Affinage

RAP1GDS1

Rap1 GTPase-GDP dissociation stimulator 1 · UniProt P52306

Length
607 aa
Mass
66.3 kDa
Annotated
2026-06-10
35 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAP1GDS1 (SmgGDS) is an atypical armadillo-repeat protein that governs the membrane targeting and signaling of small GTPases by acting both as a chaperone of the prenylation pathway and as a selective guanine-nucleotide exchange factor (PMID:20709748, PMID:21242305). Two splice variants partition these roles: SmgGDS-607 binds preprenylated GTPases through recognition of the CAAX motif and C-terminal polybasic region and gates their entry into the prenylation pathway, while SmgGDS-558 binds prenylated GTPases and facilitates their membrane trafficking (PMID:20709748, PMID:24415755). SmgGDS-607 controls prenylation not by inhibiting prenyltransferases directly but by sequestering substrate C-termini—blocking RhoA geranylgeranylation by GGTase-I in a nucleotide-dependent manner (preferring GDP-bound substrate) and differentially modulating farnesylation, inhibiting DiRas1 farnesylation while accelerating HRas product release from FTase (PMID:29940100, PMID:31197034). As a GEF, SmgGDS is highly selective: it catalyzes nucleotide exchange on RhoA and RhoC but not on a broad panel of other GTPases, using positively and negatively charged surface regions and a conserved binding groove distinct from canonical DH-domain GEFs, as defined by crystallography and active-site mutagenesis (PMID:21242305, PMID:28630045). Through these activities SmgGDS drives RhoA-dependent NF-κB transcriptional activity and cell-cycle progression in cancer cells, with the SmgGDS-607:SmgGDS-558 ratio elevated in tumors and targetable by splice-switching oligonucleotides that suppress GTPase prenylation and tumor growth (PMID:17951244, PMID:24552806, PMID:33574130). SmgGDS also retains GDP-bound RHEB/RHEBL1 in the cytosol to regulate mTORC1 localization and activity (PMID:33574130), and binds Di-Ras/DiRas GTPases as tight, non-catalytic complexes, with DiRas1 acting as a competitive inhibitor of SmgGDS engagement with other substrates (PMID:26149690, PMID:26814130).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1994 High

    Established SmgGDS as a multivalent nucleotide-exchange factor that releases GDP and stabilizes nucleotide-free intermediates across several small GTPases, defining its core biochemical activity.

    Evidence In vitro GTP[γS] incorporation and [3H]GDP/GTP exchange assays with purified RhoA, Rac1/2, Rap1A, CDC42

    PMID:7980444

    Open questions at the time
    • Did not resolve which substrates are physiological vs. promiscuous in vitro
    • Mechanism of substrate selectivity unaddressed
    • Role of prenylation in interaction left ambiguous
  2. 2000 Medium

    Showed SmgGDS preferentially associates with nucleotide-free RhoA and alters RhoA subcellular distribution, distinguishing it from RhoGDI and linking its biochemistry to localization control.

    Evidence Reciprocal co-IP of dominant-negative vs. activated RhoA from CHO cells plus microinjection/immunofluorescence

    PMID:10702222

    Open questions at the time
    • Did not establish catalytic GEF activity vs. binding
    • Single cell type
    • Functional consequence of RhoA redistribution unclear
  3. 2003 Medium

    Connected the GTPase polybasic region to nucleocytoplasmic transport, showing SmgGDS-Rac1 complexes accumulate in the nucleus via Rac1 PBR-NLS activity while RhoA complexes stay cytoplasmic.

    Evidence GFP fusions, NLS/NES mutagenesis and nuclear fractionation in cells

    PMID:12551911

    Open questions at the time
    • Nuclear function of the complexes not defined
    • Transport machinery for SmgGDS NES not identified
  4. 2002 Medium

    Defined the polybasic-residue requirement for substrate binding and showed SmgGDS binds but does not catalyze exchange on H-/N-Ras, refining its substrate scope.

    Evidence In vitro binding and exchange assays with effector/polybasic mutants

    PMID:11948427

    Open questions at the time
    • Distinction between binding and catalysis not mechanistically explained
    • In vitro only
  5. 2006 Medium

    Placed SmgGDS in a βPIX-Rac1 signaling module required for growth-factor-driven Rac1 activation and neurite outgrowth, giving it a defined cellular pathway role.

    Evidence Co-IP, FRET, modified GEF assay and siRNA knockdown in a neurite outgrowth assay

    PMID:16954223

    Open questions at the time
    • Direct vs. indirect role in βPIX-mediated exchange unresolved
    • Single cell system
  6. 2007 Medium

    Linked SmgGDS to oncogenic phenotypes—cell-cycle progression, anchorage-independent growth, migration and NF-κB activity—with effects exceeding RhoA silencing, implying multi-GTPase regulation.

    Evidence siRNA knockdown with cell-cycle, soft-agar, migration and NF-κB reporter assays in NSCLC cells

    PMID:17951244

    Open questions at the time
    • Which GTPases mediate each phenotype not separated
    • Splice variants not distinguished here
  7. 2010 High

    Resolved the two splice variants into distinct steps of the prenylation pathway: SmgGDS-607 binds nonprenylated GTPases at pathway entry, SmgGDS-558 binds prenylated GTPases for trafficking.

    Evidence Reciprocal co-IP, prenylation and membrane-trafficking assays with dominant-negative GTPase mutants

    PMID:20709748

    Open questions at the time
    • Structural basis of isoform selectivity not yet defined
    • In vivo relevance of the partition untested at this stage
  8. 2011 High

    Demonstrated SmgGDS is a bona fide, highly selective GEF for RhoA and RhoC using a non-DH-domain mechanism, settling whether its exchange activity is catalytic and substrate-restricted.

    Evidence In vitro GEF assays across a purified GTPase panel, active-site mutagenesis, homology modeling and cell-based activation

    PMID:21242305

    Open questions at the time
    • Atomic structure of catalytic surface not yet solved here
    • Reconciliation with broad 1994 exchange activity
  9. 2013 Medium

    Assigned the dominant pro-tumorigenic role to SmgGDS-558, driving proliferation, in vivo tumor growth and Rho-dependent NF-κB activation, while SmgGDS-607 was dispensable for these phenotypes.

    Evidence Isoform-specific siRNA, xenograft growth, RhoA-GTP pulldown and NF-κB reporter in breast cancer cells

    PMID:24197117

    Open questions at the time
    • Mechanistic link from trafficking to NF-κB not fully traced
    • Single tumor type
  10. 2013 Low

    Implicated SmgGDS as a TG2 cross-linking substrate triggering ER calcium release and apoptosis, suggesting a stress-signaling role beyond GTPase handling.

    Evidence TG2 wild-type/mutant overexpression with calcium imaging and apoptosis assays in Jurkat cells

    PMID:24349085

    Open questions at the time
    • No biochemical mapping of the cross-linking site
    • Single overexpression study, not independently confirmed
  11. 2014 Medium

    Established the molecular code for SmgGDS-607 substrate selection—recognition of the CAAX terminal residue with preference for geranylgeranylation substrates—via direct binding to prenylated peptides.

    Evidence Cell co-IP plus in vitro binding with recombinant proteins, prenylated peptides, CAAX mutants and FTase inhibitor

    PMID:24415755

    Open questions at the time
    • Isoform selectivity weaker in vitro than in cells
    • Cellular factors enforcing selectivity unidentified
  12. 2014 Medium

    Showed SmgGDS-558 is the principal driver of cell-cycle progression through cyclin D1 induction and p27 suppression across multiple cancer types, with dual knockdown reducing tumorigenesis.

    Evidence Isoform-specific RNAi, cell-cycle and cyclin/CDK-inhibitor immunoblotting, xenograft assay

    PMID:24552806

    Open questions at the time
    • GTPase intermediary to cyclin D1 not pinned down
    • Single lab
  13. 2015 Medium

    Revealed a non-catalytic chaperone mode: SmgGDS forms a tight complex with Di-Ras2 that lowers its nucleotide affinity and stabilizes the freshly synthesized protein in a CAAX-dependent manner.

    Evidence Co-purification from rat brain cytosol, SEC, in vitro GEF assay and pulse-chase

    PMID:26149690

    Open questions at the time
    • Physiological consequence of Di-Ras2 stabilization unclear
    • Single lab
  14. 2016 Medium

    Identified DiRas1 as a competitive endogenous inhibitor of SmgGDS, blocking its engagement with K-Ras4B, RhoA and Rap1A and dampening RhoA/SmgGDS-driven NF-κB activity.

    Evidence Co-IP, in vitro GEF and competitive binding assays, NF-κB reporter, in silico docking

    PMID:26814130

    Open questions at the time
    • Quantitative regulation in physiological settings untested
    • Structural basis of competition modeled only
  15. 2016 Medium

    Provided in vivo and extracellular evidence that SmgGDS mediates statin protection against cardiac hypertrophy and restrains Rac1/ERK/Rho-kinase signaling in cardiac fibroblasts.

    Evidence SmgGDS+/- mice with angiotensin II and statin treatment, recombinant SmgGDS rescue, cytokine profiling

    PMID:26975711

    Open questions at the time
    • Mechanism of SmgGDS secretion unknown
    • Extracellular SmgGDS receptor/uptake undefined
  16. 2017 High

    Solved the SmgGDS-558 crystal structure, defining a tandem armadillo-repeat fold and the dual charged surfaces required for RhoA binding and GEF catalysis, giving a structural basis for its non-canonical mechanism.

    Evidence X-ray crystallography with mutagenesis and GEF/binding assays

    PMID:28630045

    Open questions at the time
    • No co-structure with bound GTPase
    • Structure of SmgGDS-607 not determined
  17. 2017 Low

    Reported SmgGDS as a Cdc42 GEF in endothelial vasculogenesis responsive to simulated microgravity, broadening its substrate and developmental context.

    Evidence Pull-down/MS identification, shRNA knockdown and constitutively active Cdc42 rescue with GTPase activation assays

    PMID:29145128

    Open questions at the time
    • GEF mechanism toward Cdc42 not biochemically reconstituted
    • Conflicts with selective RhoA/RhoC GEF specificity reported elsewhere
  18. 2018 High

    Mechanistically defined how SmgGDS-607 gates prenylation—by substrate sequestration of the GTPase C-terminus rather than enzyme inhibition—and made the block nucleotide-dependent (GDP-preferring).

    Evidence Reconstituted in vitro radiolabel prenylation assay with purified GGTase-I, affinity measurements and competition assays

    PMID:29940100

    Open questions at the time
    • Cellular regulators of the GDP/GTP switch not identified
    • Single substrate (RhoA) for the mechanism
  19. 2019 High

    Showed SmgGDS-607 bidirectionally tunes farnesylation—sequestering DiRas1 from FTase while accelerating HRas product release—revealing substrate-specific kinetic control.

    Evidence Reconstituted in vitro farnesylation with purified FTase, binding assays and kinetic analysis

    PMID:31197034

    Open questions at the time
    • Determinants selecting inhibition vs. acceleration not generalized
    • Cellular validation limited
  20. 2020 High

    Demonstrated therapeutic targeting of the splice-variant ratio: lowering SmgGDS-607:SmgGDS-558 with a splice-switching oligonucleotide suppresses pan-family GTPase prenylation, ERK activity and tumor growth.

    Evidence Splice-switching oligonucleotide with prenylation, ERK, apoptosis assays and MMTV-PyMT mouse model

    PMID:32019878

    Open questions at the time
    • Off-target consequences of global prenylation suppression
    • Long-term resistance not assessed
  21. 2021 Medium

    Extended SmgGDS function to mTORC1 control by showing it binds GDP-bound RHEB/RHEBL1 and retains them in the cytosol, regulating localization rather than nucleotide loading.

    Evidence Co-IP, siRNA knockdown, subcellular fractionation and mTORC1 activity assays

    PMID:33574130

    Open questions at the time
    • Structural basis of RHEB binding undefined
    • Crosstalk with prenylation chaperone role unclear
  22. 2022 High

    Defined the structural and thermodynamic basis of SmgGDS-558 binding to farnesylated KRas, showing engagement of the HVR/farnesyl C-terminus but not the G-domain, with affinity rivaling PDEδ.

    Evidence SPR on biomimetic membranes, SAXS, MD/Monte Carlo simulations and co-IP

    PMID:35614853

    Open questions at the time
    • Functional consequence of KRas-FMe trafficking by SmgGDS-558 in cells not measured
    • Generality to other prenylated substrates untested
  23. 2023 Medium

    Linked differential SmgGDS-607 binding of RAC1B vs RAC1 to their distinct prenylation and nuclear localization, and confirmed DIRAS1 inhibition of both, integrating chaperone selectivity with GTPase localization.

    Evidence Co-IP, prenylation assays, fractionation, CAAX mutagenesis, GTP-binding assay and DIRAS1 overexpression

    PMID:37059183

    Open questions at the time
    • Functional consequences of nuclear RAC1B not defined
    • Single lab
  24. 2023 Low

    Implicated RAP1GDS1/Vimar in age-related neuronal decline via a Miro complex that promotes mitochondrial calcium overload, suggesting a role in brain aging.

    Evidence Drosophila and mouse transgenic/knockdown genetics with mitochondrial calcium imaging and aging assays

    PMID:37061660

    Open questions at the time
    • Vimar/RAP1GDS1-Miro complex not biochemically characterized
    • Link to canonical GTPase chaperone activity unestablished
  25. 2023 Medium

    Showed SmgGDS is required for glucose- and secretagogue-stimulated insulin secretion in β-cells, implicating it in stimulus-secretion coupling.

    Evidence siRNA knockdown with insulin secretion assays and fractionation in islets and INS-1 832/13 cells

    PMID:38013223

    Open questions at the time
    • Which GTPases mediate the secretion defect not identified
    • Step(s) of secretion affected not resolved
  26. 2025 Low

    Identified SmgGDS as a SARS-CoV-2 NSP2 target whose RhoA GEF activity is inhibited by direct, virus-specific binding, suggesting a host-pathogen interface.

    Evidence Affinity-purification MS, binding assay and in vitro GEF activity assay

    PMID:40253909

    Open questions at the time
    • No structural or mutagenesis mapping of the interaction
    • Cellular/physiological relevance untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the prenylation-chaperone and selective RhoA/RhoC GEF activities are coordinated on the same protein, and what dictates substrate fate across the full GTPase repertoire in cells, remains unresolved.
  • No co-structure of either isoform with a bound GTPase substrate
  • Cellular logic switching between sequestration, exchange and trafficking undefined
  • Mechanism of extracellular/secreted SmgGDS activity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140313 molecular sequestering activity 3
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2 R-HSA-9609507 Protein localization 2
Partners
ARHGEF7DIRAS1KRASRAC1RHEBRHEBL1RHOARHOC

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 SmgGDS stimulates GTP/GDP exchange on RhoA, Rac2, Rac1, Rap1A, and CDC42Hs through a substituted enzyme mechanism: it releases GDP from the GTPase, maintains the GTPase in a nucleotide-free intermediate state, and can stabilize both nucleotide-bound and nucleotide-free forms of Rac1. Isoprenoid modification is not absolutely required for interaction with SmgGDS. In vitro GTP[γS] incorporation assay, [3H]GDP/GTP exchange assay, nucleotide stability assays with purified proteins The Biochemical journal High 7980444
2000 SmgGDS co-precipitates with dominant negative RhoA(Asn-19) but not with activated RhoA(Val-14), indicating SmgGDS preferentially associates with nucleotide-free RhoA. RhoGDI co-precipitates with wild-type and activated RhoA but not with dominant negative RhoA(Asn-19). Microinjection of SmgGDS cDNA causes RhoA to redistribute away from the nucleus and cell junctions. Co-immunoprecipitation from CHO cells, peptide sequencing, Western blotting, [32P] nucleotide labeling, immunofluorescence, microinjection The Journal of biological chemistry Medium 10702222
2003 SmgGDS forms a complex with Rac1 that accumulates in the nucleus because the Rac1 polybasic region (PBR) functions as a nuclear localization signal (NLS). Rac1 activation enhances nuclear accumulation of both Rac1 and SmgGDS. SmgGDS contains a nuclear export signal (NES) that promotes its nuclear export. RhoA complexes with SmgGDS accumulate in the cytoplasm because the RhoA PBR lacks NLS activity. GFP fusion constructs, fluorescence microscopy, NLS/NES mutational analysis, nuclear fractionation The Journal of biological chemistry Medium 12551911
2002 SmgGDS specifically interacts with dominant negative and nucleotide-free forms of H-Ras and N-Ras but does not catalyze guanine nucleotide exchange on H-Ras or N-Ras in vitro. In contrast, SmgGDS substrates K-Ras, Rac1, and RhoA bind SmgGDS in both active and inactive forms, and this binding requires C-terminal polybasic residues. In vitro binding assays, GDP/GTP exchange assays with purified proteins, effector domain mutant analysis Oncogene Medium 11948427
2006 SmgGDS forms a trimeric complex with βPIX and Rac1; phosphorylation of βPIX at Ser-525/Thr-526 is required for this assembly. SmgGDS is required for βPIX-mediated Rac1 activation and neurite outgrowth downstream of bFGF stimulation, as siRNA-mediated knockdown of SmgGDS significantly inhibited both βPIX-mediated Rac1 activation and neurite outgrowth. Co-immunoprecipitation, modified GEF assay, FRET analysis, siRNA knockdown, neurite outgrowth assay The Journal of biological chemistry Medium 16954223
2007 Silencing SmgGDS by siRNA in non-small cell lung carcinoma (NSCLC) cells causes G1 phase arrest, reduced colony formation in soft agar, disrupted myosin organization, reduced cell migration, and diminished NF-κB transcriptional activity. Overexpression of SmgGDS enhances NF-κB activity. These effects are more pronounced than silencing RhoA alone, consistent with SmgGDS regulating multiple GTPases. siRNA knockdown, soft agar colony assay, cell cycle analysis, NF-κB reporter assay, immunofluorescence The Journal of biological chemistry Medium 17951244
2010 Two splice variants of SmgGDS have distinct roles in the prenylation pathway: SmgGDS-607 (607 aa) associates with nonprenylated GTPases and regulates their entry into the prenylation pathway, while SmgGDS-558 (558 aa) selectively associates with prenylated small GTPases and facilitates membrane trafficking of Rap1A. Dominant negative mutations inhibiting GDP/GTP exchange differentially alter prenylation of Rap1A, RhoA, Rac1, and K-Ras. Co-immunoprecipitation, prenylation assays, membrane trafficking assays, dominant negative GTPase mutants The Journal of biological chemistry High 20709748
2011 SmgGDS functions as a bona fide GEF that specifically activates RhoA and RhoC (but not other GTPases tested including Cdc42, Rac1, Rac2, RhoB, Rap1a, Rap1b, K-Ras) among a large panel of purified GTPases. The activation is catalytic, SmgGDS preferentially binds nucleotide-depleted RhoA, and requires the polybasic region of RhoA. SmgGDS uses a distinct exchange mechanism from canonical DH-domain GEFs. Mutation of an electronegative surface patch or a conserved binding groove abolishes GEF activity. In vitro GEF activity assay with purified proteins, nucleotide-depleted RhoA binding assay, active-site mutagenesis, homology modeling, cell-based GTPase activation assay The Journal of biological chemistry High 21242305
2013 SmgGDS-558 knockdown in breast cancer cells decreases proliferation, in vivo tumor growth, and RhoA activity. SmgGDS promotes Rho-dependent NF-κB activation in breast cancer cells. SmgGDS-607 knockdown does not significantly affect these phenotypes, establishing distinct functional roles for the two splice variants. siRNA knockdown, xenograft tumor growth assay, RhoA-GTP pull-down, NF-κB reporter assay Molecular cancer research : MCR Medium 24197117
2013 Transglutaminase 2 (TG2) cross-links RAP1GDS1/SmgGDS in Jurkat T cells, and this cross-linking initiates a signaling pathway that promotes Ca2+ release from the endoplasmic reticulum via Ins3P and ryanodine-sensitive receptors, leading to enhanced mitochondrial Ca2+ uptake and apoptosis. Overexpression of wild-type and cross-linking mutant TG2, calcium imaging, apoptosis assays in Jurkat cells PloS one Low 24349085
2014 SmgGDS-607 interacts with nonprenylated GTPases through recognition of the last amino acid in the CAAX motif, forming more stable complexes with GTPases destined for geranylgeranylation than farnesylation. Both SmgGDS-607 and SmgGDS-558 directly bind the GTPase C-terminal region using purified recombinant proteins and prenylated peptides, but isoform specificity for prenylated vs. nonprenylated GTPases is diminished in vitro. Co-immunoprecipitation in cells, in vitro binding assays with recombinant proteins and prenylated peptides, CAAX mutant analysis, farnesyltransferase inhibitor treatment The Journal of biological chemistry Medium 24415755
2014 SmgGDS-558 plays a greater role than SmgGDS-607 in cell cycle progression, promoting cyclin D1 expression and suppressing p27 in pancreatic, lung, and breast cancer cells. Knockdown of both SmgGDS splice variants simultaneously decreases NSCLC xenograft tumorigenesis in mice. Isoform-specific RNAi, cell cycle analysis, Western blotting for cyclin D1/p27/p21, xenograft tumor assay Cell cycle (Georgetown, Tex.) Medium 24552806
2015 Di-Ras2 co-purifies with SmgGDS from rat brain cytosol. SmgGDS does not act as a GEF for Di-Ras2 but instead forms a tight complex that reduces Di-Ras2 binding affinity for guanine nucleotides. Pulse-chase analysis revealed that Di-Ras2 binds SmgGDS immediately after synthesis in a CAAX motif-dependent manner, increasing Di-Ras2 stability. Co-purification from brain cytosol, size-exclusion chromatography, in vitro GEF assay with recombinant proteins, pulse-chase analysis The Journal of biological chemistry Medium 26149690
2016 DiRas1 binds to SmgGDS but SmgGDS does not catalyze GDP/GTP exchange on DiRas1. DiRas1 acts as a competitive inhibitor: it binds SmgGDS and inhibits SmgGDS binding to other small GTPases including K-Ras4B, RhoA, and Rap1A, thereby inhibiting RhoA- and SmgGDS-mediated NF-κB transcriptional activity. Co-immunoprecipitation, in vitro GEF assay, competitive binding assay, NF-κB reporter assay, in silico docking The Journal of biological chemistry Medium 26814130
2016 SmgGDS heterozygous knockout mice show that statins fail to attenuate angiotensin II-induced cardiac hypertrophy and fibrosis in SmgGDS+/- mice. SmgGDS+/- cardiac fibroblasts exhibit increased Rac1 expression, ERK1/2 activity, Rho-kinase activity, and inflammatory cytokine secretion. Atorvastatin increases SmgGDS secretion from cardiac fibroblasts, and recombinant SmgGDS reduces Rac1 expression in SmgGDS+/- cells, demonstrating extracellular SmgGDS activity. SmgGDS+/- mouse model, angiotensin II infusion, atorvastatin/pravastatin treatment, Western blotting, ELISA, Bio-plex cytokine analysis Hypertension (Dallas, Tex. : 1979) Medium 26975711
2017 Crystal structure of SmgGDS-558 reveals a fold containing tandem armadillo repeats not present in other GEFs. SmgGDS harbors distinct positively and negatively charged regions both required for RhoA binding and GEF activity; mutation of either region abolishes GEF activity. The two SmgGDS isoforms differ in RhoA binding and GEF activity depending on the lipidation state of RhoA. X-ray crystallography, mutagenesis, GEF activity assay, RhoA binding assay The Journal of biological chemistry High 28630045
2017 Rap1GDS1 was identified as a Cdc42 GEF in endothelial cells during vasculogenesis; it is upregulated by simulated microgravity, and its knockdown selectively suppresses Cdc42 activation and inhibits both baseline and microgravity-induced vascular branch morphogenesis, rescued by constitutively active Cdc42. Affinity pull-down, mass spectrometry, shRNA knockdown, rescue with constitutively active Cdc42, GTPase activation assay Stem cell research Low 29145128
2018 SmgGDS-607 inhibits RhoA prenylation by geranylgeranyltransferase I (GGTase-I) through substrate sequestration (binding and blocking access to the RhoA C-terminal tail) rather than by inhibiting the prenyltransferase enzyme directly. SmgGDS-607 binds RhoA-GDP with higher affinity than RhoA-GTP, making its prenylation-blocking function nucleotide-dependent. In vitro radiolabel prenylation assay, binding affinity measurements, mutagenesis, substrate competition assays with purified proteins Biochemistry High 29940100
2019 SmgGDS-607 differentially regulates farnesylation of small GTPases: it inhibits farnesylation of DiRas1 by sequestering it from protein farnesyltransferase (FTase), with the extent of inhibition determined by competitive binding affinities. Additionally, SmgGDS-607 increases the rate of HRas farnesylation by enhancing product release from FTase. SmgGDS-607 does not require a PBR for substrate recognition. In vitro farnesylation assay with purified recombinant enzymes, protein-binding assays, kinetic analysis The Journal of biological chemistry High 31197034
2020 SmgGDS-607 binds preprenylated small GTPases while SmgGDS-558 binds prenylated small GTPases. Cancer cells maintain a high SmgGDS-607:SmgGDS-558 ratio. A splice-switching oligonucleotide (SSO Ex5) that lowers this ratio suppresses prenylation of multiple Ras, Rho, and Rab family GTPases, inhibits ERK activity, induces ER stress and apoptosis in cancer cells, and slows mammary tumorigenesis in MMTV-PyMT mice. Splice-switching oligonucleotide, prenylation assays, ERK activity assay, apoptosis assays, MMTV-PyMT mouse model Proceedings of the National Academy of Sciences of the United States of America High 32019878
2021 SmgGDS binds RHEB and RHEBL1 (direct mTORC1 activators). SmgGDS displays high binding affinity for GDP-bound RHEBL1, retains GDP-bound RHEBs in the cytosol, and knockdown of SmgGDS reduces cytosolic RHEBL1 and mTORC1 activation without affecting RHEBL1 GTP-loading, indicating SmgGDS regulates RHEB localization rather than nucleotide exchange. Co-immunoprecipitation, siRNA knockdown, subcellular fractionation, mTORC1 activity assay Molecular cancer research : MCR Medium 33574130
2022 SmgGDS-558 interacts with the hypervariable region (HVR) and the farnesylated C-terminus of KRas-FMe but not with its G-domain, as determined by SAXS structural modeling and immunoprecipitation. SmgGDS-558 binds GTP-bound, GDP-bound, and nucleotide-free forms of farnesylated KRas with comparable affinity. The Kd for KRas-FMe/SmgGDS-558 interaction is comparable to that for KRas/PDEδ interaction. Surface plasmon resonance on biomimetic membranes, small-angle X-ray scattering (SAXS), Monte Carlo and MD simulations, co-immunoprecipitation Biophysical journal High 35614853
2023 SmgGDS-607 binds RAC1B more stably than RAC1, resulting in reduced prenylation of RAC1B compared to RAC1. Inhibiting RAC1 prenylation (CAAX mutant) promotes nuclear accumulation of RAC1, explaining the greater nuclear localization of RAC1B relative to RAC1. Non-prenylated RAC1 and RAC1B still bind GTP in cells, indicating prenylation is not a prerequisite for GTP loading. DIRAS1 inhibits binding of both RAC1 and RAC1B to SmgGDS and reduces their prenylation. Co-immunoprecipitation, prenylation assays, subcellular fractionation, CAAX mutagenesis, GTP-binding assay, DIRAS1 overexpression The Journal of biological chemistry Medium 37059183
2023 RAP1GDS1/SmgGDS (Drosophila ortholog Vimar) expression increases after middle age in neurons and promotes mitochondrial calcium overload and fragmentation. Vimar/RAP1GDS1 forms a complex with Miro. In mice, RAP1GDS1 transgenic overexpression promotes premature brain aging while RAP1GDS1 knockdown after middle age promotes healthy aging. Drosophila overexpression/knockdown genetics, RAP1GDS1 transgenic and knockdown mice, mitochondrial calcium imaging, aging behavioral assays Communications biology Low 37061660
2023 Both SmgGDS-607 and SmgGDS-558 splice variants are expressed in human islets, rat islets, and INS-1 832/13 β-cells. siRNA-mediated depletion of SmgGDS inhibits glucose-stimulated insulin secretion by ~52% and also inhibits KCl-, forskolin-, and IBMX-stimulated secretion, indicating SmgGDS regulates multiple steps of stimulus-secretion coupling in β-cells. siRNA knockdown, insulin secretion assay, subcellular fractionation, immunoblotting Molecular and cellular endocrinology Medium 38013223
2025 SARS-CoV-2 NSP2 directly binds SmgGDS (full-length NSP2 required) and inhibits its GEF activity toward RhoA, disrupting nucleotide exchange on RhoA. This interaction is specific to SARS-CoV-2 NSP2 and is not observed with corresponding proteins from SARS-CoV or MERS-CoV. Affinity purification mass spectrometry, biochemical binding assay, in vitro GEF activity assay Biochemical and biophysical research communications Low 40253909

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Novel mechanism of the co-regulation of nuclear transport of SmgGDS and Rac1. The Journal of biological chemistry 84 12551911
1999 The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood 81 10477737
2010 Splice variants of SmgGDS control small GTPase prenylation and membrane localization. The Journal of biological chemistry 68 20709748
2011 SmgGDS is a guanine nucleotide exchange factor that specifically activates RhoA and RhoC. The Journal of biological chemistry 55 21242305
2007 SmgGDS regulates cell proliferation, migration, and NF-kappaB transcriptional activity in non-small cell lung carcinoma. The Journal of biological chemistry 53 17951244
2014 The chaperone protein SmgGDS interacts with small GTPases entering the prenylation pathway by recognizing the last amino acid in the CAAX motif. The Journal of biological chemistry 39 24415755
1994 SmgGDS stabilizes nucleotide-bound and -free forms of the Rac1 GTP-binding protein and stimulates GTP/GDP exchange through a substituted enzyme mechanism. The Biochemical journal 39 7980444
2000 t(4;11)(q21;p15) translocation involving NUP98 and RAP1GDS1 genes: characterization of a new subset of T acute lymphoblastic leukaemia. British journal of haematology 30 10929031
2016 SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis: Novel Mechanism of the Pleiotropic Effects of Statins. Hypertension (Dallas, Tex. : 1979) 29 26975711
2013 The SmgGDS splice variant SmgGDS-558 is a key promoter of tumor growth and RhoA signaling in breast cancer. Molecular cancer research : MCR 28 24197117
2020 Splice switching an oncogenic ratio of SmgGDS isoforms as a strategy to diminish malignancy. Proceedings of the National Academy of Sciences of the United States of America 27 32019878
2006 betaPak-interacting exchange factor-mediated Rac1 activation requires smgGDS guanine nucleotide exchange factor in basic fibroblast growth factor-induced neurite outgrowth. The Journal of biological chemistry 27 16954223
2002 SmgGDS displays differential binding and exchange activity towards different Ras isoforms. Oncogene 27 11948427
2000 Unique in vivo associations with SmgGDS and RhoGDI and different guanine nucleotide exchange activities exhibited by RhoA, dominant negative RhoA(Asn-19), and activated RhoA(Val-14). The Journal of biological chemistry 24 10702222
2016 The Tumor-suppressive Small GTPase DiRas1 Binds the Noncanonical Guanine Nucleotide Exchange Factor SmgGDS and Antagonizes SmgGDS Interactions with Oncogenic Small GTPases. The Journal of biological chemistry 23 26814130
2021 SmgGDS: An Emerging Master Regulator of Prenylation and Trafficking by Small GTPases in the Ras and Rho Families. Frontiers in molecular biosciences 22 34222337
2009 SmgGDS is up-regulated in prostate carcinoma and promotes tumour phenotypes in prostate cancer cells. The Journal of pathology 21 18973191
2020 Mutated RAP1GDS1 causes a new syndrome of dysmorphic feature, intellectual disability & speech delay. Annals of clinical and translational neurology 18 32431071
2014 SmgGDS-558 regulates the cell cycle in pancreatic, non-small cell lung, and breast cancers. Cell cycle (Georgetown, Tex.) 18 24552806
2019 The chaperone SmgGDS-607 has a dual role, both activating and inhibiting farnesylation of small GTPases. The Journal of biological chemistry 17 31197034
2013 Transglutaminase 2 contributes to apoptosis induction in Jurkat T cells by modulating Ca2+ homeostasis via cross-linking RAP1GDS1. PloS one 15 24349085
2017 Structure-based analysis of the guanine nucleotide exchange factor SmgGDS reveals armadillo-repeat motifs and key regions for activity and GTPase binding. The Journal of biological chemistry 14 28630045
2015 Di-Ras2 Protein Forms a Complex with SmgGDS Protein in Brain Cytosol in Order to Be in a Low Affinity State for Guanine Nucleotides. The Journal of biological chemistry 14 26149690
2023 GTPase splice variants RAC1 and RAC1B display isoform-specific differences in localization, prenylation, and interaction with the chaperone protein SmgGDS. The Journal of biological chemistry 13 37059183
2015 Statins up-regulate SmgGDS through β1-integrin/Akt1 pathway in endothelial cells. Cardiovascular research 13 26598509
2012 SmgGDS antagonizes BPGAP1-induced Ras/ERK activation and neuritogenesis in PC12 cell differentiation. Molecular biology of the cell 11 23155002
2001 Molecular evaluation of the NUP98/RAP1GDS1 gene frequency in adults with T-acute lymphoblastic leukemia. Haematologica 11 11325654
2018 SmgGDS-607 Regulation of RhoA GTPase Prenylation Is Nucleotide-Dependent. Biochemistry 9 29940100
2017 Microgravity simulation activates Cdc42 via Rap1GDS1 to promote vascular branch morphogenesis during vasculogenesis. Stem cell research 6 29145128
2008 Identification and characterization of the unique guanine nucleotide exchange factor, SmgGDS, in vascular smooth muscle cells. Journal of cellular biochemistry 6 18348285
2021 Silencing of SmgGDS, a Novel mTORC1 Inducer That Binds to RHEBs, Inhibits Malignant Mesothelioma Cell Proliferation. Molecular cancer research : MCR 5 33574130
2023 Vimar/RAP1GDS1 promotes acceleration of brain aging after flies and mice reach middle age. Communications biology 4 37061660
2023 Novel regulatory roles of small G protein GDP dissociation stimulator (smgGDS) in insulin secretion from pancreatic β-cells. Molecular and cellular endocrinology 3 38013223
2022 Structural and biophysical properties of farnesylated KRas interacting with the chaperone SmgGDS-558. Biophysical journal 3 35614853
2025 SARS-CoV-2 NSP2 specifically interacts with cellular protein SmgGDS. Biochemical and biophysical research communications 0 40253909

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