Affinage

RAP1GDS1

Rap1 GTPase-GDP dissociation stimulator 1 · UniProt P52306

Length
607 aa
Mass
66.3 kDa
Annotated
2026-04-28
35 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAP1GDS1 (SmgGDS) is an armadillo-repeat protein that functions as both a prenylation-pathway chaperone and a guanine-nucleotide exchange factor (GEF) for select Ras and Rho family small GTPases, thereby integrating GTPase maturation with signaling activation. Two splice variants act sequentially: SmgGDS-607 binds nonprenylated GTPases via their C-terminal polybasic region and CAAX motif, regulating entry into the prenylation pathway by sequestering substrates from prenyltransferases in a nucleotide-state-dependent manner, while SmgGDS-558 binds prenylated GTPases and escorts them to the plasma membrane (PMID:20709748, PMID:29940100, PMID:31197034). SmgGDS-558 is a bona fide catalytic GEF with selectivity for RhoA and RhoC, operating through a PBR-dependent mechanism structurally distinct from Dbl-family GEFs, and its crystal structure reveals a tandem armadillo-repeat fold with charged surface patches essential for GTPase binding and exchange (PMID:21242305, PMID:28630045). Through activation of RhoA, Rac1, and K-Ras signaling, SmgGDS drives NF-κB transcription, cyclin D1 expression, and mTORC1 activity; an elevated SmgGDS-607:558 ratio in cancer cells sustains GTPase prenylation and malignant phenotypes, and splice-switching oligonucleotides that lower this ratio suppress tumorigenesis in vivo (PMID:17951244, PMID:24197117, PMID:32019878). The t(4;11)(q21;p15) translocation creates a NUP98–RAP1GDS1 fusion gene causally associated with T-cell acute lymphoblastic leukemia (PMID:10477737).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1994 High

    Establishing SmgGDS as a multi-substrate GEF answered whether a single non-Dbl protein could catalyze nucleotide exchange on diverse Rho/Ras-family GTPases, revealing a substituted enzyme mechanism in which SmgGDS releases GDP and transiently maintains a nucleotide-free intermediate.

    Evidence In vitro GTP/GDP exchange and nucleotide dissociation assays with purified recombinant SmgGDS and multiple GTPases

    PMID:7980444

    Open questions at the time
    • Structural basis of multi-GTPase recognition unknown
    • In vivo relevance of exchange activity not established
    • Distinction between splice variants not yet recognized
  2. 1999 High

    Identification of the NUP98–RAP1GDS1 fusion in T-ALL established that RAP1GDS1 participates in oncogenic translocations, raising the question of how its armadillo-repeat domain contributes to leukemogenesis.

    Evidence 3′ RACE, RT-PCR, and breakpoint mapping in multiple adult T-ALL patients

    PMID:10477737

    Open questions at the time
    • Oncogenic mechanism of the NRG fusion not defined
    • Whether wild-type RAP1GDS1 is haploinsufficient in the translocation unknown
  3. 2000 High

    Demonstrating that SmgGDS preferentially binds inactive (GDP-bound/dominant-negative) RhoA in vivo — opposite to RhoGDI — and alters RhoA subcellular distribution resolved the paradox of how SmgGDS differs from classical GDIs, establishing it as a nucleotide-state-selective regulator of GTPase localization.

    Evidence Co-immunoprecipitation with nucleotide-state mutants, microinjection, and immunofluorescence in living cells

    PMID:10702222

    Open questions at the time
    • Mechanism by which SmgGDS excludes RhoA from nucleus/junctions unclear
    • Prenylation dependence of the interaction not resolved
  4. 2002 High

    Defining the C-terminal polybasic region (PBR) as the GTPase determinant for SmgGDS binding and exchange selectivity explained why SmgGDS acts as a GEF for K-Ras but not H-Ras or N-Ras, introducing PBR recognition as a new principle in GEF-substrate specificity.

    Evidence Co-IP, in vitro GEF assays, and effector-domain mutant analysis with purified Ras isoforms

    PMID:11948427

    Open questions at the time
    • Structural basis of PBR recognition unknown
    • Whether other PBR-containing GTPases are substrates untested
  5. 2003 High

    Showing that SmgGDS co-translocates to the nucleus with Rac1 using the Rac1 PBR as a nuclear localization signal, while containing its own nuclear export signal, established SmgGDS as a bidirectional nuclear-cytoplasmic shuttle for GTPases.

    Evidence GFP-fusion nuclear transport assays, PBR/NLS mutagenesis, and fluorescence microscopy

    PMID:12551911

    Open questions at the time
    • Nuclear function of SmgGDS–Rac1 complex undefined
    • Whether nuclear export of SmgGDS is CRM1-dependent not determined
  6. 2006 High

    Discovery that SmgGDS forms a trimeric complex with βPIX and Rac1, and is required for βPIX-mediated Rac1 activation and neurite outgrowth, answered how SmgGDS GEF activity is regulated in a physiological signaling context.

    Evidence Reciprocal co-IP, FRET analysis, and siRNA knockdown with neurite outgrowth rescue in neuronal cells

    PMID:16954223

    Open questions at the time
    • Whether SmgGDS directly catalyzes exchange in the trimeric complex or acts as a scaffold unclear
    • Other upstream activators of SmgGDS not identified
  7. 2007 High

    Demonstrating that SmgGDS knockdown causes G1 arrest, loss of anchorage-independent growth, and reduced NF-κB activity in NSCLC cells — effects broader than RhoA knockdown alone — established SmgGDS as an essential upstream activator of multiple GTPases in cancer cell proliferation.

    Evidence siRNA knockdown, soft-agar colony assay, cell cycle analysis, and NF-κB reporter in NSCLC cells

    PMID:17951244

    Open questions at the time
    • Which individual GTPases contribute to each phenotype not dissected
    • Splice variant contributions not distinguished
  8. 2010 High

    The discovery of two splice variants — SmgGDS-607 binding nonprenylated GTPases and SmgGDS-558 binding prenylated GTPases — resolved the longstanding confusion about SmgGDS prenylation dependence and established a sequential hand-off model for GTPase maturation and membrane trafficking.

    Evidence Co-IP of splice variants with prenylated vs. nonprenylated GTPases and plasma membrane trafficking assays

    PMID:20709748

    Open questions at the time
    • Whether hand-off between 607 and 558 is direct or involves intermediates unknown
    • Stoichiometry of the two variants in normal cells undefined
  9. 2011 High

    Reconstituted GEF assays across a large GTPase panel proved SmgGDS is a bona fide catalytic GEF specific for RhoA and RhoC, operating through a PBR-dependent mechanism, settling the debate about whether SmgGDS is a true exchange factor or merely a chaperone.

    Evidence In vitro GEF assay with purified GTPase panel, nucleotide-state binding, surface mutagenesis, and homology modeling

    PMID:21242305

    Open questions at the time
    • Atomic-resolution mechanism of catalysis not resolved
    • Why RhoA/C are preferred substrates over Rac1 structurally unclear
  10. 2013 High

    Isoform-selective knockdown showing that SmgGDS-558 (not -607) drives RhoA activation, NF-κB signaling, and tumor growth in breast cancer established functional divergence between splice variants in oncogenic signaling.

    Evidence Isoform-specific siRNA, xenograft tumor growth, Rho-GTPase pull-down, NF-κB reporter in breast cancer cells

    PMID:24197117

    Open questions at the time
    • Whether SmgGDS-607 has any pro-tumorigenic role independent of prenylation regulation unclear
    • Patient-level expression data for isoform ratio not validated
  11. 2014 High

    Demonstrating SmgGDS-607 preferentially binds geranylgeranylated over farnesylated CAAX motifs, and that FTase inhibitors shunt K-Ras into geranylgeranylation increasing SmgGDS-607 binding, revealed how SmgGDS discriminates prenylation substrates and how pharmacological prenylation switching affects GTPase chaperoning.

    Evidence Co-IP, SAAX mutant analysis, FTase inhibitor treatment, and direct binding with prenylated peptides

    PMID:24415755

    Open questions at the time
    • Structural basis for CAAX-terminal amino acid discrimination by SmgGDS unknown
    • Consequences for other CAAX-containing non-GTPase substrates not tested
  12. 2015 High

    Identification of Di-Ras2 as a high-affinity SmgGDS partner that is stabilized post-translationally by SmgGDS binding immediately after synthesis, without undergoing exchange, expanded the SmgGDS chaperone model beyond canonical Ras/Rho GTPases.

    Evidence Endogenous co-purification from rat brain, recombinant reconstitution, and pulse-chase analysis

    PMID:26149690

    Open questions at the time
    • Biological function of Di-Ras2 stabilization by SmgGDS unknown
    • Whether SmgGDS-607 or -558 mediates the interaction not distinguished
  13. 2016 High

    Discovery that DiRas1 competitively inhibits SmgGDS binding to oncogenic GTPases (K-Ras4B, RhoA) and suppresses NF-κB activation identified the first endogenous negative regulator of SmgGDS, providing a tumor-suppressor mechanism acting through SmgGDS sequestration.

    Evidence Competitive binding assays, in vitro GEF assays, NF-κB reporter, and in silico docking in breast cancer and glioblastoma cells

    PMID:26814130

    Open questions at the time
    • Structural basis of competitive inhibition not determined at atomic resolution
    • In vivo tumor-suppressive role of DiRas1 via SmgGDS not validated
  14. 2017 High

    The crystal structure of SmgGDS-558 revealed a tandem armadillo-repeat fold with charged surface patches required for RhoA binding and GEF activity, providing the first atomic framework and confirming SmgGDS uses a mechanism distinct from Dbl-family GEFs.

    Evidence X-ray crystallography with functional mutagenesis and GEF activity assays

    PMID:28630045

    Open questions at the time
    • No co-crystal structure with a GTPase substrate
    • How the additional armadillo repeat in SmgGDS-607 alters the fold is unknown
  15. 2018 High

    Reconstituted prenylation assays showed SmgGDS-607 completely inhibits RhoA geranylgeranylation by substrate sequestration rather than enzyme inhibition, and does so in a nucleotide-state-dependent manner, establishing the mechanistic basis for how SmgGDS-607 gates entry into the prenylation pathway.

    Evidence In vitro radiolabel prenylation assay, fluorescence nucleotide-state binding assay, and competition with prenylated peptides

    PMID:29940100

    Open questions at the time
    • Whether sequestration is relieved by a specific cellular signal unknown
    • Kinetic parameters of competition in vivo not measured
  16. 2019 High

    Demonstrating that SmgGDS-607 paradoxically accelerates H-Ras farnesylation by enhancing product release from FTase, while inhibiting DiRas1 farnesylation by sequestration, revealed a dual substrate-selective regulatory logic operating through the same chaperone.

    Evidence Reconstituted in vitro farnesylation assays with purified FTase and SmgGDS-607

    PMID:31197034

    Open questions at the time
    • Which GTPases are accelerated vs. inhibited in vivo under physiological SmgGDS levels unknown
    • Whether SmgGDS directly contacts FTase in the accelerated mechanism not shown
  17. 2020 High

    Pharmacological lowering of the SmgGDS-607:558 ratio with splice-switching oligonucleotides suppressed prenylation of multiple GTPase families, induced ER stress and apoptosis, and reduced tumorigenesis in MMTV-PyMT mice, establishing the isoform ratio as a druggable vulnerability in cancer.

    Evidence Splice-switching ASO, prenylation assays, ERK activity, and in vivo MMTV-PyMT transgenic mouse model

    PMID:32019878

    Open questions at the time
    • Off-target effects of splice-switching on other genes not fully profiled
    • Whether the therapeutic window exists in normal tissues unknown
  18. 2021 Medium

    Identification of RHEB/RHEBL1 as SmgGDS binding partners, with SmgGDS retaining GDP-RHEB in the cytosol away from mTORC1-activating membranes, extended the chaperone model to mTOR signaling and explained how SmgGDS knockdown reduces mTORC1 activity in myeloma cells.

    Evidence Co-IP, siRNA knockdown, S6K phosphorylation readout, and subcellular fractionation in multiple myeloma cells

    PMID:33574130

    Open questions at the time
    • Whether SmgGDS acts as a GEF or solely as a chaperone for RHEB not determined
    • Single-lab study without independent confirmation
    • Effect on mTORC2 not examined
  19. 2022 High

    Biophysical characterization of the SmgGDS-558/fully processed farnesylated KRas complex showed interaction through the HVR and farnesylated C-terminus (not the G-domain) with affinity comparable to PDEδ, establishing SmgGDS-558 as an alternative prenyl-binding chaperone for KRas membrane delivery.

    Evidence SAXS, surface plasmon resonance on biomimetic membranes, molecular dynamics, and cellular co-IP

    PMID:35614853

    Open questions at the time
    • Whether SmgGDS-558 and PDEδ compete or cooperate for KRas in cells unknown
    • No co-crystal structure of the complex
  20. 2023 High

    Showing that RAC1B associates more stably with SmgGDS-607 than RAC1, leading to less prenylation and more nuclear accumulation, while DIRAS1 inhibits both interactions, revealed how splice variant-specific chaperoning and endogenous competitive inhibition together control GTPase isoform localization.

    Evidence Co-IP, prenylation assays, nuclear fractionation, CAAX mutagenesis, and DIRAS1 competition in cancer cells

    PMID:37059183

    Open questions at the time
    • Functional consequence of nuclear RAC1B accumulation through SmgGDS pathway unknown
    • Quantitative in vivo stoichiometry of DIRAS1 competition not measured
  21. 2023 Medium

    RAP1GDS1 (Vimar ortholog) was found to complex with Miro and promote mitochondrial calcium overload and fragmentation during aging, with transgenic overexpression causing premature brain aging and knockdown in aged mice promoting healthy aging, linking SmgGDS to mitochondrial quality control beyond its canonical GTPase-chaperoning role.

    Evidence Transgenic and knockdown mouse models, Drosophila Vimar studies, mitochondrial morphology imaging, and calcium measurements

    PMID:37061660

    Open questions at the time
    • Whether the Miro interaction is conserved in human cells at endogenous levels not confirmed
    • Which SmgGDS splice variant mediates the Miro interaction unknown
    • Relationship to canonical GTPase chaperoning unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of a SmgGDS–GTPase complex, the cellular signal that triggers hand-off from SmgGDS-607 to SmgGDS-558, and the mechanism by which SmgGDS regulates insulin secretion and mitochondrial calcium homeostasis independently of its canonical GTPase-chaperoning role.
  • No co-crystal structure of SmgGDS with any GTPase substrate
  • Signal triggering 607→558 hand-off unknown
  • Molecular mechanism linking SmgGDS to insulin secretion pathway undefined
  • Whether SmgGDS-Miro interaction reflects a direct GEF/chaperone function or a distinct activity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0060090 molecular adaptor activity 3 GO:0008289 lipid binding 2
Localization
GO:0005829 cytosol 4 GO:0005634 nucleus 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 9 R-HSA-1643685 Disease 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-1640170 Cell Cycle 2
Partners
ARHGEF7DIRAS1DIRAS2KRASMIRORAC1RHEBRHOA

Evidence

Reading pass · 27 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 via a substituted enzyme mechanism: SmgGDS releases GDP from Rac1, maintains Rac1 in a nucleotide-free form transiently, and also stabilizes the nucleotide-bound GTPase against inactivation; isoprenoid modification is not absolutely required for the interaction. In vitro GTP[γS] incorporation assay, [3H]GDP/GTP exchange assay, nucleotide dissociation/stabilization assays with purified recombinant proteins The Biochemical journal High 7980444
1999 The t(4;11)(q21;p15) translocation creates a NUP98-RAP1GDS1 (NRG) fusion gene in T-ALL, joining the FG repeat-rich region of NUP98 in-frame to the armadillo-repeat coding region of RAP1GDS1; NRG fusion transcripts were detected in leukemic cells of multiple adult T-ALL patients. 3' RACE, RT-PCR, somatic cell hybrid analysis, molecular breakpoint mapping Blood High 10477737
2000 SmgGDS preferentially co-precipitates with dominant-negative RhoA(Asn-19) but not with activated RhoA(Val-14) in vivo; RhoGDI shows the opposite preference; microinjection of SmgGDS cDNA into cells expressing HA-RhoA causes RhoA to be excluded from the nucleus and cell junctions, mimicking the RhoA(Asn-19) distribution. Co-immunoprecipitation with peptide sequencing/Western blotting, 32P-nucleotide binding in intact cells, immunofluorescence microscopy, microinjection The Journal of biological chemistry High 10702222
2002 SmgGDS specifically interacts with dominant-negative and nucleotide-free (but not oncogenic) forms of H-Ras and N-Ras; an effector-domain mutant (HRasN17G37) loses SmgGDS binding; SmgGDS does not catalyze guanine nucleotide exchange on H-Ras or N-Ras in vitro, despite doing so for K-Ras, Rac1, and RhoA; the C-terminal polybasic region (PBR) of GTPases is required for both SmgGDS binding and nucleotide exchange. Co-immunoprecipitation, in vitro GEF assay with purified proteins, effector-domain mutant analysis Oncogene High 11948427
2003 SmgGDS and Rac1 co-accumulate in the nucleus driven by the Rac1 C-terminal polybasic region (PBR), which functions as a nuclear localization signal (NLS); Rac1 activation enhances nuclear accumulation of both proteins; SmgGDS contains a nuclear export signal that promotes its cytoplasmic retention; RhoA PBR lacks NLS activity and SmgGDS·RhoA complexes accumulate in the cytoplasm. GFP fusion nuclear transport assays, PBR/NLS mutation analysis, nuclear export signal identification, fluorescence microscopy, co-immunoprecipitation The Journal of biological chemistry High 12551911
2006 SmgGDS forms a trimeric complex with βPIX and Rac1; phosphorylation-dependent association of βPIX with Rac1 via its GIT-binding domain recruits SmgGDS to activate Rac1 GEF activity; siRNA knockdown of SmgGDS significantly inhibits βPIX-mediated Rac1 activation and bFGF-induced neurite outgrowth. Co-immunoprecipitation, in vitro binding/GEF assay, FRET analysis, siRNA knockdown with neurite outgrowth readout The Journal of biological chemistry High 16954223
2007 SmgGDS knockdown in NSCLC cells causes G1 arrest, loss of colony formation in soft agar, disrupted myosin organization, reduced cell migration, and diminished NF-κB transcriptional activity; SmgGDS overexpression enhances NF-κB activity; these effects are broader than those of RhoA knockdown alone, consistent with SmgGDS activating multiple GTPases. siRNA knockdown, cDNA overexpression, soft-agar colony assay, cell cycle analysis, NF-κB reporter assay, immunofluorescence The Journal of biological chemistry High 17951244
2010 Two splice variants of SmgGDS have distinct roles: SmgGDS-607 (607 residues) associates with nonprenylated GTPases and regulates entry of Rap1A, RhoA, and Rac1 into the prenylation pathway, while SmgGDS-558 (558 residues) selectively associates with prenylated GTPases and facilitates trafficking of Rap1A to the plasma membrane; dominant-negative mutation inhibiting GDP/GTP exchange differentially affects prenylation of different GTPases. Co-immunoprecipitation of splice variants with prenylated vs. nonprenylated GTPases, plasma membrane trafficking assay, dominant-negative GTPase mutation analysis The Journal of biological chemistry High 20709748
2011 SmgGDS is a bona fide GEF that specifically activates RhoA and RhoC (not other GTPases in a large panel); activation is catalytic; SmgGDS preferentially binds nucleotide-depleted RhoA; the RhoA PBR is required for SmgGDS-mediated exchange (unlike canonical GEFs); an electronegative surface patch and a conserved binding groove on SmgGDS are both required for RhoA binding and GEF activity. In vitro GEF assay with large purified GTPase panel, nucleotide state-dependent binding assay, mutagenesis of SmgGDS surface residues, homology modeling, cellular activity 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 RhoA-dependent NF-κB transcriptional activation; SmgGDS-607 knockdown does not show these effects, establishing an isoform-specific role for SmgGDS-558 in RhoA/NF-κB-driven breast cancer malignancy. Isoform-selective siRNA knockdown, in vivo xenograft tumor growth, Rho-GTPase pull-down activity assay, NF-κB reporter assay Molecular cancer research : MCR High 24197117
2013 Transglutaminase 2 (TG2) cross-links RAP1GDS1/SmgGDS in a Ca2+-dependent manner; cross-linked SmgGDS initiates a signaling pathway that promotes Ca2+ release from the ER via IP3 and ryanodine receptors, leading to enhanced mitochondrial Ca2+ uptake and apoptosis in Jurkat T cells. TG2 overexpression (WT and cross-linking mutant), co-localization, Ca2+ imaging, ER Ca2+ release measurements PloS one Medium 24349085
2014 SmgGDS-607 associates more stably with nonprenylated, geranylgeranylated GTPases than with nonprenylated, farnesylated GTPases, recognizing the last amino acid of the CAAX motif; farnesyltransferase inhibitors shunt K-Ras into the geranylgeranylation pathway and increase K-Ras binding to SmgGDS-607; both SmgGDS-607 and SmgGDS-558 directly bind GTPase C-terminal regions in vitro via recombinant proteins and prenylated peptides. Co-immunoprecipitation in cells, SAAX mutant analysis, farnesyltransferase inhibitor treatment, recombinant protein direct binding with prenylated peptides, structural homology modeling The Journal of biological chemistry High 24415755
2014 SmgGDS-558 promotes cyclin D1 expression and suppresses p27 to drive cell cycle progression in pancreatic, lung, and breast cancer cells; SmgGDS-558 knockdown has greater anti-proliferative effects than SmgGDS-607 knockdown; simultaneous knockdown of both variants decreases NSCLC xenograft tumorigenesis in mice. Isoform-selective siRNA, cell cycle analysis, Western blotting for cyclin D1/p27/p21, in vivo xenograft model Cell cycle (Georgetown, Tex.) High 24552806
2015 Di-Ras2 co-purifies with SmgGDS from rat brain cytosol and forms a high-affinity complex with SmgGDS; SmgGDS does not act as a GEF for Di-Ras2 but instead reduces Di-Ras2 binding affinity for guanine nucleotides; pulse-chase analysis reveals Di-Ras2 binds SmgGDS immediately after synthesis in a CAAX motif-dependent manner, increasing Di-Ras2 stability. Endogenous co-purification from rat brain, size-exclusion chromatography of recombinant proteins, nucleotide binding assay, pulse-chase analysis The Journal of biological chemistry High 26149690
2016 DiRas1 binds SmgGDS but is not a substrate for SmgGDS GEF activity; instead, DiRas1 acts as a competitive inhibitor of SmgGDS, blocking its binding to oncogenic GTPases (K-Ras4B, RhoA, Rap1A) and inhibiting SmgGDS-mediated NF-κB transcriptional activity and RhoA activation. Co-immunoprecipitation, in vitro GEF assay, competitive binding assay, in silico docking, NF-κB reporter assay in breast cancer and glioblastoma cell lines The Journal of biological chemistry High 26814130
2016 SmgGDS heterozygous knockout mice show enhanced Rac1 expression, ERK1/2, and Rho-kinase activity in cardiac fibroblasts, and statin-mediated cardioprotection (reduction of cardiac hypertrophy and fibrosis) is lost in SmgGDS+/- mice; atorvastatin stimulates SmgGDS secretion from cardiac fibroblasts and recombinant SmgGDS reduces Rac1 expression in SmgGDS+/- fibroblasts. SmgGDS+/- mouse model, Ang II infusion with statin treatment, recombinant protein rescue, Bio-plex cytokine profiling, conditioned medium assay Hypertension (Dallas, Tex. : 1979) High 26975711
2017 Crystal structure of SmgGDS-558 reveals a fold of tandem armadillo repeats distinct from canonical GEFs; SmgGDS has distinct positively and negatively charged regions both required for RhoA binding and GEF activity; SmgGDS-558 and SmgGDS-607 differ in GTPase binding and GEF activity depending on lipidation state of the GTPase. X-ray crystallography, mutagenesis of charged surface regions, GEF activity assays comparing splice variants with lipidated vs. non-lipidated GTPases The Journal of biological chemistry High 28630045
2017 RAP1GDS1/Rap1GDS1 acts as a GEF for Cdc42 in endothelial cells; simulated microgravity upregulates Rap1GDS1 expression, leading to Cdc42 activation; shRNA knockdown of Rap1GDS1 selectively suppresses Cdc42 activation and inhibits baseline and microgravity-induced vascular branch morphogenesis, rescued by constitutively active Cdc42. Affinity pull-down assay, mass spectrometry identification, shRNA knockdown, constitutively active Cdc42 rescue, Cdc42/Rac1 activity assays in embryoid body vasculogenesis model Stem cell research Medium 29145128
2018 SmgGDS-607 completely inhibits RhoA prenylation by GGTase-I in vitro via substrate sequestration (blocking access to RhoA C-terminal tail, not inhibiting GGTase-I itself); SmgGDS-607 binds RhoA-GDP with higher affinity than RhoA-GTP, making prenylation inhibition nucleotide-dependent. In vitro radiolabel prenylation incorporation assay, fluorescence-based nucleotide state-dependent binding assay, prenylated C-terminal peptide competition assay Biochemistry High 29940100
2019 SmgGDS-607 inhibits farnesylation of DiRas1 by sequestering the GTPase from FTase, with the extent of inhibition determined by competitive binding affinities; SmgGDS-607 paradoxically increases the rate of farnesylation of H-Ras by enhancing product release from FTase; SmgGDS-607 binds a broad range of GTPases and does not strictly require a PBR for recognition. In vitro farnesylation assay with recombinant purified enzymes, protein-binding assays, competition kinetics The Journal of biological chemistry High 31197034
2020 Cancer cells have an elevated SmgGDS-607:SmgGDS-558 ratio that promotes small GTPase prenylation; a splice-switching oligonucleotide (SSO Ex5) targeting exon 5 of SmgGDS pre-mRNA lowers this ratio, suppresses prenylation of multiple Ras, Rho, and Rab family GTPases, inhibits ERK activity, induces ER stress and apoptosis in breast and lung cancer cells, and slows tumorigenesis in MMTV-PyMT mice. Splice-switching oligonucleotide (ASO), prenylation assays, ERK activity measurement, apoptosis assay, in vivo 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 with high affinity for the inactive GDP-bound form; SmgGDS knockdown reduces cytosolic RHEBL1 without affecting mTORC1-activating GTP-RHEBL1 on membranes, and reduces mTORC1 activation and MM cell proliferation; SmgGDS thus retains GDP-bound RHEBs in the cytosol, regulating RHEB localization and mTORC1 signaling. Co-immunoprecipitation identifying RHEB as SmgGDS binding partner, siRNA knockdown of SmgGDS, mTORC1 activity assay (S6K phosphorylation), subcellular fractionation Molecular cancer research : MCR Medium 33574130
2022 SmgGDS-558 interacts with the hypervariable region (HVR) and farnesylated C-terminus (but not the G-domain) of fully processed farnesylated KRas; SmgGDS-558 binds GTP-, GDP-, and nucleotide-free forms of prenylated KRas equally in cells; the Kd for SmgGDS-558/KRas-FMe is comparable to that of PDEδ/KRas. Small-angle X-ray scattering (SAXS), surface plasmon resonance on biomimetic membranes, Monte Carlo/molecular dynamics simulation, co-immunoprecipitation Biophysical journal High 35614853
2023 RAC1B more stably associates with SmgGDS-607 than RAC1, resulting in less RAC1B prenylation and greater nuclear accumulation of RAC1B; DIRAS1 inhibits binding of both RAC1 and RAC1B to SmgGDS and reduces their prenylation; non-prenylated RAC1 and RAC1B (CAAX mutants) can still bind GTP in cells, indicating prenylation is not a prerequisite for activation. Co-immunoprecipitation, prenylation assays, nuclear/cytoplasmic fractionation, CAAX mutant analysis, GTP-binding assays in cells The Journal of biological chemistry High 37059183
2023 RAP1GDS1 (Vimar ortholog) forms a complex with Miro and promotes mitochondrial calcium overload and fragmentation; RAP1GDS1 expression increases after middle age in mice; RAP1GDS1 transgenic mice display premature brain aging and mitochondrial calcium overload, while RAP1GDS1 knockdown in aged mice promotes healthy aging. Transgenic overexpression and knockdown mouse models, mitochondrial morphology imaging, calcium measurements, genetic rescue experiments, Drosophila Vimar orthologue studies Communications biology Medium 37061660
2023 SmgGDS is required for glucose-stimulated insulin secretion in pancreatic β-cells; siRNA depletion of smgGDS inhibits GSIS by ~52%, as well as KCl-, forskolin-, and IBMX-stimulated insulin secretion; subcellular distribution of smgGDS between cytosol and membrane fractions does not detectably change upon glucose stimulation. siRNA knockdown, insulin secretion assay, subcellular fractionation, Western blotting Molecular and cellular endocrinology Medium 38013223
2025 SARS-CoV-2 NSP2 directly binds SmgGDS (full-length NSP2 required) and inhibits SmgGDS GEF activity, disrupting nucleotide exchange on RhoA; this interaction is specific to SARS-CoV-2 NSP2 and is not recapitulated by corresponding proteins of SARS-CoV or MERS-CoV. Biochemical direct binding assay, in vitro GEF activity assay with NSP2 co-incubation, sequence conservation analysis Biochemical and biophysical research communications Medium 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 83 12551911
1999 The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood 80 10477737
2010 Splice variants of SmgGDS control small GTPase prenylation and membrane localization. The Journal of biological chemistry 67 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
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
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 38 24415755
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 21 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 16 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