Affinage

RGS19

Regulator of G-protein signaling 19 · UniProt P49795

Length
217 aa
Mass
24.6 kDa
Annotated
2026-06-10
51 papers in source corpus 30 papers cited in narrative 30 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

RGS19 (GAIP) is a GTPase-accelerating protein (GAP) that terminates heterotrimeric G protein signaling by accelerating GTP hydrolysis on Gαi-subfamily subunits, with which it interacts preferentially in the GTP-bound state through its conserved ~125-residue RGS domain (PMID:8524874, PMID:8756726, PMID:8986788, PMID:9207071). Its substrate selectivity for the Gi/o/z subfamily — and exclusion of Gαs — is dictated by a single Switch 3 residue in the Gα GTPase domain (PMID:10364213), and it also acts as a GAP for Gαq, additionally occluding the effector-binding site to block phospholipase Cβ activation (PMID:9012799); in cells RGS19 attenuates both Gi-mediated cAMP inhibition and Gq-mediated PLCβ activation (PMID:9177187). RGS19 partitions between a soluble pool and a membrane-anchored pool that is palmitoylated on an N-terminal cysteine string motif, faces the cytoplasm, and is phosphorylated on Ser-24 by casein kinase 2 selectively on the membrane fraction (PMID:8986788, PMID:10760275). It is the first GAP localized to clathrin-coated vesicles and Golgi/TGN-derived carriers, where it retains GAP activity toward Gαi3 and participates in vesicle budding and secretory trafficking (PMID:9571244, PMID:10359779, PMID:9950778, PMID:12656990). A unique C-terminal PDZ-binding motif (SEA) recruits the PDZ-scaffold GIPC, which targets RGS19 to specific GPCRs including the dopamine D2 receptor, mu-opioid receptor, and ORL1, conferring receptor-selective signal regulation (PMID:9770488, PMID:15356268, PMID:14997173, PMID:23197645, PMID:16219326). Through its N-terminal cysteine string motif RGS19 also binds the RING E3 ligase GIPN, acting as a bifunctional adaptor that links Gαi3 to proteasomal degradation (PMID:12826607). Beyond direct G protein regulation, RGS19 modulates growth and survival pathways: it dampens canonical Wnt-β-catenin signaling via Gαo inactivation (PMID:17855383), inhibits Ras-ERK signaling by upregulating Nm23-H1/2 (PMID:23416464), and in hepatocellular carcinoma stabilizes MYH9 by competing with the E3 ligase STUB1, driving a β-catenin/c-Myc positive feedback loop (PMID:38825640). Its own stability is controlled by intracellular iron, which gates GIPN-mediated proteolysis and a downstream Gαi3-dependent growth-inhibitory (NDRG1) signal (PMID:26116529).

Mechanistic history

Synthesis pass · year-by-year structured walk · 29 steps
  1. 1995 High

    Established that RGS19 physically engages a heterotrimeric G protein, defining its first molecular partner and localizing the interaction to the conserved RGS domain.

    Evidence Yeast two-hybrid and GST pulldown with in vitro-translated Gαi3, plus deletion mapping

    PMID:8524874

    Open questions at the time
    • Did not test whether binding requires the GTP-bound state
    • No enzymatic activity demonstrated
  2. 1996 High

    Defined RGS19 as an enzyme — a GAP that accelerates Gαi GTP hydrolysis — and delimited its substrate range to the Gi subfamily, excluding Gs.

    Evidence In vitro GTPase assay with purified recombinant Gα subunits

    PMID:8756726

    Open questions at the time
    • Structural basis of catalysis not addressed
    • Cellular consequence not yet shown
  3. 1996 High

    Resolved how RGS19 associates with membranes and confirmed activation-state selectivity, establishing dual soluble/membrane pools.

    Evidence [3H]palmitate labeling, carbonate extraction, proteinase K protection, yeast two-hybrid Gα panel

    PMID:8986788

    Open questions at the time
    • Palmitoyl transferase responsible not identified
    • Functional difference between pools unresolved at this stage
  4. 1997 High

    Extended RGS19 GAP activity to Gαq and showed a second mode of inhibition — effector-site occlusion — broadening its regulatory repertoire beyond hydrolysis acceleration.

    Evidence In vitro GTPase and PLCβ activation assays with purified Gαq and plasma membranes

    PMID:9012799

    Open questions at the time
    • Relative contribution of GAP vs occlusion in cells unquantified
  5. 1997 High

    Demonstrated that the isolated RGS domain is sufficient for GAP activity and mapped catalytic determinants by mutagenesis, isolating the enzymatic module from the regulatory N-terminus.

    Evidence In vitro GTPase assays, surface plasmon resonance, RGS-domain mutagenesis

    PMID:9207071

    Open questions at the time
    • Did not address how flanking regions modulate domain function in vivo
  6. 1997 High

    Confirmed in living cells that RGS19 negatively regulates Gi- and Gq-coupled signaling with the same selectivity seen in vitro, bridging biochemistry and cellular physiology.

    Evidence Stable mammalian expression with cAMP and IP3/PLCβ readouts

    PMID:9177187

    Open questions at the time
    • Which endogenous receptors are regulated not defined
    • Subcellular site of action not localized
  7. 1997 Medium

    Linked RGS19 to a cellular process — macroautophagy — through Gαi3 cycling, the first non-canonical functional output placed downstream of its GAP activity.

    Evidence Transient transfection, protein degradation assay, GTPase-dead Gαi3 epistasis

    PMID:9305927

    Open questions at the time
    • Single lab, overexpression-based
    • Molecular intermediates between Gαi3 and autophagy machinery unknown
  8. 1998 High

    Identified GIPC as a PDZ-domain partner binding the unique C-terminal SEA motif, providing a scaffold mechanism distinct from the RGS domain and unique among RGS proteins tested.

    Evidence Yeast two-hybrid, GST pulldown, deletion mapping, immunofluorescence/immuno-EM

    PMID:9770488

    Open questions at the time
    • Functional consequence of GIPC binding not yet defined
    • Whether GIPC links RGS19 to receptors not yet shown
  9. 1998 High

    Localized RGS19 to clathrin-coated vesicles in vivo, establishing it as the first GAP on intracellular membranes and predicting a role in vesicular G protein signaling.

    Evidence Cell fractionation and immunogold EM in pituitary and liver tissue

    PMID:9571244

    Open questions at the time
    • Did not demonstrate that vesicle-bound RGS19 is catalytically active
  10. 1999 High

    Showed that CCV-associated RGS19 is functional GAP, directly coupling its membrane localization to enzymatic activity.

    Evidence In vitro GTPase assay on vesicle fractions with immunodepletion controls and EM

    PMID:10359779

    Open questions at the time
    • The vesicular Gα effector pathway regulated remained undefined
  11. 1999 High

    Pinpointed a single Switch 3 residue in Gα as the determinant of RGS19 subfamily selectivity, explaining its discrimination among Gi-class subunits.

    Evidence GST pulldown with Gαi chimeras/point mutants and in vitro GTPase assays

    PMID:10364213

    Open questions at the time
    • Selectivity for Gαq/Gαo not mapped to a comparable determinant
  12. 1999 High

    Provided the solution structure of free RGS19, revealing which interface residues are pre-organized for Gα binding versus domain folding.

    Evidence NMR structure with dipolar coupling restraints, comparison to RGS4–Gα complex

    PMID:10452897

    Open questions at the time
    • No structure of an RGS19–Gα complex
    • N-terminal cysteine string region not structurally resolved
  13. 1999 Medium

    Extended RGS19's membrane trafficking role to Golgi-derived budding vesicles and secretory protein export, distinguishing pre- from post-Golgi steps.

    Evidence Stable expression, immuno-EM, in vitro Golgi budding assay, proteoglycan secretion

    PMID:9950778

    Open questions at the time
    • Single lab
    • Direct Gα substrate at the Golgi not identified
  14. 2000 High

    Identified casein kinase 2 as the writer phosphorylating RGS19 on Ser-24 exclusively on the membrane pool, adding pool-specific post-translational regulation.

    Evidence Metabolic 32P labeling, phosphoamino acid analysis, in vitro CK2 and CCV phosphorylation, site mapping

    PMID:10760275

    Open questions at the time
    • Functional effect of Ser-24 phosphorylation on GAP activity not resolved
  15. 2001 Medium

    Placed the GIPC–RGS19 module on TrkA-bearing retrograde vesicles, suggesting it tunes receptor tyrosine kinase output (ERK) via GIPC scaffolding.

    Evidence Co-IP in transfected and endogenous cells, colocalization, overexpression functional assays

    PMID:11251075

    Open questions at the time
    • RGS19's own role inferred indirectly through GIPC
    • No direct RGS19–TrkA interaction shown
  16. 2002 Medium

    Positioned the RGS19/GIPC/Gαi3 complex at megalin-mediated endocytic sites, linking G protein regulation to receptor endocytosis in epithelia.

    Evidence Immunofluorescence, immuno-EM, fractionation, GST pulldown of GIPC–megalin

    PMID:11912251

    Open questions at the time
    • Functional consequence for megalin trafficking not demonstrated
    • Single lab
  17. 2003 High

    Revealed a bifunctional adaptor role: RGS19's cysteine string motif binds the RING E3 ligase GIPN to channel Gαi3 toward proteasomal degradation, coupling signal termination to subunit turnover.

    Evidence Yeast two-hybrid, Co-IP, in vitro ubiquitination, pulse-chase, proteasome inhibition

    PMID:12826607

    Open questions at the time
    • Whether GAP activity and GIPN adaptor function are coordinated unresolved
  18. 2003 Medium

    Implicated RGS19 in the budding machinery of a distinct TGN-derived exocytic carrier class, where a dominant-negative N-terminus blocks carrier formation and surface cargo delivery.

    Evidence In vitro TGN budding assay, live VSV-G-GFP imaging, NT-GAIP dominant-negative

    PMID:12656990

    Open questions at the time
    • Single lab
    • Mechanistic link between GAP activity and budding not established
  19. 2003 Medium

    Provided a spatial model for GAP-mediated signal termination: agonist drives Gαi3 into clathrin-coated pits where RGS19 resides, segregating active Gα for inactivation.

    Evidence Deconvolution microscopy, Co-IP, dominant-negative dynamin

    PMID:12815156

    Open questions at the time
    • Single lab
    • Causality of segregation for signaling kinetics not quantified
  20. 2004 High

    Demonstrated that GIPC dynamically recruits RGS19 to the dopamine D2 receptor to selectively regulate its G protein signaling, establishing scaffold-directed receptor targeting.

    Evidence Co-IP, live-cell translocation imaging, knockdown, cAMP/functional assays

    PMID:15356268

    Open questions at the time
    • Generality of GIPC-directed recruitment across GPCRs not yet shown at this point
  21. 2004 Medium

    Showed receptor-selective action in the CNS: RGS19/GIPC regulate mu- but not delta-opioid antinociception in vivo, situating RGS19 in Gαz-mediated mu-opioid signaling.

    Evidence Antisense knockdown with supraspinal antinociception assays in mice

    PMID:14997173

    Open questions at the time
    • Single lab
    • Molecular basis of mu- vs delta-receptor selectivity not resolved
  22. 2005 Medium

    Established that the N-terminal cysteine string domain confers receptor preference, with full-length RGS19 favoring ORL1 over opioid receptors.

    Evidence COS-7 co-expression, GTPase and cAMP assays, N-terminal truncation

    PMID:16219326

    Open questions at the time
    • Single lab
    • How the N-terminus encodes receptor preference mechanistically unknown
  23. 2007 Medium

    Connected RGS19 to canonical Wnt signaling via Gαo inactivation, placing it upstream of Dvl3 and β-catenin.

    Evidence Overexpression/knockdown, constitutively active Gαo rescue, β-catenin and Lef-Tcf reporter assays

    PMID:17855383

    Open questions at the time
    • Opposing effects of overexpression and knockdown unresolved
    • Single lab
  24. 2010 Medium

    Separated RGS19's growth-promoting activity from its GAP activity, showing proliferation requires the GIPC-binding SEA motif rather than catalysis.

    Evidence Stable lines, deletion-mutant Co-IP, proliferation assays, GIPC knockdown

    PMID:20599498

    Open questions at the time
    • Downstream proliferative effectors of the RGS19–GIPC complex undefined
    • Single lab
  25. 2013 Medium

    Defined a Ras-ERK inhibitory mechanism in which RGS19 upregulates Nm23-H1/2 to phosphorylate and nuclear-sequester KSR.

    Evidence Stable expression, Co-IP, nuclear fractionation, phospho-KSR, Nm23 knockdown rescue

    PMID:23416464

    Open questions at the time
    • How RGS19 raises Nm23 levels not mechanistically resolved
    • Single lab
  26. 2013 Medium

    Implicated RGS19 (with Gαi3) and RIP3 in zVAD-induced autophagy and autophagic cell death, extending its autophagy role to a programmed cell death context.

    Evidence Co-IP (RIP3–RGS19), shRNA knockdown, LC3 flux, TNF measurement in L929 cells

    PMID:24751948

    Open questions at the time
    • Direct vs indirect RIP3 interaction unclear
    • Single lab
  27. 2014 Medium

    Linked Notch-regulated RGS19 phosphorylation to Akt-dependent macrophage survival, adding an immune-context regulatory axis.

    Evidence Phospho-proteomics, gamma-secretase inhibition, siRNA, RBP-Jκ knockout, viability analysis

    PMID:24775271

    Open questions at the time
    • Kinase/site of Notch-dependent phosphorylation not defined
    • Single lab
  28. 2015 Medium

    Revealed that intracellular iron gates RGS19 stability by controlling GIPN-mediated proteolysis, coupling metabolic state to Gαi3-dependent growth-inhibitory signaling.

    Evidence Iron co-purification, UV spectroscopy, GIPN proteolysis-protection, NDRG1 readout

    PMID:26116529

    Open questions at the time
    • Iron-binding site on RGS19 not mapped
    • Single lab
  29. 2024 Medium

    Identified a tumor-promoting mechanism whereby RGS19 stabilizes MYH9 by competing with STUB1, driving a β-catenin/c-Myc feedback loop in hepatocellular carcinoma.

    Evidence Co-IP, domain mapping, ubiquitination assays, tumor growth assays, c-Myc luciferase reporter

    PMID:38825640

    Open questions at the time
    • Relationship between MYH9 stabilization and canonical GAP activity unclear
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RGS19's distinct functional modules — RGS-domain GAP activity, GIPC-mediated receptor targeting, GIPN-linked degradation, and growth/survival regulation — are integrated and coordinately controlled in a single cell remains unresolved.
  • No structure of an RGS19–Gα complex
  • No knockout organism phenotype in the corpus
  • Crosstalk between membrane-pool phosphorylation, iron sensing, and adaptor functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 1
Localization
GO:0031410 cytoplasmic vesicle 4 GO:0005794 Golgi apparatus 3 GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 2
Partners
GIPC1GIPNGNAI3MYH9NME1NME2RIPK3STUB1

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 GAIP (RGS19) specifically interacts with the heterotrimeric G protein Gαi3, identified by yeast two-hybrid screening and confirmed by GST-fusion pulldown with in vitro-translated Gαi3. The conserved 125-amino acid core (RGS) domain was demonstrated by deletion mutant analysis to be the site of interaction with Gαi3. Yeast two-hybrid, GST pulldown with in vitro-translated protein, deletion mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 8524874
1996 GAIP (RGS19) is a GTPase-activating protein (GAP) that accelerates the rate of GTP hydrolysis by Gαi1 at least 40-fold in vitro. All Gi subfamily members assayed were substrates; Gsα was not a substrate. In vitro GTPase activity assay with purified recombinant proteins Cell High 8756726
1996 GAIP (RGS19) is membrane-anchored via palmitoylation of its N-terminal cysteine string motif. Two pools exist: a soluble unpalmitoylated pool and a membrane-anchored palmitoylated pool. GAIP faces the cytoplasm and interacts preferentially with the GTP-bound (activated) form of Gαi3. Interaction specificity in the yeast two-hybrid system extended to Gαi1, Gαi2, Gαi3, Gαz, and Gαo, but not Gαs, Gαq, or Gα12/13. [3H]palmitic acid metabolic labeling, sodium carbonate extraction, proteinase K protection assay, yeast two-hybrid with Gα subunit panel Proceedings of the National Academy of Sciences of the United States of America High 8986788
1997 GAIP (RGS19) also acts as a GAP for Gαq, accelerating GTP hydrolysis, and blocks activation of phospholipase Cβ by GTPγS-Gαq apparently by occluding the effector-binding site on Gα, not solely through GAP activity. In vitro GTPase assay with purified Gαq, phospholipase Cβ activation assay with plasma membranes Proceedings of the National Academy of Sciences of the United States of America High 9012799
1997 The isolated RGS domain of GAIP (RGS19) retains GTPase-accelerating activity for Gi-class substrates (Gαi1, Gαo, Gαz) in vitro. Short deletions within the RGS domain abolished GAP activity and Gαi1 substrate binding. In vitro GTPase assay with purified RGS domain constructs, surface plasmon resonance binding assay, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 9207071
1997 Stable expression of GAIP (RGS19) in transfected mammalian cells attenuated Gi-mediated inhibition of cAMP synthesis and Gq-mediated activation of phospholipase Cβ, confirming its role as a negative regulator in vivo with selectivity matching in vitro data. Stable transfection in mammalian cells, cAMP assay, IP3/PLCβ assay Proceedings of the National Academy of Sciences of the United States of America High 9177187
1997 Overexpression of GAIP (RGS19) in undifferentiated HT-29 intestinal cells stimulated macroautophagic protein degradation. This effect required active Gαi3 GTPase cycling, as GAIP overexpression did not stimulate autophagy in cells expressing the GTPase-dead Q204L Gαi3 mutant, placing GAIP upstream of Gαi3 in autophagy regulation. Transient transfection, protein degradation assay, pertussis toxin treatment, GTPase-dead mutant epistasis The Journal of biological chemistry Medium 9305927
1998 GIPC (GAIP-interacting protein, C-terminus), containing a central PDZ domain, specifically interacts with the C-terminal 11 amino acids (PDZ-binding motif SEA) of GAIP (RGS19). GIPC does not interact with other RGS family members tested. GIPC has both a soluble cytosolic pool and a membrane-associated pool near the plasma membrane in HeLa cells. Yeast two-hybrid, GST-GIPC pulldown, deletion mutant analysis, immunofluorescence, immunoelectron microscopy Proceedings of the National Academy of Sciences of the United States of America High 9770488
1998 GAIP (RGS19) is localized on clathrin-coated vesicles (CCVs) in the Golgi region of pituitary cells and on CCVs near the sinusoidal plasma membrane of rat liver, as determined by cell fractionation and immunogold labeling. This makes GAIP the first GAP found on intracellular membranes/CCVs. Cell fractionation, immunogold electron microscopy Molecular biology of the cell High 9571244
1999 Clathrin-coated vesicle fractions enriched for GAIP (RGS19) possess GAP activity toward recombinant Gαi3 in vitro. Immunodepletion of GAIP from the vesicle fraction reduced GAP activity, directly demonstrating that membrane-associated GAIP on CCVs is functional. In vitro GTPase activity assay with vesicle fractions, immunodepletion, immunogold EM Proceedings of the National Academy of Sciences of the United States of America High 10359779
1999 The selectivity of GAIP (RGS19) for Gαi subfamily members is determined by a single amino acid (Asp229 in Gαi1, corresponding to Ala230 in Gαi2) in Switch 3 of the GTPase domain. Substituting Ala230 in Gαi2 with Asp conferred strong GAIP binding and GAP substrate activity; mutating Asp229 in Gαi1 abolished interaction. GST pulldown with Gαi chimeras and site-directed mutants, in vitro GTPase activity assay The Journal of biological chemistry High 10364213
1999 The solution structure of human GAIP (RGS19) was determined by NMR with dipolar couplings in two liquid crystal media. Structural comparison with the RGS4–Gα crystal complex identified residues at the Gα-binding interface that adopt similar orientations in free GAIP, suggesting these residues contribute to RGS domain folding/stability in addition to Gα binding. NMR solution structure determination with dipolar coupling restraints Journal of molecular biology High 10452897
1999 GAIP (RGS19) associates with Golgi-derived budding vesicles in epithelial LLC-PK1 cells and regulates secretory protein trafficking upstream of the trans-Golgi network (but not post-Golgi secretion), as assessed by in vitro Golgi vesicle budding assay and measurement of sulfated proteoglycan secretion in GAIP-overexpressing cell lines. Stable transfection, immunogold EM, in vitro Golgi vesicle budding assay, sulfated proteoglycan secretion assay The American journal of physiology Medium 9950778
2000 Membrane-anchored GAIP (RGS19) is a phosphoprotein. Phosphorylation occurs exclusively on the membrane-anchored pool (not the soluble pool), predominantly on serine residues including Ser-24. Casein kinase 2 (CK2) phosphorylates the N-terminus of recombinant GAIP in a Mn2+-dependent manner, and isolated CCVs also phosphorylate GAIP in vitro. Alkaline phosphatase treatment, [32P]orthophosphate metabolic labeling, immunoprecipitation, phosphoamino acid analysis, in vitro phosphorylation with purified CK2 and isolated CCVs, site identification Proceedings of the National Academy of Sciences of the United States of America High 10760275
2001 GIPC and GAIP (RGS19) form a coprecipitable complex with the TrkA receptor in transfected HEK293T cells and in PC12 cells endogenously expressing TrkA. GIPC binds TrkA through its PDZ domain at the juxtamembrane region, and colocalizes with phosphorylated TrkA in retrograde transport vesicles. Overexpression of GIPC reduces NGF-induced ERK1/2 phosphorylation but not Akt, PLCγ1, or Shc phosphorylation. Co-immunoprecipitation in transfected and endogenous systems, immunofluorescence colocalization, overexpression functional assays Molecular biology of the cell Medium 11251075
2002 GAIP (RGS19) and GIPC colocalize with Gαi3 and megalin in endocytic compartments (clathrin-coated pits, apical tubules) of proximal tubule epithelial cells. GIPC binds the cytoplasmic tail of megalin in GST-pulldown assays, suggesting a signaling complex linking G protein regulation to megalin-mediated endocytosis. Immunofluorescence, immunoelectron microscopy, cell fractionation, GST pulldown Journal of the American Society of Nephrology Medium 11912251
2003 GIPN (GAIP interacting protein N-terminus), a RING finger-containing protein, binds exclusively to RGS subfamily A members (GAIP/RGS19, RGSZ1, RGSZ2) through its leucine-rich N-terminal region interacting with the cysteine string motif of GAIP. GIPN displays E3 ubiquitin ligase activity (Zn2+- and E1/E2-dependent autoubiquitination in vitro) and overexpression promotes proteasome-dependent degradation of Gαi3. RGS-GAIP thus acts as a bifunctional adaptor linking Gαi3 to proteasomal degradation via GIPN. Yeast two-hybrid, co-immunoprecipitation, in vitro ubiquitination assay, pulse-chase half-life assay, proteasome inhibitor treatment Proceedings of the National Academy of Sciences of the United States of America High 12826607
2003 GAIP (RGS19) is recruited to a specific population of trans-Golgi network-derived vesicles distinct from COPI- or clathrin-coated vesicles. An N-terminal truncation mutant (NT-GAIP) blocks membrane budding at the TGN, stabilizes tubular carrier intermediates, and reduces surface delivery of VSV-G, establishing GAIP as part of the budding machinery for a subset of post-Golgi exocytic carriers. In vitro TGN budding assay, live-cell imaging of VSV-G-GFP trafficking, overexpression of dominant-negative truncation mutant Traffic Medium 12656990
2003 After agonist (delta-opioid receptor) stimulation, Gαi3 translocates from non-clathrin-coated plasma membrane microdomains into clathrin-coated pits (CCPs) where GAIP (RGS19) resides. GAIP and Gαi3-YFP form a coprecipitable complex. Blocking endocytosis with dynamin K44A mutant causes striking colocalization of DOR, Gαi3, and GAIP in CCPs, supporting a model of spatial segregation as a mechanism for GAP-mediated signal termination. Immunofluorescence deconvolution microscopy, co-immunoprecipitation, dominant-negative dynamin expression Molecular pharmacology Medium 12815156
2004 GIPC recruits GAIP (RGS19) to the plasma membrane upon dopamine D2 receptor (D2R) activation. D2R activation drives dynamic translocation of GAIP to the plasma membrane in a GIPC-dependent manner. Two D2R-mediated G protein signaling responses were attenuated by GAIP's GTPase activity in a GIPC-dependent manner, demonstrating that GIPC scaffolds GAIP to specific GPCRs to selectively regulate their signaling. Co-immunoprecipitation, live-cell translocation imaging, siRNA/antisense knockdown, cAMP and functional signaling assays in neuronal/neuroendocrine cells Molecular biology of the cell High 15356268
2004 RGSZ1 and GAIP (RGS19) regulate mu-opioid receptor signaling but not delta-opioid receptor signaling in the CNS. Antisense knockdown of GAIP or GIPC increased morphine/DAMGO/endomorphin-1 antinociception without altering DPDPE or deltorphin II effects, placing GAIP in the Gαz-mediated mu-opioid signaling cascade. Antisense oligodeoxynucleotide knockdown, supraspinal antinociception assay in mice Neuropsychopharmacology Medium 14997173
2005 Full-length GAIP/RGS19 selectively enhances GTPase activity and reverses agonist-induced cAMP inhibition preferentially at ORL1 receptor over mu, delta, and kappa opioid receptors. An N-terminally truncated variant (lacking 22 residues) loses this receptor selectivity, demonstrating that the N-terminal cysteine string domain is required for GAIP's receptor preference. COS-7 cell co-expression, GTPase activity assay, cAMP inhibition assay, truncation mutant analysis Journal of molecular biology Medium 16219326
2007 RGS19 attenuates canonical Wnt-β-catenin signaling in mouse F9 cells by inactivating Gαo. Overexpression of RGS19 blocks β-catenin accumulation, Dvl3 phosphorylation, and Wnt-responsive gene transcription in response to Wnt3a; constitutively active Gαo rescues this inhibition. Epistasis places RGS19 upstream of Gαo and upstream of Dvl3 in the Wnt pathway. Conversely, siRNA knockdown of RGS19 also suppresses Wnt signaling, indicating a complex regulatory role. Overexpression, siRNA knockdown, constitutively active Gαo rescue, β-catenin accumulation assay, Lef-Tcf luciferase reporter, Dvl3 phosphorylation assay Journal of cell science Medium 17855383
2010 RGS19's ability to stimulate cell proliferation requires its C-terminal PDZ-binding motif (SEA) for interaction with GIPC. Deletion mutants of RGS19 lacking the PDZ-binding motif fail to complex with GIPC and lose the growth-promoting effect, even though GAP activity is retained. Overexpression of GIPC alone stimulates proliferation. Stable cell line generation, deletion mutant co-immunoprecipitation, cell proliferation assays, GIPC knockdown Cellular signalling Medium 20599498
2012 RGS19 is abundantly expressed in SH-SY5Y cells and acts as a GAP specifically at mu-opioid receptors (MOR) but not at delta-opioid (DOR) or nociceptin (NOPR) receptors. shRNA-mediated RGS19 knockdown increases MOR agonist-mediated inhibition of adenylyl cyclase and MAPK activation. Chronic MOR or DOR agonist treatment increases RGS19 protein levels via a PKC- and MAPK kinase-dependent mechanism. Lentiviral shRNA knockdown, adenylyl cyclase inhibition assay, MAPK activation assay, pharmacological inhibitor profiling Molecular pharmacology Medium 23197645
2013 RGS19 inhibits Ras-mediated ERK signaling through upregulation of Nm23-H1/2. In HEK293 cells stably expressing RGS19, Nm23-H1 and H2 are upregulated and phosphorylate the kinase suppressor of Ras (KSR), sequestering it in the nucleus. Co-IP demonstrates that Nm23H1/2 forms complexes with RGS19, Ras, and KSR. Nm23H1/2 knockdown partially restores ERK responses, confirming the mechanistic link. Stable transfection, Co-immunoprecipitation, nuclear fractionation, phospho-KSR detection, siRNA knockdown of Nm23H1/2 Cellular signalling Medium 23416464
2013 RGS19 and its partner GNAI3 (Gαi3) are required for zVAD-induced autophagy and autophagic cell death in L929 cells. RGS19 was identified as a RIP3-interacting protein. Knockdown of RGS19 or GNAI3 impairs zVAD-induced autophagy and subsequent TNF production, while not affecting TNF-induced cell death directly. Co-immunoprecipitation (RIP3-RGS19 interaction), shRNA knockdown, autophagy flux assay (LC3), TNF production measurement PloS one Medium 24751948
2014 Notch signaling regulates RGS19 phosphorylation in LPS-stimulated macrophages, and RGS19 in turn supports Akt Thr308 phosphorylation and cell survival. Gamma-secretase inhibitor (GSI) treatment decreases RGS19 phosphorylation without altering its mRNA level; silencing RGS19 impairs Akt phosphorylation and shifts cells toward a subG1/cell death population. Phospho-proteomics, GSI pharmacological inhibition, siRNA knockdown, RBP-Jκ conditional knockout macrophages, cell cycle and viability analysis Immunobiology Medium 24775271
2015 RGS19 senses cellular iron availability: it is co-purified with iron and is protected from GIPN-mediated proteolysis under iron-depleted conditions. An iron-deficient RGS19 mutant is stable in the presence of GIPN and retains GAP activity. RGS19 stabilization under iron deprivation activates a Gαi3-dependent growth-inhibitory signal (NDRG1 induction); overexpression of Gαi3 represses NDRG1 induction. Iron co-purification, UV absorption spectroscopy, GIPN proteolysis protection assay, mutant stability assay, siRNA/overexpression with NDRG1 expression readout Biochemical and biophysical research communications Medium 26116529
2024 RGS19 stabilizes the MYH9 protein by directly competing with STUB1 (an E3 ubiquitin ligase) for MYH9 binding via its RGS domain, preventing STUB1-mediated degradation. Stabilized MYH9 activates β-catenin/c-Myc signaling, and c-Myc transcriptionally drives RGS19 expression, forming a positive feedback loop in hepatocellular carcinoma cells. Co-immunoprecipitation (RGS19-MYH9-STUB1), domain deletion mapping, ubiquitination assay, in vitro and in vivo tumor growth assays, luciferase reporter for c-Myc transcriptional regulation Experimental & molecular medicine Medium 38825640

Source papers

Stage 0 corpus · 51 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. Cell 677 8756726
1997 RGS4 and GAIP are GTPase-activating proteins for Gq alpha and block activation of phospholipase C beta by gamma-thio-GTP-Gq alpha. Proceedings of the National Academy of Sciences of the United States of America 330 9012799
1995 GAIP, a protein that specifically interacts with the trimeric G protein G alpha i3, is a member of a protein family with a highly conserved core domain. Proceedings of the National Academy of Sciences of the United States of America 272 8524874
1998 GIPC, a PDZ domain containing protein, interacts specifically with the C terminus of RGS-GAIP. Proceedings of the National Academy of Sciences of the United States of America 202 9770488
1997 The regulators of G protein signaling (RGS) domains of RGS4, RGS10, and GAIP retain GTPase activating protein activity in vitro. Proceedings of the National Academy of Sciences of the United States of America 155 9207071
1996 GAIP is membrane-anchored by palmitoylation and interacts with the activated (GTP-bound) form of G alpha i subunits. Proceedings of the National Academy of Sciences of the United States of America 154 8986788
1997 Attenuation of Gi- and Gq-mediated signaling by expression of RGS4 or GAIP in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 149 9177187
2001 GIPC and GAIP form a complex with TrkA: a putative link between G protein and receptor tyrosine kinase pathways. Molecular biology of the cell 139 11251075
2006 C terminus of RGS-GAIP-interacting protein conveys neuropilin-1-mediated signaling during angiogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 101 16754745
1998 RGS-GAIP, a GTPase-activating protein for Galphai heterotrimeric G proteins, is located on clathrin-coated vesicles. Molecular biology of the cell 92 9571244
2001 Regional distribution of regulators of G-protein signaling (RGS) 1, 2, 13, 14, 16, and GAIP messenger ribonucleic acids by in situ hybridization in rat brain. Brain research. Molecular brain research 72 11295237
2014 GAIP interacting protein C-terminus regulates autophagy and exosome biogenesis of pancreatic cancer through metabolic pathways. PloS one 68 25469510
2003 Promotion of G alpha i3 subunit down-regulation by GIPN, a putative E3 ubiquitin ligase that interacts with RGS-GAIP. Proceedings of the National Academy of Sciences of the United States of America 66 12826607
2002 GAIP, GIPC and Galphai3 are concentrated in endocytic compartments of proximal tubule cells: putative role in regulating megalin's function. Journal of the American Society of Nephrology : JASN 66 11912251
2004 GIPC recruits GAIP (RGS19) to attenuate dopamine D2 receptor signaling. Molecular biology of the cell 58 15356268
1999 Solution structure of human GAIP (Galpha interacting protein): a regulator of G protein signaling. Journal of molecular biology 58 10452897
2004 RGSZ1 and GAIP regulate mu- but not delta-opioid receptors in mouse CNS: role in tachyphylaxis and acute tolerance. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 49 14997173
1997 Control of the expression and activity of the Galpha-interacting protein (GAIP) in human intestinal cells. The Journal of biological chemistry 48 9305927
2006 Expression and regulatory role of GAIP-interacting protein GIPC in pancreatic adenocarcinoma. Cancer research 41 17079444
1999 GAIP, a Galphai-3-binding protein, is associated with Golgi-derived vesicles and protein trafficking. The American journal of physiology 41 9950778
2000 Membrane-associated GAIP is a phosphoprotein and can be phosphorylated by clathrin-coated vesicles. Proceedings of the National Academy of Sciences of the United States of America 40 10760275
2007 RGS19 regulates Wnt-beta-catenin signaling through inactivation of Galpha(o). Journal of cell science 31 17855383
2003 Spatial regulation of Galphai protein signaling in clathrin-coated membrane microdomains containing GAIP. Molecular pharmacology 28 12815156
2011 RGS19 stimulates cell proliferation by deregulating cell cycle control and enhancing Akt signaling. Cancer letters 27 21705135
2000 A core-promoter region functions bi-directionally for human opioid-receptor-like gene ORL1 and its 5'-adjacent gene GAIP. Journal of molecular biology 27 11090272
2013 RGS19 inhibits Ras signaling through Nm23H1/2-mediated phosphorylation of the kinase suppressor of Ras. Cellular signalling 25 23416464
1999 Structural basis for the selectivity of the RGS protein, GAIP, for Galphai family members. Identification of a single amino acid determinant for selective interaction of Galphai subunits with GAIP. The Journal of biological chemistry 23 10364213
2010 RGS-GAIP-interacting protein controls breast cancer progression. Molecular cancer research : MCR 22 21047775
2001 Differential capacities of the RGS1, RGS16 and RGS-GAIP regulators of G protein signaling to enhance alpha2A-adrenoreceptor agonist-stimulated GTPase activity of G(o1)alpha. Journal of neurochemistry 22 11520900
2014 Notch signaling regulates the phosphorylation of Akt and survival of lipopolysaccharide-activated macrophages via regulator of G protein signaling 19 (RGS19). Immunobiology 21 24775271
1999 Clathrin-coated vesicles bearing GAIP possess GTPase-activating protein activity in vitro. Proceedings of the National Academy of Sciences of the United States of America 21 10359779
2003 GAIP participates in budding of membrane carriers at the trans-Golgi network. Traffic (Copenhagen, Denmark) 20 12656990
2012 Modulation of μ-opioid receptor signaling by RGS19 in SH-SY5Y cells. Molecular pharmacology 19 23197645
2005 N-terminally truncated variant of the mouse GAIP/RGS19 lacks selectivity of full-length GAIP/RGS19 protein in regulating ORL1 receptor signaling. Journal of molecular biology 18 16219326
2010 Effects of regulator of G protein signaling 19 (RGS19) on heart development and function. The Journal of biological chemistry 16 20562099
2017 RGS19 upregulates Nm23-H1/2 metastasis suppressors by transcriptional activation via the cAMP/PKA/CREB pathway. Oncotarget 15 29050254
2003 Gene structure, dual-promoters and mRNA alternative splicing of the human and mouse regulator of G protein signaling GAIP/RGS19. Journal of molecular biology 15 12507475
2013 Normal autophagic activity in macrophages from mice lacking Gαi3, AGS3, or RGS19. PloS one 14 24312373
2011 GAIP-interacting protein, C-terminus is involved in the induction of zinc-finger protein 143 in response to insulin-like growth factor-1 in colon cancer cells. Molecules and cells 14 21909943
2010 RGS19 enhances cell proliferation through its C-terminal PDZ motif. Cellular signalling 14 20599498
2012 Rgs19 regulates mouse palatal fusion by modulating cell proliferation and apoptosis in the MEE. Mechanisms of development 13 22841956
2024 RGS19 activates the MYH9/β-catenin/c-Myc positive feedback loop in hepatocellular carcinoma. Experimental & molecular medicine 12 38825640
2014 Regulator of G-protein signaling 19 (RGS19) and its partner Gα-inhibiting activity polypeptide 3 (GNAI3) are required for zVAD-induced autophagy and cell death in L929 cells. PloS one 12 24751948
2021 Genome-wide screening for the G-protein-coupled receptor (GPCR) pathway-related therapeutic gene RGS19 (regulator of G protein signaling 19) in bladder cancer. Bioengineered 9 34482807
2002 Unique isoform of Galpha -interacting protein (RGS-GAIP) selectively discriminates between two Go-mediated pathways that inhibit Ca2+ channels. The Journal of biological chemistry 8 12270936
2015 RGS19 converts iron deprivation stress into a growth-inhibitory signal. Biochemical and biophysical research communications 5 26116529
2011 Elevated expression of RGS19 impairs the responsiveness of stress-activated protein kinases to serum. Molecular and cellular biochemistry 3 22045062
2015 Critical role of Rgs19 in mouse embryonic stem cell proliferation and differentiation. Differentiation; research in biological diversity 2 25766428
2026 Targeted inhibition of RGS19 alleviates renal fibrosis by restoring autophagy and modulating immune cell infiltration. Journal of nanobiotechnology 0 41761314
2026 RGS19 drives tumor progression and immunosuppression in clear cell renal cell carcinoma by modulating CAMs and EMT. World journal of surgical oncology 0 42010588
2026 Comparative transcriptomics unveils the role of DELLA protein GAIP-B in cold tolerance of mango (Mangifera indica L.). BMC plant biology 0 42026469

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