS14. RGS14 selectively inhibits PDGF- but not EGF- or serum-stimulated ERK phosphorylation, dependent on H-Ras binding. Gαi1 binding to RGS14 is mutually exclusive with Raf binding, and Gαi1 recruits RGS14 to the plasma membrane to reverse inhibition of ERK signaling. Co-immunoprecipitation, subcellular localization imaging, ERK phosphorylation assays, domain mutant analysis Cellular signalling Medium 19878719
2011 RGS14 forms a Gαi/o-dependent complex with the α2A-adrenergic receptor (α2A-AR) in live cells, as measured by BRET. Receptor agonist (UK14304) stimulation disrupts the RGS14·α2A-AR complex while preserving the RGS14·Gαi1 complex. Ric-8A (a non-receptor GEF) facilitates dissociation of both the RGS14·Gαi1 complex and the Gαi1-dependent RGS14·α2A-AR complex after receptor activation. Bioluminescence resonance energy transfer (BRET) in live cells, pharmacological receptor stimulation The Journal of biological chemistry Medium 21880739
2012 RGS14 preferentially binds activated H-Ras-GTP in live cells, and inactive Gαi1-GDP markedly enhances RGS14 affinity for H-Ras-GTP (but active Gαi1-GTP does not). Active H-Ras-GTP interacts with a native RGS14·Gαi1 complex in brain lysates. Co-expression of RGS14 and Gαi1 in PC12 cells greatly enhances H-Ras-stimulatory effects on neurite outgrowth. Stimulation of α2A-AR induces a conformational change in the Gαi1·RGS14·H-Ras ternary complex. BRET in live cells, co-immunoprecipitation from brain lysates, PC12 neurite outgrowth assays The Journal of biological chemistry High 23250758
2013 The RBD region of RGS14 mediates an intramolecular interaction that enhances GAP activity of the RGS domain while simultaneously inhibiting GDI activity of the GPSM/GoLoco domain. The RBD region also binds members of the B/R4 subfamily of RGS proteins and enhances their effects on GPCR-activated Gi/o proteins. In vitro GTPase/GDI assays with isolated domains and full-length protein, protein-protein binding assays Journal of cellular biochemistry Medium 23255434
2015 RGS14 forms a stable complex with inactive Gαi1-GDP at the plasma membrane via its GPR motif and is also recruited to the plasma membrane by activated Gαo-AlF4(-) via its RGS domain. RGS14 undergoes allosteric conformational changes upon Gαi1-GDP binding to the GPR motif, as revealed by hydrogen/deuterium exchange mass spectrometry. RGS14 can form a ternary complex with Gαo-AlF4(-) and a Gαi1-GDP mutant (G42R) simultaneously, and a preformed RGS14·Gαi1-GDP complex retains full capacity to stimulate GTPase activity of Gαo-GTP. Size exclusion chromatography, hydrogen/deuterium exchange mass spectrometry (HDX-MS), BRET, biochemical reconstitution, cellular localization assays The Journal of biological chemistry High 25666614
2016 RGS14 acts as a dedicated GAP for Gαo/i signaling and does not prolong Gβγ signaling following receptor activation. Co-expression of RGS14 inhibits free Gβγ release after agonist stimulation and increases the deactivation rate of Gα, consistent with GAP activity. Overexpression of inactive Gαi1 to recruit RGS14 to the plasma membrane did not alter RGS14's GAP activity toward a second Gαo protein, indicating the GPR motif functions independently of the RGS domain for GAP activity. BRET in live cells, GPCR agonist/antagonist kinetics analysis Pharmacology research & perspectives Medium 27713821
2017 Endogenous RGS14 in neuroblastoma (B35) cells localizes to juxtanuclear membranes encircling the nucleus, at nuclear pore complexes on both sides of the nuclear envelope and within intranuclear membrane channels, and within chromatin-rich and chromatin-poor nuclear regions in a cell-cycle-dependent manner. Endogenous RGS14 was absent from the plasma membrane in resting cells but could be trafficked to the plasma membrane from juxtanuclear membranes (derived from ER/Golgi) following AlF4¯ activation of its G protein binding partners. Confocal imaging, 3D-structured illumination microscopy, AlF4¯ pharmacological activation, subcellular fractionation PloS one Medium 28934222
2018 RGS14 directly interacts with Ca2+/calmodulin (CaM) and is phosphorylated by CaMKII in vitro. RGS14 associates with CaMKII and CaM in hippocampal CA2 neurons in vivo. These interactions were identified via immunoprecipitation-mass spectrometry proteomics of endogenous RGS14 from mouse brain, validated by direct biochemical binding assays. Immunoprecipitation-mass spectrometry from mouse brain, direct binding assays, in vitro CaMKII phosphorylation assay, confocal colocalization Journal of proteome research Medium 29518331
2018 RGS14 suppresses plasticity in hippocampal area CA2 by restricting calcium (Ca2+) elevations in dendritic spines. Genetic KO of RGS14 results in nascent LTP requiring NMDA receptors, CaMK, and PKA. WT CA2 neurons display significantly attenuated spine Ca2+ transients during structural plasticity induction compared with RGS14 KO CA2 or CA1 controls. Acute overexpression of RGS14 is sufficient to block spine structural plasticity, and elevated extracellular Ca2+ restores plasticity to RGS14-expressing neurons. Genetic KO mice, two-photon calcium imaging in dendritic spines, pharmacological inhibition (NMDA receptor, CaMK, PKA antagonists), overexpression experiments eNeuro High 29911178
2018 14-3-3γ directly binds RGS14 at two distinct sites: one phosphorylation-independent site and one phosphorylation-dependent site at Ser-218, potentiated by active H-Ras signaling. The pSer-218-dependent interaction inhibits active Gαi1-AlF4- binding to the RGS domain but does not affect H-Ras or inactive Gαi1-GDP binding. The phosphorylation-independent 14-3-3 interaction inhibits RGS14 nuclear import/nucleocytoplasmic shuttling without affecting Gαi interactions. BRET in live cells, direct binding assays, site-directed mutagenesis at Ser-218 The Journal of biological chemistry Medium 30093406
2020 Human genetic variants L505R (LR) and R507Q (RQ) in the nuclear export sequence of RGS14 disrupt RGS14 binding to Gαi1-GDP and to Exportin 1 (XPO1), disturb nucleocytoplasmic equilibrium, and abolish RGS14's capacity to inhibit LTP. Variant LR accumulates irreversibly in the nucleus, preventing membrane localization to dendritic spines. When introduced into mice by CRISPR/Cas9, RGS14-LR is predominantly nuclear in neurons of hippocampus, amygdala, piriform cortex, and striatum. Unlike complete RGS14 KO, LR mice show normal spatial learning, suggesting distinct nuclear vs. dendritic spine functions. Site-directed mutagenesis, co-immunoprecipitation, electrophysiology (LTP), CRISPR/Cas9 knock-in mice, confocal imaging, behavioral testing The Journal of biological chemistry High 33410399
2022 RGS14 possesses a carboxy-terminal PDZ ligand required for binding to NHERF1 scaffold protein (at PDZ2) and thereby regulates NPT2A-mediated renal phosphate transport. RGS14 blocks PTH- and FGF23-induced dissociation of the NPT2A-NHERF1 complex and thereby suppresses hormone-sensitive (but not basal) phosphate uptake. RGS14 genetic variants bearing mutations in the PDZ ligand disrupt NHERF1 binding and PTH-sensitive phosphate transport. RGS14 does not affect PTH-directed G protein activation or cAMP formation, implying a post-receptor site of action. Isotope uptake measurements, BRET assays, siRNA knockdown, pull-down and overlay assays, molecular modeling, direct binding assays in proximal tubule cells The Journal of biological chemistry High 35307350
2007 RGS14 associates with mu-opioid receptors (MOR) in periaqueductal gray (PAG) neurons. When RGS14 is silenced, morphine increases serine 375 phosphorylation of MOR (a GRK substrate), leading to receptor internalization and recycling and resensitization to morphine with reduced tolerance. RGS14 prevents GRKs from phosphorylating MOR residues required for β-arrestin-mediated endocytosis. Morphine (but not DAMGO) also triggers CaMKII activation in PAG neurons via a mechanism requiring RGS14. siRNA knockdown in vivo, receptor phosphorylation assays, internalization/recycling assays, behavioral antinociception measurement Cellular signalling Medium 17825524
2013 RGS14 regulates αMβ2 integrin activation during phagocytosis in macrophages. Exogenous RGS14 expression in COS-7 cells increases binding of C3bi-opsonized targets. Knockdown of RGS14 in J774.A1 macrophages decreases association with C3bi-opsonized particles. This function requires the R333 residue of the RGS14 RBD and the F754 residue of β2, indicating regulation occurs through the Rap/RBD axis. Exogenous expression, siRNA knockdown, binding assays with opsonized particles, point mutant analysis PloS one Medium 23805333
2023 RGS14 localizes to mitochondria in hippocampal CA2 pyramidal cells and reduces mitochondrial respiration in vitro. Loss of RGS14 dramatically increases 3-nitrotyrosine levels (oxidative stress marker) in CA2 cells, which is exacerbated following kainic acid-induced status epilepticus and correlates with a lack of SOD2 induction. RGS14 KO mice show accelerated onset of limbic motor seizures and increased mortality. RGS14 KO also results in absence of microgliosis in CA1 and CA2 following seizure. Mitochondrial localization imaging, in vitro mitochondrial respiration assay, kainic acid seizure model in KO mice, proteomics, immunostaining for oxidative stress markers Neurobiology of disease Medium 37075948
2025 Small-molecule inhibitors targeting the solvent-exposed 'canyon' in the RGS14 RGS-box that interacts with the Gα switch I region can non-covalently and selectively inhibit RGS14 GAP activity. Two second-generation analogs (Z55660043 and Z55627844) inhibited RGS14 GAP activity in both fluorescence-based and radioactive GTP hydrolysis assays without measurable cytotoxicity. One analog showed favorable in vivo pharmacokinetics and CNS penetration. Structure-guided virtual screening, fluorescence-based GAP assays, radioactive GTP hydrolysis assays, cytotoxicity assays, in vivo pharmacokinetics bioRxivpreprint Medium bio_10.1101_2025.06.11.659181
2025 RGS14 physically interacts with GNAI3 (Gαi3) in spermatogonial stem cells (SSCs), as shown by co-immunoprecipitation. RGS14 knockdown suppresses SSC proliferation, induces apoptosis, inhibits PLPP2 expression, and reduces MAPK signaling activation. Overexpression of PLPP2 rescues phenotypic defects caused by RGS14 depletion, identifying a RGS14–GNAI3–PLPP2 regulatory axis. Single-cell RNA sequencing, siRNA knockdown, co-immunoprecipitation, RNA sequencing, PLPP2 rescue overexpression, proliferation/apoptosis assays Frontiers in cell and developmental biology Medium 40352663
2025 RGS14 regulates hormone-sensitive renal phosphate transport through a linker region between the RGS and RBD1 domains: Ser266 and Ser269 within this α-helical linker are phosphorylated in response to PTH and FGF23. Ser266Ala/Ser269Ala substitutions abolish RGS14 regulatory effects on hormone-sensitive phosphate transport while an intact PDZ ligand is also required. Truncation constructs lacking the RGS domain are fully functional for phosphate transport regulation. RGS14 truncation constructs, phosphorylation assays with PTH and FGF23, phosphate uptake measurements, alanine mutagenesis of Ser266/Ser269 The Biochemical journal Medium 39792018

Source papers

Stage 0 corpus · 52 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
2010 RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory. Proceedings of the National Academy of Sciences of the United States of America 172 20837545
1997 Molecular cloning and expression analysis of rat Rgs12 and Rgs14. Biochemical and biophysical research communications 108 9168931
2000 RGS14 is a novel Rap effector that preferentially regulates the GTPase activity of galphao. The Biochemical journal 82 10926822
2000 RGS14, a GTPase-activating protein for Gialpha, attenuates Gialpha- and G13alpha-mediated signaling pathways. Molecular pharmacology 73 10953050
2010 RGS14 is a multifunctional scaffold that integrates G protein and Ras/Raf MAPkinase signalling pathways. Cellular signalling 70 19878719
2001 RGS14 is a bifunctional regulator of Galphai/o activity that exists in multiple populations in brain. Journal of neurochemistry 63 11739605
2004 The RGS14 GoLoco domain discriminates among Galphai isoforms. The Journal of biological chemistry 55 15337739
2004 RGS14 is a mitotic spindle protein essential from the first division of the mammalian zygote. Developmental cell 51 15525537
2003 Phosphorylation of RGS14 by protein kinase A potentiates its activity toward G alpha i. Biochemistry 48 12534294
2014 Postnatal developmental expression of regulator of G protein signaling 14 (RGS14) in the mouse brain. The Journal of comparative neurology 47 23817783
2004 RGS14 is a centrosomal and nuclear cytoplasmic shuttling protein that traffics to promyelocytic leukemia nuclear bodies following heat shock. The Journal of biological chemistry 43 15520006
2018 RGS14 Restricts Plasticity in Hippocampal CA2 by Limiting Postsynaptic Calcium Signaling. eNeuro 42 29911178
2012 Assembly and function of the regulator of G protein signaling 14 (RGS14)·H-Ras signaling complex in live cells are regulated by Gαi1 and Gαi-linked G protein-coupled receptors. The Journal of biological chemistry 42 23250758
2006 Selective interactions between Gi alpha1 and Gi alpha3 and the GoLoco/GPR domain of RGS14 influence its dynamic subcellular localization. Cellular signalling 41 16870394
2009 Regulator of G-protein signaling 14 (RGS14) is a selective H-Ras effector. PloS one 40 19319189
2004 The RGS (regulator of G-protein signalling) and GoLoco domains of RGS14 co-operate to regulate Gi-mediated signalling. The Biochemical journal 36 15112653
2005 RGS14 is a microtubule-associated protein. Cell cycle (Georgetown, Tex.) 29 15917656
2011 G protein-coupled receptors and resistance to inhibitors of cholinesterase-8A (Ric-8A) both regulate the regulator of g protein signaling 14 RGS14·Gαi1 complex in live cells. The Journal of biological chemistry 28 21880739
2011 RGS14 at the interface of hippocampal signaling and synaptic plasticity. Trends in pharmacological sciences 28 21906825
2007 RGS14 prevents morphine from internalizing Mu-opioid receptors in periaqueductal gray neurons. Cellular signalling 27 17825524
2017 Regulator of G protein signaling 14 (RGS14) is expressed pre- and postsynaptically in neurons of hippocampus, basal ganglia, and amygdala of monkey and human brain. Brain structure & function 25 28776200
2018 Interactome Analysis Reveals Regulator of G Protein Signaling 14 (RGS14) is a Novel Calcium/Calmodulin (Ca2+/CaM) and CaM Kinase II (CaMKII) Binding Partner. Journal of proteome research 24 29518331
2015 Integration of G protein α (Gα) signaling by the regulator of G protein signaling 14 (RGS14). The Journal of biological chemistry 23 25666614
2021 RGS14 Regulation of Post-Synaptic Signaling and Spine Plasticity in Brain. International journal of molecular sciences 22 34201943
2019 The rs1256328 (ALPL) and rs12654812 (RGS14) Polymorphisms are Associated with Susceptibility to Calcium Nephrolithiasis in a Taiwanese population. Scientific reports 22 31754202
2022 RGS14 regulates PTH- and FGF23-sensitive NPT2A-mediated renal phosphate uptake via binding to the NHERF1 scaffolding protein. The Journal of biological chemistry 17 35307350
2006 Biochemical characterization of RGS14: RGS14 activity towards G-protein alpha subunits is independent of its binding to Rap2A. The Biochemical journal 17 16246175
2023 Exercise enhancement by RGS14 disruption is mediated by brown adipose tissue. Aging cell 16 36905127
2013 The Ras-binding domain region of RGS14 regulates its functional interactions with heterotrimeric G proteins. Journal of cellular biochemistry 16 23255434
2005 Novel activity of RGS14 on Goalpha and Gialpha nucleotide binding and hydrolysis distinct from its RGS domain and GDI activity. Biochemistry 16 15807543
2018 14-3-3γ binds regulator of G protein signaling 14 (RGS14) at distinct sites to inhibit the RGS14:Gαi-AlF4- signaling complex and RGS14 nuclear localization. The Journal of biological chemistry 15 30093406
2020 Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons. The Journal of biological chemistry 13 33410399
2017 Endogenous RGS14 is a cytoplasmic-nuclear shuttling protein that localizes to juxtanuclear membranes and chromatin-rich regions of the nucleus. PloS one 13 28934222
2016 RGS14 regulates the lifetime of Gα-GTP signaling but does not prolong Gβγ signaling following receptor activation in live cells. Pharmacology research & perspectives 13 27713821
2019 RGS14414 treatment induces memory enhancement and rescues episodic memory deficits. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 12 31365833
2013 Regulator of G-Protein Signalling-14 (RGS14) Regulates the Activation of αMβ2 Integrin during Phagocytosis. PloS one 12 23805333
2021 RGS14 modulates locomotor behavior and ERK signaling induced by environmental novelty and cocaine within discrete limbic structures. Psychopharmacology 11 34184126
2023 RGS14 limits seizure-induced mitochondrial oxidative stress and pathology in hippocampus. Neurobiology of disease 10 37075948
2004 Purification and in vitro functional analyses of RGS12 and RGS14 GoLoco motif peptides. Methods in enzymology 9 15488192
2022 RGS14 expression in CA2 hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease. Hippocampus 8 36541898
2018 Significant association between RGS14 rs12654812 and nephrolithiasis risk among Guangxi population in China. Journal of clinical laboratory analysis 8 29577426
2020 Genetic Polymorphisms of RGS14 and Renal Stone Disease. Archives of medical research 6 33309307
2024 Distinct and overlapping RGS14 and RGS12 actions regulate NPT2A-mediated phosphate transport. Biochemical and biophysical research communications 3 39293332
2025 RGS14 promotes the progression of hepatocellular carcinoma by activating the cAMP/PKA/CREB signaling pathway. Journal of cancer research and clinical oncology 2 40312502
2025 Noncanonical RGS14 structural determinants control hormone-sensitive NPT2A-mediated phosphate transport. The Biochemical journal 1 39792018
2024 Endogenous Regulator of G protein Signaling 14 (RGS14) suppresses cocaine-induced emotionally motivated behaviors in female mice. bioRxiv : the preprint server for biology 1 39314405
2023 RGS14 is neuroprotective against seizure-induced mitochondrial oxidative stress and pathology in hippocampus. bioRxiv : the preprint server for biology 1 36778349
2025 Regulator of G-protein signaling 14 (RGS14) promotes cancer growth in hepatocellular carcinoma. Cancer genetics 0 40245482
2025 RGS14 binds to GNAI3 and regulates the proliferation and apoptosis of human spermatogonial stem cells by affecting PLPP2 expression and MAPK signaling. Frontiers in cell and developmental biology 0 40352663
2025 Endogenous regulator of G protein signaling 14 (RGS14) blunts cocaine-induced emotionally motivated behaviors in female mice. Addiction neuroscience 0 41306987
2007 Backbone and sidechain 1H, 13C and 15N resonance assignments of the RGS domain from human RGS14. Biomolecular NMR assignments 0 19636837

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