Affinage

GEM

GTP-binding protein GEM · UniProt P55040

Length
296 aa
Mass
33.9 kDa
Annotated
2026-06-10
100 papers in source corpus 23 papers cited in narrative 23 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

GEM encodes a GDP-preferring Ras-related (RGK family) small GTPase whose crystal structure reveals a canonical Ras G-domain fold with markedly divergent switch regions and a C-terminal extension that packs along the α5 helix to modulate nucleotide handling (PMID:17107948, PMID:17052716). Its best-characterized function is direct inhibition of high-voltage-activated Ca2+ channels: GTP-bound Gem binds the Ca2+ channel β-subunit, reducing α1-subunit surface expression and suppressing L-type and P/Q-type currents, with distinct C-terminal and Ras-core motifs jointly mediating the β-dependent inhibition (PMID:11395774, PMID:22589533). This channel control is governed by Ca2+/calmodulin binding to the C-terminal extension, which drives cytoplasmic localization required for the inhibitory effect (PMID:8810259, PMID:11395774). In parallel, Gem remodels the cytoskeleton by binding the ROKβ coiled-coil to selectively block phosphorylation of myosin substrates and by engaging the RhoGAP GMIP and active Ezrin to inactivate RhoA at the membrane-cytoskeleton interface, driving cell flattening, neurite extension, and spindle positioning during mitosis (PMID:11956230, PMID:17267693, PMID:25173885). These two activities are genetically separable: GTP/CaM binding mediates channel inhibition, whereas phosphorylation of C-terminal serines 261/289 (via cdc42/PKCζ) plus bidentate 14-3-3 binding controls cytoskeletal effects and protein stability, and 14-3-3, calmodulin, and importin α5 together set Gem's nucleocytoplasmic distribution (PMID:14701738, PMID:17605761, PMID:15860732). Gem is a mitogen- and activity-inducible gene whose transcription via CREB/CRE elements links neuronal and circadian stimulation to Ca2+ channel suppression, providing neuroprotection against excitotoxicity/ischemia and tuning light-evoked Ca2+ signaling in the circadian clock (PMID:34349016, PMID:35613591).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 Medium

    Established GEM as a mitogen-inducible GTP-binding protein, defining it as a candidate signaling GTPase rather than a structural or housekeeping product.

    Evidence cDNA cloning, GTP-binding and tyrosine phosphorylation assays, and proliferation assays in T cells and 3T3 cells

    PMID:7912851

    Open questions at the time
    • No structural or effector mechanism defined
    • Tyrosine phosphorylation sites and responsible kinase unidentified
  2. 1996 High

    Identified calmodulin as a Ca2+-dependent regulator that binds the C-terminal extension and inhibits GTP binding, linking Gem activity to Ca2+ signaling.

    Evidence Fluorescence spectrometry, CaM overlay, GST pulldown, and W269G mutagenesis in vitro

    PMID:8810259

    Open questions at the time
    • Functional consequence in cells not yet established
    • Did not connect CaM binding to a downstream effector pathway
  3. 2001 High

    Defined the core molecular function: GTP-bound Gem inhibits high-voltage-activated Ca2+ channels by binding the β-subunit and reducing α1 surface expression, with CaM-driven cytoplasmic localization required.

    Evidence Co-IP, whole-cell patch clamp, surface-expression and exocytosis assays in secretory cells

    PMID:11395774

    Open questions at the time
    • Precise structural determinants on Gem for β-subunit binding not mapped
    • Mechanism reducing α1 surface expression unresolved
  4. 2001 Medium

    Connected Gem to the cytoskeleton, showing it drives morphological change and binds the kinesin-like KIF9, the first RGK link to microtubules, and promotes neurite extension.

    Evidence Yeast two-hybrid, Co-IP, cytoskeletal drug treatments, and overexpression morphology assays in neuroblastoma cells

    PMID:11423971 PMID:11483511

    Open questions at the time
    • Whether KIF9 binding is direct in vivo unclear
    • Signaling intermediates between Gem and actin remodeling unknown
  5. 2002 High

    Resolved the cytoskeletal mechanism: Gem inhibits the Rho/ROKβ pathway by binding the ROKβ coiled-coil to alter substrate specificity, and recruits the RhoA-specific GAP GMIP.

    Evidence Co-IP, in vitro kinase and GAP assays, domain-deletion epistasis, and stress-fiber morphology assays

    PMID:11956230 PMID:12093360

    Open questions at the time
    • How Gem coordinates ROKβ inhibition with GMIP recruitment not integrated
    • Selectivity for myosin substrates over LIMK mechanistically unexplained
  6. 2004 High

    Demonstrated that channel inhibition and cytoskeletal remodeling are genetically separable functions controlled by distinct molecular inputs, with C-terminal serine phosphorylation and 14-3-3 binding governing the cytoskeletal arm and stability.

    Evidence Site-directed mutagenesis, electrophysiology, morphology, 14-3-3 binding assays, and kinase-pathway inhibition

    PMID:14701738

    Open questions at the time
    • Direct kinase acting on S261/S289 not definitively identified
    • In vivo relevance of the two separable functions untested
  7. 2004 Medium

    Extended Gem channel inhibition to cardiac physiology and probed antagonism by tau, showing Gem reduces L-type current and shapes excitability while microtubule stabilization opposes its morphological action.

    Evidence Adenoviral overexpression, patch clamp, ECG, in vivo cardiac gene delivery; co-transfection and expression profiling for tau

    PMID:15087445 PMID:15242970

    Open questions at the time
    • Tau antagonism is indirect; mediating microtubule mechanism unmapped
    • Endogenous cardiac role of Gem not established
  8. 2005 High

    Unified Gem's regulators into a competition model in which 14-3-3, calmodulin, and Ca2+ channel β-subunits bind mutually exclusively to partition Gem between localization and functional states.

    Evidence Reciprocal Co-IP, competition binding assays, subcellular fractionation, and functional readouts

    PMID:15860732

    Open questions at the time
    • Stoichiometry and kinetics of the competing complexes not quantified
    • Spatial control in living cells not directly visualized
  9. 2006 High

    Provided structural and biochemical definition: Gem adopts a Ras fold with divergent switch regions, prefers GDP, and uses its N/C-terminal extensions to regulate GTPase activity, with separable mutation clusters controlling its two functions.

    Evidence Two independent X-ray structures (2.1 and 2.4 Å), nucleotide affinity/GTPase assays, and structure-guided mutagenesis

    PMID:17052716 PMID:17107948

    Open questions at the time
    • No structure of Gem bound to an effector (β-subunit, ROKβ)
    • Conformational basis of GDP preference's functional meaning unclear
  10. 2007 High

    Mechanistically resolved the RhoA arm: GTP-Gem binds active Ezrin and requires GMIP to down-regulate RhoA and dissolve stress fibers and focal adhesions, driving cell elongation.

    Evidence Co-IP, RhoA pull-down, siRNA epistasis, and immunofluorescence

    PMID:17267693

    Open questions at the time
    • Order of Ezrin vs GMIP engagement not resolved
    • How Gem localizes GMIP to membranes not defined
  11. 2007 High

    Defined the nuclear import mechanism, showing importin α5 drives Gem nuclear entry through a C-terminal bipartite NLS that CaM and phosphorylation modulate, independently of channel function.

    Evidence NLS mutagenesis, importin α5 RNAi, Co-IP, and fluorescence microscopy

    PMID:17605761

    Open questions at the time
    • Nuclear function of Gem itself not identified
    • Phospho-sites controlling NLS access not biochemically mapped
  12. 2012 Medium

    Established a mitotic role: Gem regulates spindle length and chromosome alignment through Kif9-dependent control of microtubule dynamics, and broadened channel inhibition to P/Q-type channels via two cooperative Gem motifs.

    Evidence RNAi/overexpression with live-cell spindle imaging; Xenopus oocyte electrophysiology with systematic mutagenesis

    PMID:22589533 PMID:22964304

    Open questions at the time
    • Whether mitotic role uses GTPase or scaffolding activity unclear
    • GMIP/Kif9 division of labor in mitosis not fully integrated
  13. 2014 Medium

    Connected Gem to migration and mitotic spindle positioning through a Gem/GMIP/RhoA axis, and showed transcriptional induction (via Tax-recruited CREB/CBP) couples Gem to actin-dependent T-cell behaviors and viral spread.

    Evidence Overexpression/RNAi with dominant-negative/active RhoA rescue and spindle assays; ChIP, migration, and viral-transmission assays

    PMID:24586148 PMID:25173885

    Open questions at the time
    • Generality of CRE-driven induction beyond HTLV-1 context untested here
    • Link between spindle positioning and tumorigenic phenotypes correlative
  14. 2021 High

    Placed Gem in activity-dependent neuroprotection, showing Npas4-driven induction suppresses L-type VGCC surface expression to limit excitotoxic Ca2+ influx after ischemia.

    Evidence Expression profiling, in vivo MCAO, oxygen-glucose deprivation, AAV gain/loss-of-function, VGCC surface and calcium imaging, and human cerebral organoids

    PMID:34349016

    Open questions at the time
    • Therapeutic window and dosage of Gem induction undefined
    • Whether endogenous Gem levels are sufficient for protection unclear
  15. 2022 High

    Demonstrated a physiological in vivo role using Gem-knockout mice: light-induced, CRE-driven Gem attenuates L-type channel Ca2+ signaling to constrain circadian phase shifts.

    Evidence Gem-KO mice with SCN electrophysiology, locomotor behavior, ex vivo clock-gene imaging, and nifedipine rescue

    PMID:35613591

    Open questions at the time
    • Cytoskeletal/Rho functions of Gem in SCN not assessed
    • Broader behavioral consequences of Gem loss not surveyed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The nuclear function of Gem and the structural basis of its direct effector binding (Ca2+ channel β-subunit, ROKβ) remain unresolved.
  • No structure of Gem bound to β-subunit or ROKβ
  • No defined molecular role for nuclear-localized Gem
  • Physiological coordination of channel vs cytoskeletal functions in one cell unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0098772 molecular function regulator activity 3 GO:0003924 GTPase activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Partners
CACNBCALM1EZRGMIPKIF9KPNA1ROCK2YWHAB

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 GEM encodes a 35 kDa GTP-binding protein that is transiently expressed in human peripheral blood T cells in response to mitogenic stimulation, is phosphorylated on tyrosine residues, and localizes to the cytosolic face of the plasma membrane. Deregulated Gem expression prevented proliferation of normal and transformed 3T3 cells. cDNA cloning, GTP-binding assay, tyrosine phosphorylation detection, subcellular fractionation, cell proliferation assay Science Medium 7912851
1996 Calmodulin (CaM) binds to the C-terminal extension of Kir/Gem in a strictly Ca2+-dependent manner with ~1 nM affinity, and this interaction inhibits GTP binding to Gem. A single point mutation W269G in the CaM-binding domain abolishes this interaction. Fluorescence spectrometry with dansyl-CaM, gel-shift assay, [32P]CaM overlay, GST pulldown, GTP binding assay, site-directed mutagenesis The Journal of biological chemistry High 8810259
2001 The GTP-bound form of Kir/Gem inhibits high-voltage-activated Ca2+ channel activity by directly interacting with the Ca2+ channel beta-subunit, reducing alpha1-subunit expression at the plasma membrane. Ca2+/CaM binding to Gem promotes its cytoplasmic localization, which is required for the inhibitory effect. Inhibition of L-type Ca2+ channels by Gem prevents Ca2+-triggered exocytosis in hormone-secreting cells. Co-immunoprecipitation, whole-cell patch clamp, immunofluorescence/surface expression assay, exocytosis assay, dominant-negative and overexpression approaches Nature High 11395774
2001 Gem promotes profound changes in cell morphology requiring intact microtubules and microfilaments; Gem associates with both cytoskeletal components. Gem interacts with a novel kinesin-like protein KIF9 as identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation, representing the first molecular link between RGK family members and the microtubule cytoskeleton. Yeast two-hybrid screen, co-immunoprecipitation, overexpression morphology assay, cytoskeletal drug treatments The EMBO journal Medium 11483511
2001 Ectopic Gem expression stimulates cell flattening and neurite extension in neuroblastoma cells, demonstrating a role in cytoskeletal rearrangement and morphological differentiation. Gem protein is expressed in differentiating ganglionic neurons in clinical neuroblastoma samples and developing trigeminal ganglia in mouse embryos. Overexpression in neuroblastoma cell lines, morphological analysis, immunostaining of clinical samples and mouse embryos Oncogene Medium 11423971
2002 Gem and Rad are negative regulators of the Rho-Rho kinase pathway. Gem binds ROKbeta (Rho kinase beta) in the coiled-coil region adjacent to the Rho binding domain, independently of RhoA. Gem inhibits ROKbeta-mediated phosphorylation of myosin light chain and myosin phosphatase, but not LIM kinase, suggesting Gem modifies the substrate specificity of ROKbeta rather than blocking its catalytic activity. Gem binding to ROKbeta is required for these effects (demonstrated by deletion mutant rescue experiments). Co-immunoprecipitation, in vitro kinase assay, overexpression/morphology assay, interference assays with deletion mutants, anchorage-independent growth and invasion assays The Journal of cell biology High 11956230
2002 A yeast two-hybrid screen identified GMIP (Gem-interacting protein) as a novel binding partner of Gem. GMIP contains a RhoGAP domain that specifically stimulates GTPase activity of RhoA in vitro, but not Rac1 or Cdc42, and down-regulates RhoA-dependent stress fibers in fibroblasts in vivo. Yeast two-hybrid screen, in vitro GAP assay, co-immunoprecipitation, stress fiber morphology assay The Biochemical journal High 12093360
2004 Phosphorylation of Gem at serines 261 and 289 (in the C-terminal extension) is required for Gem-mediated cytoskeletal reorganization, while GTP and calmodulin binding are required for calcium channel inhibition, demonstrating that these two functions are separable. Phosphorylation of serine 289 in conjunction with serine 23 results in bidentate 14-3-3 binding, increasing Gem protein half-life. Phosphorylation of serine 261 is mediated via a cdc42/PKCzeta-dependent pathway. Site-directed mutagenesis, electrophysiology, morphology assays, 14-3-3 binding assay, kinase pathway inhibition Molecular and cellular biology High 14701738
2004 Adenovirus-mediated overexpression of Gem in ventricular myocytes markedly decreased L-type calcium current density, abbreviating action potential duration and shortening QTc interval. Focal delivery of Gem to the atrioventricular node significantly slowed AV nodal conduction, reducing heart rate during atrial fibrillation. Adenoviral gene transfer, whole-cell patch clamp, electrocardiography, in vivo cardiac gene delivery Circulation research Medium 15242970
2004 Gem GTPase-induced cell elongation in CHO cells is antagonized by tau. This anti-elongation activity of tau is attributed to its microtubule-binding domain, and Gem expression is increased in tau-deficient mouse brains. Tau does not bind directly to Gem GTPase, suggesting the antagonism is indirect through microtubule stabilization. Gene expression profiling (11,000 mRNAs), transient overexpression, co-transfection, morphology assay, co-immunoprecipitation (negative result for direct binding) The Journal of biological chemistry Medium 15087445
2005 14-3-3 and calmodulin regulate the subcellular distribution of Kir/Gem between cytoplasm and nucleus. Competition experiments show that binding of 14-3-3, calmodulin, and calcium channel beta-subunits to Kir/Gem is mutually exclusive, providing a rationale for how these regulators modulate Kir/Gem localization and function (cell shape remodeling and calcium channel downregulation). Co-immunoprecipitation, competition binding assay, subcellular fractionation, fluorescence microscopy, functional assays for cell shape and calcium channel activity Journal of cell science High 15860732
2006 Crystal structure of human Gem G-domain in complex with Mg·GDP at 2.1 Å resolution reveals that the G-domain fold and Mg·GDP binding site are similar to other Ras family GTPases, but the switch regions differ from Ras. The C-terminal extension adopts an alpha-helical conformation extending along the alpha5 helix and interacting with the interswitch. Biochemical studies show Gem has micromolar affinity for GDP and GTP (lower than H-Ras), higher GTPase activity than H-Ras, and GTPase activity regulated by both N- and C-terminal extensions. The bulky DXWEX motif in switch II affects the conformation of switch I and the phosphate-binding site. X-ray crystallography (2.1 Å), biochemical GTP/GDP affinity assays, GTPase activity assay The Journal of biological chemistry High 17107948
2006 Crystal structure of the Gem G-domain in complex with nucleotide at 2.4 Å resolution confirms the basic Ras fold but reveals that the Gem switch regions differ emphatically from Ras. Biochemical characterization shows the Gem G-domain markedly prefers GDP over GTP. Mutations in spatially separated clusters affect the two known functions of Gem (calcium channel inhibition and cytoskeletal regulation) distinctly. X-ray crystallography (2.4 Å), nucleotide preference assay, structure-guided mutagenesis FEBS letters High 17052716
2007 GTP-bound Gem interacts with active (phosphorylated) Ezrin at the plasma membrane-cytoskeleton interface. Coexpression of Gem and Ezrin induces cell elongation with disappearance of actin stress fibers and focal adhesions. Endogenous Gem down-regulates active RhoA and actin stress fibers. The effects of Gem on ERM phosphorylation and actin stress fiber loss require the Rho-GAP partner Gmip, which is enriched in membranes under conditions of Gem-induced cell elongation. Co-immunoprecipitation, overexpression morphology assay, RhoA activity assay (pull-down), immunofluorescence, siRNA knockdown Molecular biology of the cell High 17267693
2007 Nuclear localization of Kir/Gem requires specific nuclear localization signals (NLS). Importin alpha5 binds to Kir/Gem, and its depletion by RNA interference impairs nuclear translocation. Calmodulin binding and predicted serine phosphorylations within or near the C-terminal bipartite NLS regulate nuclear translocation by interfering with importin alpha5 association. These phosphorylations do not affect calcium channel downregulation but interfere with cell-shape remodeling. NLS deletion/mutation analysis, RNAi knockdown of importin alpha5, co-immunoprecipitation, fluorescence microscopy Traffic High 17605761
2012 Gem is required for proper mitotic progression: loss of Gem by RNAi leads to misaligned chromosomes and prometaphase delay. Gem depletion induces spindle elongation while enforced Gem expression results in spindle shortening, acting through the kinesin Kif9. Kif9 depletion increases steady-state spindle alpha-tubulin levels by increasing microtubule polymerization rate. RNAi knockdown, overexpression, live-cell microscopy, spindle length measurement, microtubule dynamics assay FASEB journal Medium 22964304
2012 GMIP (Gem-interacting protein, a RhoA-GAP) was identified as a factor associating with the Rab27a effector JFC1 via proteomics, and modulates vesicular transport and exocytosis. GMIP down-regulation induced RhoA activation and actin polymerization, impairing vesicular transport and exocytosis. RhoA activity polarizes around JFC1-containing secretory granules, and JFC1 knockout neutrophils showed increased RhoA activity with azurophilic granules unable to traverse cortical actin. Proteomic identification, siRNA knockdown, live-cell microscopy, RhoA activity assay, neutrophil knockout, exocytosis assay Molecular biology of the cell Medium 22438581
2012 Gem suppresses P/Q-type Ca2+ channel activity on the plasma membrane in a Ca(v)beta-dependent manner. A 12-amino acid fragment in the Gem C-terminus is sufficient to produce Ca(v)beta-dependent inhibition; a three-amino acid motif in the Ras-like core also contributes. Mutating either site individually did not abolish inhibition, but mutating both sites together completely abolished Gem inhibition without disrupting Gem interaction with Cav2.1 or Cavbeta. Mutating calmodulin, 14-3-3, or phosphatidylinositol lipid interaction residues did not significantly affect Gem inhibition of P/Q channels. Xenopus oocyte expression system, electrophysiology, site-directed mutagenesis, co-immunoprecipitation The Journal of biological chemistry High 22589533
2014 Gem is induced by the HTLV-1 Tax protein through Tax-mediated recruitment of CREB and CBP to a CRE element in the gem promoter. Gem co-localizes with F-actin in Tax-expressing T cells and is required for T-cell spontaneous migration and chemotaxis toward SDF-1/CXCL12. Gem knockdown in HTLV-1-infected cells decreases cell migration, conjugate formation with target cells, and cell-to-cell viral transmission. ChIP assay, promoter analysis, co-localization by microscopy, siRNA knockdown, migration assay, viral transmission assay PLoS pathogens Medium 24586148
2014 Gem overexpression leads to cortical actin disruption and spindle mispositioning during metaphase. This regulation of spindle positioning requires Gmip as a downstream effector (Gmip knockdown rescued Gem-induced spindle phenotype). RhoA GTPase acts as an important effector of Gem/Gmip signaling: dominant-negative RhoA prevented normal spindle positioning, and active RhoA rescued actin and spindle positioning defects caused by Gem or Gmip overexpression. Overexpression, siRNA knockdown, dominant-negative/constitutively active mutants, immunofluorescence, spindle positioning assay Carcinogenesis Medium 25173885
2021 Gem is induced in cortical neurons by the activity-dependent transcription factor Npas4 (identified by systematic screen of Npas4-downstream genes). Gem suppresses membrane localization of L-type VGCCs to inhibit excess Ca2+ influx, protecting neurons from excitotoxic death after in vitro ischemia (oxygen-glucose deprivation) and in vivo stroke (MCAO). Gem is also induced in human cerebral organoids under ischemic conditions. Gene expression profiling, in vivo MCAO model, in vitro oxygen-glucose deprivation, adeno-associated virus-mediated Gem overexpression and knockdown, surface expression assay for L-type VGCCs, calcium imaging, human cerebral organoid model Proceedings of the National Academy of Sciences of the United States of America High 34349016
2022 Gem is rapidly induced by light in suprachiasmatic nucleus (SCN) neurons via the Ca2+-mediated CREB/CRE transcriptional pathway. Gem attenuates light-induced calcium signaling through interaction with VDCCs (L-type channels). Gem-deficient mice show increased Ca2+ currents through L-type channels in SCN neurons, larger phase shifts of clock gene transcription, and increased locomotor activity rhythm phase shifts in response to light; these effects are normalized by the L-type VDCC blocker nifedipine. Gem knockout mouse model, voltage-clamp electrophysiology of SCN neurons, locomotor activity recording, ex vivo SCN slice imaging of clock gene transcription, pharmacological rescue with nifedipine Cell reports High 35613591
2019 ASD-associated CaVβ2d mutations (G167S, S197F, V2D) increase Ba2+ currents through CaV1.2. All CaVβ2d mutants interact with Gem by co-immunoprecipitation, but differ in the degree and characteristics of modulation by Gem (e.g., decrease of fraction of active sweeps: CaVβ2d_G167S > CaVβ2d_V2D > CaVβ2d_S197F), demonstrating that the CaVβ2 subunit mutation status differentially influences Gem-mediated regulation. Whole-cell and single-channel patch clamp, co-immunoprecipitation Neurobiology of disease Medium 31887354

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Regulation of Ca2+ channel expression at the cell surface by the small G-protein kir/Gem. Nature 252 11395774
1994 Gem: an induced, immediate early protein belonging to the Ras family. Science (New York, N.Y.) 179 7912851
2002 The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway. The Journal of cell biology 153 11956230
2016 Lentiviral Vector Gene Transfer of Endostatin/Angiostatin for Macular Degeneration (GEM) Study. Human gene therapy 148 27710144
2016 Gingival Mesenchymal Stem/Progenitor Cells: A Unique Tissue Engineering Gem. Stem cells international 142 27313628
1994 Perlecan: a gem of a proteoglycan. Matrix biology : journal of the International Society for Matrix Biology 122 7921536
2006 Preclinical characterization of AEG35156/GEM 640, a second-generation antisense oligonucleotide targeting X-linked inhibitor of apoptosis. Clinical cancer research : an official journal of the American Association for Cancer Research 108 16951243
2015 Innovative genomic collaboration using the GENESIS (GEM.app) platform. Human mutation 97 26173844
2018 trans-Hydrogenation, gem-Hydrogenation, and trans-Hydrometalation of Alkynes: An Interim Report on an Unorthodox Reactivity Paradigm. Journal of the American Chemical Society 95 30422659
1997 Rem is a new member of the Rad- and Gem/Kir Ras-related GTP-binding protein family repressed by lipopolysaccharide stimulation. The Journal of biological chemistry 92 9268335
2006 Development of lactococcal GEM-based pneumococcal vaccines. Vaccine 90 17081660
2000 Glycosylation effect on membrane domain (GEM) involved in cell adhesion and motility: a preliminary note on functional alpha3, alpha5-CD82 glycosylation complex in ldlD 14 cells. Biochemical and biophysical research communications 87 11162423
2012 Vesicular trafficking through cortical actin during exocytosis is regulated by the Rab27a effector JFC1/Slp1 and the RhoA-GTPase-activating protein Gem-interacting protein. Molecular biology of the cell 83 22438581
2004 Creation of a genetic calcium channel blocker by targeted gem gene transfer in the heart. Circulation research 82 15242970
2020 CircHIPK3 Promotes Gemcitabine (GEM) Resistance in Pancreatic Cancer Cells by Sponging miR-330-5p and Targets RASSF1. Cancer management and research 76 32104074
2018 Half-Sandwich Ruthenium Carbene Complexes Link trans-Hydrogenation and gem-Hydrogenation of Internal Alkynes. Journal of the American Chemical Society 75 29429344
2005 14-3-3 and calmodulin control subcellular distribution of Kir/Gem and its regulation of cell shape and calcium channel activity. Journal of cell science 73 15860732
2001 The Ras-like GTPase Gem is involved in cell shape remodelling and interacts with the novel kinesin-like protein KIF9. The EMBO journal 70 11483511
2004 Phosphorylation of critical serine residues in Gem separates cytoskeletal reorganization from down-regulation of calcium channel activity. Molecular and cellular biology 66 14701738
2017 Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia 61 28111466
2019 Long Noncoding RNA HCP5 Regulates Pancreatic Cancer Gemcitabine (GEM) Resistance By Sponging Hsa-miR-214-3p To Target HDGF. OncoTargets and therapy 57 31632071
2003 gem-Diamine 1-N-iminosugars and related iminosugars, candidate of therapeutic agents for tumor metastasis. Current topics in medicinal chemistry 56 12570867
2018 CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial. The Lancet. Haematology 55 29703335
1996 Calmodulin binds to and inhibits GTP binding of the ras-like GTPase Kir/Gem. The Journal of biological chemistry 50 8810259
2021 GEM: scalable and flexible gene-environment interaction analysis in millions of samples. Bioinformatics (Oxford, England) 48 34695175
2002 A novel Rho GTPase-activating-protein interacts with Gem, a member of the Ras superfamily of GTPases. The Biochemical journal 48 12093360
2002 Gemcitabine (GEM) and carboplatin (CBDCA) versus cisplatin (CDDP) and vinblastine (VLB) in advanced non-small-cell lung cancer (NSCLC) stages III and IV: a phase III randomised trial. Lung cancer (Amsterdam, Netherlands) 47 12057861
2021 Photocatalytic gem-Difluoroolefination Reactions by a Formal C-C Coupling/Defluorination Reaction with Diazoacetates. Angewandte Chemie (International ed. in English) 45 34716734
2005 Gemcitabine, cisplatin and methylprednisolone (GEM-P) is an effective salvage regimen in patients with relapsed and refractory lymphoma. British journal of cancer 45 15812553
2017 CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains. Proceedings of the National Academy of Sciences of the United States of America 44 29158404
2002 Monosialyl-Gb5 organized with cSrc and FAK in GEM of human breast carcinoma MCF-7 cells defines their invasive properties. FEBS letters 44 12401210
2020 gem-Difluoromethylene Alkyne-Enabled Diverse C-H Functionalization and Application to the on-DNA Synthesis of Difluorinated Isocoumarins. Angewandte Chemie (International ed. in English) 43 33022872
2007 Gem associates with Ezrin and acts via the Rho-GAP protein Gmip to down-regulate the Rho pathway. Molecular biology of the cell 43 17267693
2000 Glycosylation affects translocation of integrin, Src, and caveolin into or out of GEM. Biochemical and biophysical research communications 42 10873579
2021 Recent advances in radical-based C-F bond activation of polyfluoroarenes and gem-difluoroalkenes. Chemical communications (Cambridge, England) 41 34714301
2020 Ru-Catalyzed Geminal Hydroboration of Silyl Alkynes via a New gem-Addition Mechanism. Journal of the American Chemical Society 40 32668156
2001 The Gem GTP-binding protein promotes morphological differentiation in neuroblastoma. Oncogene 40 11423971
2021 Nickel-Catalyzed Stereo- and Enantioselective Cross-Coupling of gem-Difluoroalkenes with Carbon Electrophiles by C-F Bond Activation. Angewandte Chemie (International ed. in English) 39 34889493
2019 Oridonin overcomes the gemcitabine resistant PANC-1/Gem cells by regulating GST pi and LRP/1 ERK/JNK signalling. OncoTargets and therapy 39 31410021
2013 Emodin sensitizes the gemcitabine-resistant cell line Bxpc-3/Gem to gemcitabine via downregulation of NF-κB and its regulated targets. International journal of oncology 38 23440366
2006 GEM System: automatic prototyping of cell-wide metabolic pathway models from genomes. BMC bioinformatics 38 16553966
2014 Gem-induced cytoskeleton remodeling increases cellular migration of HTLV-1-infected cells, formation of infected-to-target T-cell conjugates and viral transmission. PLoS pathogens 37 24586148
2022 N6-methyladenosine-mediated SH3BP5-AS1 upregulation promotes GEM chemoresistance in pancreatic cancer by activating the Wnt signaling pathway. Biology direct 36 36397058
2000 Ges, A human GTPase of the Rad/Gem/Kir family, promotes endothelial cell sprouting and cytoskeleton reorganization. The Journal of cell biology 36 10831614
2016 Gene, Environment and Methylation (GEM): a tool suite to efficiently navigate large scale epigenome wide association studies and integrate genotype and interaction between genotype and environment. BMC bioinformatics 35 27480116
2018 Hyaluronic Acid-Modified Micelles Encapsulating Gem-C12 and HNK for Glioblastoma Multiforme Chemotherapy. Molecular pharmaceutics 33 29397747
2006 Biochemical and structural characterization of the gem GTPase. The Journal of biological chemistry 33 17107948
2004 Gem GTPase and tau: morphological changes induced by gem GTPase in cho cells are antagonized by tau. The Journal of biological chemistry 31 15087445
2016 GEM, a member of the GRAM domain family of proteins, is part of the ABA signaling pathway. Scientific reports 30 26939893
2020 novoPathFinder: a webserver of designing novel-pathway with integrating GEM-model. Nucleic acids research 29 32313937
2017 Predictive factors of response to immunotherapy-a review from the Spanish Melanoma Group (GEM). Annals of translational medicine 28 29114547
2014 GEm-Related 5 (GER5), an ABA and stress-responsive GRAM domain protein regulating seed development and inflorescence architecture. Plant science : an international journal of experimental plant biology 28 24767125
2003 Clinical studies in patients with solid tumors using a second-generation antisense oligonucleotide (GEM 231) targeted against protein kinase A type I. Annals of the New York Academy of Sciences 28 14751840
2009 Release, biological potency, and biochemical integrity of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) combined with Augment(TM) Bone Graft or GEM 21S beta-tricalcium phosphate (beta-TCP). Journal of controlled release : official journal of the Controlled Release Society 27 19577598
2014 Gem depletion: amyotrophic lateral sclerosis and spinal muscular atrophy crossover. CNS neuroscience & therapeutics 26 24645792
2007 Nuclear transport of Kir/Gem requires specific signals and importin alpha5 and is regulated by calmodulin and predicted serine phosphorylations. Traffic (Copenhagen, Denmark) 24 17605761
2014 High expression of GEM and EDNRA is associated with metastasis and poor outcome in patients with advanced bladder cancer. BMC cancer 23 25175477
2007 A green GEM: intriguing analogies with animal geminin. Trends in cell biology 23 17997094
2006 Structure-function studies of the G-domain from human gem, a novel small G-protein. FEBS letters 23 17052716
2021 Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra®. Oncotarget 22 33889297
2019 Sequential regiospecific gem-diprenylation of tetrahydroxyxanthone by prenyltransferases from Hypericum sp. The New phytologist 21 30485455
2002 GEM 231, a second-generation antisense agent complementary to protein kinase A RIalpha subunit, potentiates antitumor activity of irinotecan in human colon, pancreas, prostate and lung cancer xenografts. International journal of oncology 21 12063551
2019 Development of GEM-PA-nanotrap for purification of foot-and-mouth disease virus. Vaccine 20 31036456
2019 Potential Functions of Gem-Associated Protein 2-Like Isoform X1 in the Oriental River Prawn Macrobrachium nipponense: Cloning, qPCR, In Situ Hybridization, and RNAi Analysis. International journal of molecular sciences 20 31426338
2011 Gem formation upon constitutive Gemin3 overexpression in Drosophila. Cell biology international 20 21627586
2018 Petasis-Type gem-Difluoroallylation Reactions Assisted by the Neighboring Hydroxyl Group in Amines. Organic letters 19 29652153
2005 Methodology and recruitment of probands and their families for the Genes in Myopia (GEM) Study. Ophthalmic epidemiology 19 16283990
2016 Subtilisin QK-2: secretory expression in Lactococcus lactis and surface display onto gram-positive enhancer matrix (GEM) particles. Microbial cell factories 18 27176475
2012 Molecular determinants of Gem protein inhibition of P/Q-type Ca2+ channels. The Journal of biological chemistry 18 22589533
1995 Chromosomal organization and transcriptional regulation of human GEM and localization of the human and mouse GEM loci encoding an inducible Ras-like protein. Genomics 18 8825643
2022 GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer. Cellular oncology (Dordrecht, Netherlands) 17 35503594
2021 Cancer immunotherapy in special challenging populations: recommendations of the Advisory Committee of Spanish Melanoma Group (GEM). Journal for immunotherapy of cancer 17 33782108
2020 Genomics of MPNST (GeM) Consortium: Rationale and Study Design for Multi-Omic Characterization of NF1-Associated and Sporadic MPNSTs. Genes 17 32252413
2019 Site-Directed Spin Labeling of RNA with a Gem-Diethylisoindoline Spin Label: PELDOR, Relaxation, and Reduction Stability. Molecules (Basel, Switzerland) 17 31817785
2016 Epoxomicin and Eponemycin Biosynthesis Involves gem-Dimethylation and an Acyl-CoA Dehydrogenase-Like Enzyme. Chembiochem : a European journal of chemical biology 17 26789439
2012 The GTPase Gem and its partner Kif9 are required for chromosome alignment, spindle length control, and mitotic progression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 22964304
2009 Detection of a gem-diamine and a stable quinonoid intermediate in the reaction catalyzed by serine-glyoxylate aminotransferase from Hyphomicrobium methylovorum. Biochimica et biophysica acta 16 19264108
2021 Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke. Proceedings of the National Academy of Sciences of the United States of America 15 34349016
2021 Protein C-GeM: A Coarse-Grained Electron Model for Fast and Accurate Protein Electrostatics Prediction. Journal of chemical information and modeling 15 34490776
2019 Mechanism of metformin enhancing the sensitivity of human pancreatic cancer cells to gem-citabine by regulating the PI3K/Akt/mTOR signaling pathway. European review for medical and pharmacological sciences 15 31841183
1990 The bacteriophage Mu gem gene: a positive regulator of the C operon required for normal levels of late transcription. Virology 15 2173258
2022 Electrochemical Synthesis of gem-Difluoro- and γ-Fluoro-Allyl Boronates and Silanes. Chemistry (Weinheim an der Bergstrasse, Germany) 14 36067044
2021 An antigen display system of GEM nanoparticles based on affinity peptide ligands. International journal of biological macromolecules 14 34699894
2005 The Gem interacting protein (GMIP) gene is associated with major depressive disorder. Neurogenetics 14 16086184
2023 Rhodium-Catalyzed Enantioselective 1,4-Oxyamination of Conjugated gem-Difluorodienes via Coupling with Carboxylic Acids and Dioxazolones. Angewandte Chemie (International ed. in English) 13 37357836
2023 A hidden gem in multidisciplinary antimicrobial stewardship: a systematic review on bedside nurses' activities in daily practice regarding antibiotic use. JAC-antimicrobial resistance 13 38021036
2022 DWI Metrics Differentiating Benign Intraductal Papillary Mucinous Neoplasms from Invasive Pancreatic Cancer: A Study in GEM Models. Cancers 13 36011011
2020 Synthesis and Characterization of Folic Acid Conjugated Gemcitabine Tethered Silver Nanoparticles (FA-GEM-AgNPs) for Targeted Delivery. Current pharmaceutical design 13 32175835
2022 A light-induced small G-protein gem limits the circadian clock phase-shift magnitude by inhibiting voltage-dependent calcium channels. Cell reports 12 35613591
2020 pH and singlet oxygen dual-responsive GEM prodrug micelles for efficient combination therapy of chemotherapy and photodynamic therapy. Journal of materials chemistry. B 12 32538389
2014 Gem GTPase acts upstream Gmip/RhoA to regulate cortical actin remodeling and spindle positioning during early mitosis. Carcinogenesis 12 25173885
2007 Gemcitabine, cisplatin and methylprednisolone (GEM-P) with or without Rituximab in relapsed and refractory patients with diffuse large B cell lymphoma (DLBCL). Hematology (Amsterdam, Netherlands) 12 17454196
2006 Gem protein signaling and regulation. Methods in enzymology 12 16757346
2023 Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV). European journal of medicinal chemistry 11 37080108
2023 Ti-Catalyzed Modular Ketone Synthesis from Carboxylic Derivatives and gem-Dihaloalkanes. Journal of the American Chemical Society 11 37365677
2022 GEM-PA-Based Subunit Vaccines of Crimean Congo Hemorrhagic Fever Induces Systemic Immune Responses in Mice. Viruses 11 36016285
2019 GeM-Pro: a tool for genome functional mining and microbial profiling. Applied microbiology and biotechnology 11 30729287
2019 Autism-associated mutations in the CaVβ2 calcium-channel subunit increase Ba2+-currents and lead to differential modulation by the RGK-protein Gem. Neurobiology of disease 11 31887354
2018 Molecular characterization of GTP binding protein overexpressed in skeletal muscle (GEM) and its role in promoting adipogenesis in goat intramuscular preadipocytes. Animal biotechnology 11 30570352
2014 Upregulation of Gem relates to retinal ganglion cells apoptosis after optic nerve crush in adult rats. Journal of molecular histology 11 24948002

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