{"gene":"GEM","run_date":"2026-04-28T18:06:52","timeline":{"discoveries":[{"year":1994,"finding":"GEM was identified as a mitogen-induced immediate-early gene encoding a 35 kDa GTP-binding protein (Ras-family, RGK subfamily) expressed in human peripheral blood T cells following mitogenic stimulation. GEM protein was found to be phosphorylated on tyrosine residues, localized to the cytosolic face of the plasma membrane, and deregulated expression prevented proliferation of normal and transformed 3T3 cells, indicating a role in receptor-mediated signal transduction.","method":"Molecular cloning, subcellular fractionation, tyrosine phosphorylation assay, GTP-binding assay, proliferation assay (overexpression in 3T3 cells)","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — original discovery paper with multiple orthogonal methods (cloning, localization, phosphorylation, functional overexpression phenotype)","pmids":["7912851"],"is_preprint":false},{"year":1996,"finding":"Calmodulin (CaM) binds to the C-terminal extension of GEM/Kir in a strict Ca2+-dependent manner with ~1 nM affinity, and this binding inhibits GTP binding to GEM. A single point mutation W269G in the CaM-binding domain abolished the interaction. Full-length GEM and Rad proteins were confirmed to bind CaM by a [32P]CaM overlay technique. This establishes a direct link between Ca2+/CaM signaling and the RGK GTPase.","method":"Fluorescence spectrometry (dansyl-CaM titration), site-directed mutagenesis (W269G), [32P]CaM overlay assay, GTP-binding inhibition assay with GST-fusion proteins","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis and multiple orthogonal biochemical methods in single study","pmids":["8810259"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of a truncated human GEM protein (G domain plus first part of C-terminal extension) complexed with Mg·GDP was solved at 2.1 Å resolution. The G-domain fold is similar to other Ras GTPases, but the DXWEX motif in switch II (characteristic of RGK proteins) distorts switch I and the phosphate-binding site. The C-terminal extension adopts an α-helical conformation extending along the α5 helix and interacting with the interswitch. GEM's affinities for GDP and GTP are in the micromolar range (much lower than H-Ras), and GTPase activity is higher than H-Ras and regulated by both N- and C-terminal extensions.","method":"X-ray crystallography (2.1 Å), biochemical nucleotide-binding assays, GTPase activity assays with truncation mutants","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional biochemical validation, multiple methods in single rigorous study","pmids":["17107948"],"is_preprint":false},{"year":2004,"finding":"GEM GTPase expression was upregulated in tau-deficient mouse brains. Overexpression of GEM GTPase in CHO cells (which lack tau) induced marked cell elongation, acting as a negative regulator of the Rho–Rho kinase pathway for cytoskeletal organization. Co-expression of tau antagonized this elongation effect, an activity attributed to tau's microtubule-binding domain (homologous domains of MAP2 and MAP4 showed similar antagonism). Tau did not bind directly to GEM GTPase, indicating the antagonism is indirect, mediated through microtubule binding.","method":"Transcriptomic profiling (tau-KO mouse brain, ~11,000 mRNAs), transient overexpression in CHO cells, co-expression rescue experiments, direct binding assay (negative result), domain mapping","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2/3 — clean overexpression phenotype with domain mapping, but indirect mechanism inferred; single lab","pmids":["15087445"],"is_preprint":false}],"current_model":"GEM is a mitogen-induced, immediately-early RGK-family Ras GTPase that localizes to the cytosolic face of the plasma membrane, is phosphorylated on tyrosine, binds GDP/GTP with unusually low (micromolar) affinity via a structurally distinctive G domain (resolved at 2.1 Å), has its GTPase activity regulated by N- and C-terminal extensions, and is inhibited in nucleotide binding by Ca²⁺/calmodulin binding to its C-terminal extension; GEM also acts as a negative regulator of the Rho–Rho kinase cytoskeletal pathway, inducing cell elongation that is antagonized indirectly by tau's microtubule-binding activity."},"narrative":{"teleology":[{"year":1994,"claim":"Identification of GEM as a mitogen-induced GTPase established the existence of a Ras-related protein linking mitogenic receptor signaling to cell proliferation control.","evidence":"Molecular cloning from stimulated human T cells, subcellular fractionation, tyrosine phosphorylation assay, and overexpression-induced growth arrest in 3T3 fibroblasts","pmids":["7912851"],"confidence":"High","gaps":["Downstream effectors of GEM signaling were not identified","The kinase responsible for GEM tyrosine phosphorylation is unknown","Whether GEM acts in the GTP- or GDP-bound state for its anti-proliferative effect was not resolved"]},{"year":1996,"claim":"Demonstration that Ca²⁺/calmodulin binds the C-terminal extension and inhibits GTP loading revealed a direct regulatory link between calcium signaling and GEM nucleotide cycling.","evidence":"Fluorescence titration with dansyl-CaM, W269G point mutant ablating binding, [³²P]CaM overlay, and GTP-binding inhibition assays with recombinant GST-GEM","pmids":["8810259"],"confidence":"High","gaps":["Physiological consequences of CaM-mediated GTP-loading inhibition in cells were not tested","Whether CaM binding affects GEM localization or effector interactions is unknown"]},{"year":2004,"claim":"Showing that GEM overexpression induces cell elongation through inhibition of the Rho–Rho kinase pathway provided the first defined cytoskeletal effector axis for this GTPase, and revealed an indirect antagonism by tau through microtubule binding.","evidence":"Transcriptomic profiling of tau-KO mouse brain, overexpression in CHO cells, co-expression rescue with tau and MAPs, direct binding assay (negative)","pmids":["15087445"],"confidence":"Medium","gaps":["The direct molecular target through which GEM inhibits Rho–Rho kinase signaling was not identified","Reliance on overexpression in a single cell type limits generalizability","Whether endogenous GEM levels are sufficient to modulate cytoskeletal organization in neurons or T cells is untested"]},{"year":2006,"claim":"The 2.1 Å crystal structure of the GEM G domain explained the biochemical basis for its unusually low nucleotide affinity and showed how the N- and C-terminal extensions regulate GTPase activity, providing a structural framework for understanding RGK-family divergence from classical Ras.","evidence":"X-ray crystallography of truncated GEM·Mg·GDP complex, nucleotide-binding and GTPase activity assays with truncation mutants","pmids":["17107948"],"confidence":"High","gaps":["No structure of full-length GEM or GEM bound to an effector or calmodulin is available","Whether the GTP-bound conformation differs sufficiently to act as a classical switch remains unresolved","The structural basis of membrane association is not captured in the truncated construct"]},{"year":null,"claim":"The direct effector(s) mediating GEM's anti-proliferative and cytoskeletal functions, and the in vivo physiological roles of GEM in immune cells and neurons, remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No GEM effector protein has been identified by direct binding","Loss-of-function studies (knockout, knockdown) in physiologically relevant cell types are lacking","Regulation of GEM by upstream kinases is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":["CALM1"],"other_free_text":[]},"mechanistic_narrative":"GEM is a mitogen-induced, immediate-early RGK-family GTPase that localizes to the cytosolic face of the plasma membrane, is phosphorylated on tyrosine, and participates in receptor-mediated signal transduction in T cells and fibroblasts [PMID:7912851]. Its G domain binds GDP and GTP with unusually low (micromolar) affinity owing to a distinctive DXWEX motif in switch II that distorts the phosphate-binding site, and its intrinsic GTPase activity is modulated by N- and C-terminal extensions, as revealed by a 2.1 Å crystal structure [PMID:17107948]. Ca²⁺/calmodulin binds the C-terminal extension with ~1 nM affinity and inhibits GTP loading, directly coupling calcium signaling to GEM nucleotide cycling [PMID:8810259]. GEM also functions as a negative regulator of the Rho–Rho kinase cytoskeletal pathway, inducing cell elongation that is indirectly antagonized by the microtubule-binding activity of tau [PMID:15087445]."},"prefetch_data":{"uniprot":{"accession":"P55040","full_name":"GTP-binding protein GEM","aliases":["GTP-binding mitogen-induced T-cell protein","RAS-like protein KIR"],"length_aa":296,"mass_kda":33.9,"function":"Could be a regulatory protein, possibly participating in receptor-mediated signal transduction at the plasma membrane. Has guanine nucleotide-binding activity but undetectable intrinsic GTPase activity","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P55040/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GEM","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GEM","total_profiled":1310},"omim":[{"mim_id":"619333","title":"NEURODEVELOPMENTAL DISORDER WITH CEREBELLAR ATROPHY AND MOTOR DYSFUNCTION; NEDCAM","url":"https://www.omim.org/entry/619333"},{"mim_id":"619039","title":"REPLICATION INITIATOR 1; REPIN1","url":"https://www.omim.org/entry/619039"},{"mim_id":"617913","title":"NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, CATARACTS, AND RENAL ABNORMALITIES; NEDMCR","url":"https://www.omim.org/entry/617913"},{"mim_id":"616955","title":"RRAD- AND GEM-LIKE GTPase 2; REM2","url":"https://www.omim.org/entry/616955"},{"mim_id":"613004","title":"HUNTINGTIN; HTT","url":"https://www.omim.org/entry/613004"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"gallbladder","ntpm":214.9}],"url":"https://www.proteinatlas.org/search/GEM"},"hgnc":{"alias_symbol":["KIR"],"prev_symbol":[]},"alphafold":{"accession":"P55040","domains":[{"cath_id":"3.40.50.300","chopping":"74-245","consensus_level":"medium","plddt":90.416,"start":74,"end":245}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P55040","model_url":"https://alphafold.ebi.ac.uk/files/AF-P55040-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P55040-F1-predicted_aligned_error_v6.png","plddt_mean":72.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GEM","jax_strain_url":"https://www.jax.org/strain/search?query=GEM"},"sequence":{"accession":"P55040","fasta_url":"https://rest.uniprot.org/uniprotkb/P55040.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P55040/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P55040"}},"corpus_meta":[{"pmid":"11861603","id":"PMC_11861603","title":"KIR: diverse, rapidly evolving receptors of innate and adaptive immunity.","date":"2001","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11861603","citation_count":742,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10781084","id":"PMC_10781084","title":"Plasticity in the organization and sequences of human KIR/ILT gene families.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10781084","citation_count":505,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18635379","id":"PMC_18635379","title":"The Yin and Yang of HLA and KIR in human disease.","date":"2008","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18635379","citation_count":292,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17100885","id":"PMC_17100885","title":"KIR and disease: a model system or system of models?","date":"2006","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/17100885","citation_count":230,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16563220","id":"PMC_16563220","title":"Inwardly rectifying potassium channels (Kir) in central nervous system glia: a special role for Kir4.1 in glial functions.","date":"2006","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16563220","citation_count":229,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20028428","id":"PMC_20028428","title":"The extensive polymorphism of KIR genes.","date":"2010","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20028428","citation_count":226,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35258337","id":"PMC_35258337","title":"KIR+CD8+ T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35258337","citation_count":211,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17694058","id":"PMC_17694058","title":"Global diversity and evidence for coevolution of KIR and HLA.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17694058","citation_count":190,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7912851","id":"PMC_7912851","title":"Gem: an induced, immediate early protein belonging to the Ras family.","date":"1994","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/7912851","citation_count":179,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15809348","id":"PMC_15809348","title":"Understanding how combinations of HLA and KIR genes influence disease.","date":"2005","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15809348","citation_count":178,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22264929","id":"PMC_22264929","title":"NK cell MHC class I specific receptors (KIR): from biology to clinical intervention.","date":"2012","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22264929","citation_count":159,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11904677","id":"PMC_11904677","title":"Distinctive KIR and HLA diversity in a panel of north Indian Hindus.","date":"2002","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/11904677","citation_count":133,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21873457","id":"PMC_21873457","title":"Maternal KIR and fetal HLA-C: a fine balance.","date":"2011","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/21873457","citation_count":131,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7921536","id":"PMC_7921536","title":"Perlecan: a gem of a proteoglycan.","date":"1994","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/7921536","citation_count":122,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19923897","id":"PMC_19923897","title":"Natural killer cells and cancer: regulation by the killer cell Ig-like receptors (KIR).","date":"2009","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/19923897","citation_count":118,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16329188","id":"PMC_16329188","title":"The impact of variation at the KIR gene cluster on human disease.","date":"2006","source":"Current topics in microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16329188","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26173844","id":"PMC_26173844","title":"Innovative genomic collaboration using the GENESIS (GEM.app) platform.","date":"2015","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/26173844","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26284478","id":"PMC_26284478","title":"Human KIR repertoires: shaped by genetic diversity and evolution.","date":"2015","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/26284478","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21629750","id":"PMC_21629750","title":"KIR/HLA interactions and pathogen immunity.","date":"2011","source":"Journal of biomedicine & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/21629750","citation_count":79,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16123537","id":"PMC_16123537","title":"Hanging in the balance. KIR and their role in disease.","date":"2005","source":"Molecular interventions","url":"https://pubmed.ncbi.nlm.nih.gov/16123537","citation_count":78,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15580655","id":"PMC_15580655","title":"The KIR gene family: life in the fast lane of evolution.","date":"2005","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15580655","citation_count":78,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18370147","id":"PMC_18370147","title":"KIR locus polymorphisms: genotyping and disease association analysis.","date":"2008","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/18370147","citation_count":72,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23637128","id":"PMC_23637128","title":"Influence of KIR gene copy number on natural killer cell education.","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23637128","citation_count":69,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24678311","id":"PMC_24678311","title":"TLR/NCR/KIR: Which One to Use and When?","date":"2014","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24678311","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18675345","id":"PMC_18675345","title":"Role of KIRs and KIR ligands in hematopoietic transplantation.","date":"2008","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18675345","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23394822","id":"PMC_23394822","title":"Recombinant structures expand and contract inter and intragenic diversification at the KIR locus.","date":"2013","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/23394822","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15042349","id":"PMC_15042349","title":"Expression and coexpression of CO2-sensitive Kir channels in brainstem neurons of rats.","date":"2004","source":"The Journal of membrane biology","url":"https://pubmed.ncbi.nlm.nih.gov/15042349","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19664139","id":"PMC_19664139","title":"Activating and inhibitory killer immunoglobulin-like receptors (KIR) in haploidentical haemopoietic stem cell transplantation to cure high-risk leukaemias.","date":"2009","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19664139","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28695287","id":"PMC_28695287","title":"The role of KIR and HLA interactions in pregnancy complications.","date":"2017","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/28695287","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16929347","id":"PMC_16929347","title":"Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility.","date":"2006","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/16929347","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16698429","id":"PMC_16698429","title":"KIR gene in ethnic and Mestizo populations from Mexico.","date":"2006","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16698429","citation_count":54,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28972044","id":"PMC_28972044","title":"Neuroblastoma Patients' KIR and KIR-Ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report from the Children's Oncology Group.","date":"2017","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/28972044","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23849068","id":"PMC_23849068","title":"Genotype List String: a grammar for describing HLA and KIR genotyping results in a text string.","date":"2013","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/23849068","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8810259","id":"PMC_8810259","title":"Calmodulin binds to and inhibits GTP binding of the ras-like GTPase Kir/Gem.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8810259","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33424762","id":"PMC_33424762","title":"Role of Astrocytic Inwardly Rectifying Potassium (Kir) 4.1 Channels in Epileptogenesis.","date":"2020","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33424762","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28569259","id":"PMC_28569259","title":"Revealing complete complex KIR haplotypes phased by long-read sequencing technology.","date":"2017","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/28569259","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15607801","id":"PMC_15607801","title":"Shaping the human NK cell repertoire: an epigenetic glance at KIR gene regulation.","date":"2005","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15607801","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11782245","id":"PMC_11782245","title":"The KIR and CD94/NKG2 families of molecules in the rhesus monkey.","date":"2001","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/11782245","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37169596","id":"PMC_37169596","title":"Efficient and accurate KIR and HLA genotyping with massively parallel sequencing data.","date":"2023","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/37169596","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23161492","id":"PMC_23161492","title":"Modulation of the natural killer cell KIR repertoire by cytomegalovirus infection.","date":"2012","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23161492","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25950617","id":"PMC_25950617","title":"2DL1, 2DL2 and 2DL3 all contribute to KIR phenotype variability on human NK cells.","date":"2015","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/25950617","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27890259","id":"PMC_27890259","title":"How important is NK alloreactivity and KIR in allogeneic transplantation?","date":"2016","source":"Best practice & research. Clinical haematology","url":"https://pubmed.ncbi.nlm.nih.gov/27890259","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23357483","id":"PMC_23357483","title":"Altered Kir and gap junction channels in temporal lobe epilepsy.","date":"2013","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/23357483","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24409153","id":"PMC_24409153","title":"Phosphoinositide regulation of inward rectifier potassium (Kir) channels.","date":"2014","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24409153","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25139336","id":"PMC_25139336","title":"KIR diversity in Māori and Polynesians: populations in which HLA-B is not a significant KIR ligand.","date":"2014","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/25139336","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17107948","id":"PMC_17107948","title":"Biochemical and structural characterization of the gem GTPase.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17107948","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16085405","id":"PMC_16085405","title":"KIR matching in hematopoietic stem cell transplantation.","date":"2005","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16085405","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22884899","id":"PMC_22884899","title":"Activating killer-cell immunoglobulin-like receptors (KIR) and their cognate HLA ligands are significantly increased in autism.","date":"2012","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/22884899","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15087445","id":"PMC_15087445","title":"Gem GTPase and tau: morphological changes induced by gem GTPase in cho cells are antagonized by tau.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15087445","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32313937","id":"PMC_32313937","title":"novoPathFinder: a webserver of designing novel-pathway with integrating GEM-model.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/32313937","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23936864","id":"PMC_23936864","title":"Role of HLA, KIR, MICA, and cytokines genes in leprosy.","date":"2013","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/23936864","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30099516","id":"PMC_30099516","title":"HLA and KIR Associations of Cervical Neoplasia.","date":"2018","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30099516","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19936734","id":"PMC_19936734","title":"Distribution of killer cell immunoglobulin-like receptors (KIR) and their HLA-C ligands in two Iranian populations.","date":"2010","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19936734","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17159886","id":"PMC_17159886","title":"Identification of distal KIR promoters and transcripts.","date":"2006","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/17159886","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21850526","id":"PMC_21850526","title":"Diversity of the KIR gene cluster in an urban Brazilian population.","date":"2011","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/21850526","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23426663","id":"PMC_23426663","title":"Inward-rectifying potassium (Kir) channels regulate pacemaker activity in spinal nociceptive circuits during early life.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23426663","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27913469","id":"PMC_27913469","title":"Can we make a better match or mismatch with KIR genotyping?","date":"2016","source":"Hematology. American Society of Hematology. Education Program","url":"https://pubmed.ncbi.nlm.nih.gov/27913469","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33013938","id":"PMC_33013938","title":"The Genetic Mechanisms Driving Diversification of the KIR Gene Cluster in Primates.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33013938","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32184413","id":"PMC_32184413","title":"Killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen-C (HLA-C) allorecognition patterns in women with endometriosis.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32184413","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14679294","id":"PMC_14679294","title":"Expression of KIR and C-type lectin receptors in Behcet's disease.","date":"2003","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/14679294","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30564240","id":"PMC_30564240","title":"Extensive Alternative Splicing of KIR Transcripts.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30564240","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21245333","id":"PMC_21245333","title":"Killer cell Ig-like receptor (KIR) 3DL1 down-regulation enhances inhibition of type 1 diabetes by autoantigen-specific regulatory T cells.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21245333","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35610960","id":"PMC_35610960","title":"Immunity at maternal-fetal interface: KIR/HLA (Allo)recognition.","date":"2022","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/35610960","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26557119","id":"PMC_26557119","title":"MHC and KIR Polymorphisms in Rhesus Macaque SIV Infection.","date":"2015","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26557119","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28716449","id":"PMC_28716449","title":"Venom-derived peptides inhibiting Kir channels: Past, present, and future.","date":"2017","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28716449","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17997094","id":"PMC_17997094","title":"A green GEM: intriguing analogies with animal geminin.","date":"2007","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17997094","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17450354","id":"PMC_17450354","title":"Complexity in cattle KIR genes: transcription and genome analysis.","date":"2007","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17450354","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26063437","id":"PMC_26063437","title":"Identification of the Conformational transition pathway in PIP2 Opening Kir Channels.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26063437","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34929414","id":"PMC_34929414","title":"Association of KIR gene polymorphisms with COVID-19 disease.","date":"2021","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/34929414","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32226430","id":"PMC_32226430","title":"Estimation of German KIR Allele Group Haplotype Frequencies.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32226430","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32376502","id":"PMC_32376502","title":"Significance of KIR like natural killer cell receptors in autoimmune disorders.","date":"2020","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/32376502","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21710469","id":"PMC_21710469","title":"The extreme plasticity of killer cell Ig-like receptor (KIR) haplotypes differentiates rhesus macaques from humans.","date":"2011","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21710469","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28188495","id":"PMC_28188495","title":"Cancer treatment and the KIR-HLA system: an overview.","date":"2017","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28188495","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21239231","id":"PMC_21239231","title":"Molecular determinant-based typing of KIR alleles and KIR ligands.","date":"2011","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/21239231","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30485455","id":"PMC_30485455","title":"Sequential regiospecific gem-diprenylation of tetrahydroxyxanthone by prenyltransferases from Hypericum sp.","date":"2019","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/30485455","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38839374","id":"PMC_38839374","title":"Full-resolution HLA and KIR gene annotations for human genome assemblies.","date":"2024","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/38839374","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34745129","id":"PMC_34745129","title":"ERAP, KIR, and HLA-C Profile in Recurrent Implantation Failure.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34745129","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20722764","id":"PMC_20722764","title":"The tortoise and the hare: slowly evolving T-cell responses take hastily evolving KIR.","date":"2010","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20722764","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35333652","id":"PMC_35333652","title":"A molecular switch controls the impact of cholesterol on a Kir channel.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/35333652","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20173785","id":"PMC_20173785","title":"Natural killer-cell KIR repertoire reconstitution after haploidentical SCT.","date":"2010","source":"Bone marrow transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/20173785","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34043881","id":"PMC_34043881","title":"Regulatory KIR+ RA+ T cells accumulate with age and are highly activated during viral respiratory disease.","date":"2021","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/34043881","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16712646","id":"PMC_16712646","title":"Inhibitory and activatory KIR gene frequencies in the Polish population.","date":"2006","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/16712646","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20454893","id":"PMC_20454893","title":"Differential RNA expression of KIR alleles.","date":"2010","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/20454893","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29358278","id":"PMC_29358278","title":"Human and Rhesus Macaque KIR Haplotypes Defined by Their Transcriptomes.","date":"2018","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/29358278","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33317205","id":"PMC_33317205","title":"The Role of HLA and KIR Immunogenetics in BK Virus Infection after Kidney Transplantation.","date":"2020","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/33317205","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23863987","id":"PMC_23863987","title":"Identification of a KIR antisense lncRNA expressed by progenitor cells.","date":"2013","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/23863987","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20082621","id":"PMC_20082621","title":"Killer cell immunoglobulin-like receptor (KIR) genes in systemic sclerosis.","date":"2010","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20082621","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16283990","id":"PMC_16283990","title":"Methodology and recruitment of probands and their families for the Genes in Myopia (GEM) Study.","date":"2005","source":"Ophthalmic epidemiology","url":"https://pubmed.ncbi.nlm.nih.gov/16283990","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26656451","id":"PMC_26656451","title":"Characterization of KIR intermediate promoters reveals four promoter types associated with distinct expression patterns of KIR subtypes.","date":"2015","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/26656451","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35050404","id":"PMC_35050404","title":"High-resolution human KIR genotyping.","date":"2022","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/35050404","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18571006","id":"PMC_18571006","title":"KIR and HLA gene combinations in Vogt-Koyanagi-Harada disease.","date":"2008","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18571006","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15288178","id":"PMC_15288178","title":"Role of a KIR/HLA-C allorecognition system in pregnancy.","date":"2004","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15288178","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24055695","id":"PMC_24055695","title":"Genetic profile of KIR and HLA in southern Chinese Han population.","date":"2013","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24055695","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33283280","id":"PMC_33283280","title":"The combinatorial diversity of KIR and HLA class I allotypes in Peninsular Malaysia.","date":"2020","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33283280","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35079013","id":"PMC_35079013","title":"Ion currents through Kir potassium channels are gated by anionic lipids.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35079013","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24529855","id":"PMC_24529855","title":"The role of KIR2DS1 in multiple sclerosis--KIR in Portuguese MS patients.","date":"2014","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/24529855","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30321631","id":"PMC_30321631","title":"Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop.","date":"2018","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30321631","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32759296","id":"PMC_32759296","title":"Ascorbic Acid Promotes KIR Demethylation during Early NK Cell Differentiation.","date":"2020","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/32759296","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29869002","id":"PMC_29869002","title":"Nomenclature for the KIR of non-human species.","date":"2018","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29869002","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21150302","id":"PMC_21150302","title":"Lipids driving protein structure? Evolutionary adaptations in Kir channels.","date":"2010","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/21150302","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9635433","id":"PMC_9635433","title":"Geminin, an inhibitor of DNA replication, is degraded during mitosis.","date":"1998","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9635433","citation_count":765,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11125146","id":"PMC_11125146","title":"Inhibition of eukaryotic DNA replication by geminin binding to Cdt1.","date":"2000","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/11125146","citation_count":604,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8125298","id":"PMC_8125298","title":"Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8125298","citation_count":492,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20360068","id":"PMC_20360068","title":"Systematic analysis of human protein complexes identifies chromosome segregation proteins.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20360068","citation_count":421,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15232106","id":"PMC_15232106","title":"Self-assembling protein microarrays.","date":"2004","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15232106","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8889548","id":"PMC_8889548","title":"Normalization and subtraction: two approaches to facilitate gene discovery.","date":"1996","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/8889548","citation_count":401,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16482215","id":"PMC_16482215","title":"Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16482215","citation_count":328,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14578910","id":"PMC_14578910","title":"Radiation-mediated proteolysis of CDT1 by CUL4-ROC1 and CSN complexes constitutes a new checkpoint.","date":"2003","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14578910","citation_count":256,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15558010","id":"PMC_15558010","title":"Autonomous regulation of the anaphase-promoting complex couples mitosis to S-phase entry.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15558010","citation_count":248,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14574404","id":"PMC_14574404","title":"The DNA sequence and analysis of human chromosome 6.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/14574404","citation_count":242,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17207965","id":"PMC_17207965","title":"hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes.","date":"2007","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17207965","citation_count":222,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15159417","id":"PMC_15159417","title":"Loss of Geminin induces rereplication in the presence of functional p53.","date":"2004","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15159417","citation_count":218,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27705803","id":"PMC_27705803","title":"A High-Density Map for Navigating the Human Polycomb Complexome.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27705803","citation_count":216,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15282313","id":"PMC_15282313","title":"Rereplication by depletion of geminin is seen regardless of p53 status and activates a G2/M checkpoint.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15282313","citation_count":204,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11562349","id":"PMC_11562349","title":"Substrate recognition by the Cdc20 and Cdh1 components of the anaphase-promoting complex.","date":"2001","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/11562349","citation_count":203,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14973488","id":"PMC_14973488","title":"Direct interaction of geminin and Six3 in eye development.","date":"2004","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/14973488","citation_count":202,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9671596","id":"PMC_9671596","title":"Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation.","date":"1998","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9671596","citation_count":190,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41771,"output_tokens":1287,"usd":0.072309},"stage2":{"model":"claude-opus-4-6","input_tokens":4508,"output_tokens":3156,"usd":0.15216},"total_usd":0.466585,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":52951,"output_tokens":1935,"usd":0.093939},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4822,"output_tokens":2987,"usd":0.148177}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"GEM was identified as a novel 35-kDa GTP-binding protein belonging to the Ras superfamily, with distinct structural features including a G3 GTP-binding motif, extensive N- and C-terminal extensions beyond the Ras-related domain, and a membrane-association motif. GEM was transiently expressed in mitogen-stimulated human peripheral blood T cells, phosphorylated on tyrosine residues, and localized to the cytosolic face of the plasma membrane. Deregulated GEM expression prevented proliferation of normal and transformed 3T3 cells.\",\n      \"method\": \"Molecular cloning, GTP-binding assays, tyrosine phosphorylation assay, subcellular fractionation/localization, overexpression in 3T3 cells with proliferation readout\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery paper with multiple orthogonal methods (cloning, biochemistry, localization, functional overexpression)\",\n      \"pmids\": [\"7912851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Calmodulin (CaM) binds directly to the C-terminal extension of GEM/Kir in a Ca2+-dependent manner with ~1 nM affinity, and this binding inhibits GTP binding to GEM. A single point mutation (W269G) in the CaM-binding domain of GEM abolished the high-affinity interaction. This establishes a direct link between Ca2+/CaM signaling and the GEM GTPase.\",\n      \"method\": \"Fluorescence spectrometry (dansyl-CaM titration), gel-shift analysis, [32P]CaM overlay on GST-fusion proteins, site-directed mutagenesis (W269G), GTP-binding inhibition assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis and multiple orthogonal binding assays\",\n      \"pmids\": [\"8810259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GEM GTPase overexpression in Chinese hamster ovary (CHO) cells induced marked cell elongation, acting as a negative regulator of the Rho–Rho kinase pathway for cytoskeletal organization. Co-expression of tau antagonized GEM-induced elongation through tau's microtubule-binding domain, although tau did not bind GEM directly. GEM expression was upregulated in tau-deficient mouse brains, suggesting tau modulates GEM-mediated signal transduction.\",\n      \"method\": \"mRNA profiling from tau-deficient mice, transient overexpression in CHO cells, co-expression assays, co-IP (negative result for direct binding), domain deletion analysis\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean overexpression phenotype with domain-mapping and epistasis, but single lab\",\n      \"pmids\": [\"15087445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The crystal structure of truncated human GEM protein (G domain plus the first part of the C-terminal extension) in complex with Mg·GDP was solved at 2.1 Å resolution, revealing a canonical Ras-family G-domain fold. The C-terminal extension forms an α-helix that interacts with the α5 helix and the interswitch tip. GEM has significantly lower affinity for GDP and GTP (micromolar range) compared with H-Ras, and higher intrinsic GTPase activity than H-Ras. Both N- and C-terminal extensions regulate GTPase activity. The bulky DXWEX motif in switch II affects switch I conformation and the phosphate-binding site.\",\n      \"method\": \"X-ray crystallography (2.1 Å), fluorescence-based nucleotide binding assays, GTPase activity assay, truncation mutant analysis\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with biochemical characterization and mutagenesis in a single study\",\n      \"pmids\": [\"17107948\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GEM is a Ras-superfamily small GTPase (RGK family) that is transiently expressed at the cytosolic face of the plasma membrane upon mitogenic stimulation, binds GDP/GTP with unusually low affinity and elevated intrinsic GTPase activity (regulated by its N- and C-terminal extensions as revealed by crystal structure), is inhibited in nucleotide binding by Ca2+/calmodulin interaction with its C-terminal extension, negatively regulates the Rho–Rho kinase cytoskeletal pathway to control cell morphology and proliferation, and is phosphorylated on tyrosine residues downstream of receptor signaling.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nThe target gene is **GEM** — the human GEM GTPase (also called Kir/Gem), a Ras-family small GTPase (RGK family). Key papers: PMID:7912851 (original discovery), PMID:8810259 (calmodulin binding), PMID:17107948 (crystal structure), PMID:15087445 (morphological role).\n\n- Papers about KIR (Killer Immunoglobulin-like Receptors) → EXCLUDE (alias collision: \"KIR\" is a different gene/protein family)\n- Papers about Kir (inward rectifying K+ channels) → EXCLUDE (alias collision)\n- Papers about Geminin (GMNN) → EXCLUDE (different gene, shares \"Gem\" nickname)\n- Papers about GEM plant protein → EXCLUDE (symbol collision, plant)\n- Papers about KIR antisense lncRNA → EXCLUDE (alt-locus product, and different gene)\n- Papers about GEM Study (Genes in Myopia) → EXCLUDE (not about the protein)\n- Papers about novoPathFinder/GEM-model → EXCLUDE (metabolic model software)\n- Papers about Perlecan \"gem\" → EXCLUDE (metaphorical use)\n- General interactome/proteomics papers (BioPlex, etc.) that incidentally include GEM → these are large-scale screens; only KEEP if they provide specific mechanistic insight about GEM protein itself\n\n**KEEP papers:**\n- PMID:7912851 — original GEM discovery\n- PMID:8810259 — calmodulin binds GEM/Kir\n- PMID:17107948 — crystal structure of GEM GTPase\n- PMID:15087445 — GEM GTPase morphological role, tau antagonism\n\nLarge interactome papers (26186194, 28514442, 33961781, 25416956, 32296183, 26496610, 26344197, 21988832) — these are genome-scale screens with no specific mechanistic findings about GEM extracted in abstracts → not useful for mechanistic extraction.\n\nPMID:15232106 (protein microarrays) — mentions Cdt1/geminin interactions but this is about Geminin (GMNN), not GEM GTPase → EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"GEM was identified as a mitogen-induced immediate-early gene encoding a 35 kDa GTP-binding protein (Ras-family, RGK subfamily) expressed in human peripheral blood T cells following mitogenic stimulation. GEM protein was found to be phosphorylated on tyrosine residues, localized to the cytosolic face of the plasma membrane, and deregulated expression prevented proliferation of normal and transformed 3T3 cells, indicating a role in receptor-mediated signal transduction.\",\n      \"method\": \"Molecular cloning, subcellular fractionation, tyrosine phosphorylation assay, GTP-binding assay, proliferation assay (overexpression in 3T3 cells)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original discovery paper with multiple orthogonal methods (cloning, localization, phosphorylation, functional overexpression phenotype)\",\n      \"pmids\": [\"7912851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Calmodulin (CaM) binds to the C-terminal extension of GEM/Kir in a strict Ca2+-dependent manner with ~1 nM affinity, and this binding inhibits GTP binding to GEM. A single point mutation W269G in the CaM-binding domain abolished the interaction. Full-length GEM and Rad proteins were confirmed to bind CaM by a [32P]CaM overlay technique. This establishes a direct link between Ca2+/CaM signaling and the RGK GTPase.\",\n      \"method\": \"Fluorescence spectrometry (dansyl-CaM titration), site-directed mutagenesis (W269G), [32P]CaM overlay assay, GTP-binding inhibition assay with GST-fusion proteins\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis and multiple orthogonal biochemical methods in single study\",\n      \"pmids\": [\"8810259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of a truncated human GEM protein (G domain plus first part of C-terminal extension) complexed with Mg·GDP was solved at 2.1 Å resolution. The G-domain fold is similar to other Ras GTPases, but the DXWEX motif in switch II (characteristic of RGK proteins) distorts switch I and the phosphate-binding site. The C-terminal extension adopts an α-helical conformation extending along the α5 helix and interacting with the interswitch. GEM's affinities for GDP and GTP are in the micromolar range (much lower than H-Ras), and GTPase activity is higher than H-Ras and regulated by both N- and C-terminal extensions.\",\n      \"method\": \"X-ray crystallography (2.1 Å), biochemical nucleotide-binding assays, GTPase activity assays with truncation mutants\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional biochemical validation, multiple methods in single rigorous study\",\n      \"pmids\": [\"17107948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GEM GTPase expression was upregulated in tau-deficient mouse brains. Overexpression of GEM GTPase in CHO cells (which lack tau) induced marked cell elongation, acting as a negative regulator of the Rho–Rho kinase pathway for cytoskeletal organization. Co-expression of tau antagonized this elongation effect, an activity attributed to tau's microtubule-binding domain (homologous domains of MAP2 and MAP4 showed similar antagonism). Tau did not bind directly to GEM GTPase, indicating the antagonism is indirect, mediated through microtubule binding.\",\n      \"method\": \"Transcriptomic profiling (tau-KO mouse brain, ~11,000 mRNAs), transient overexpression in CHO cells, co-expression rescue experiments, direct binding assay (negative result), domain mapping\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — clean overexpression phenotype with domain mapping, but indirect mechanism inferred; single lab\",\n      \"pmids\": [\"15087445\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GEM is a mitogen-induced, immediately-early RGK-family Ras GTPase that localizes to the cytosolic face of the plasma membrane, is phosphorylated on tyrosine, binds GDP/GTP with unusually low (micromolar) affinity via a structurally distinctive G domain (resolved at 2.1 Å), has its GTPase activity regulated by N- and C-terminal extensions, and is inhibited in nucleotide binding by Ca²⁺/calmodulin binding to its C-terminal extension; GEM also acts as a negative regulator of the Rho–Rho kinase cytoskeletal pathway, inducing cell elongation that is antagonized indirectly by tau's microtubule-binding activity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GEM is a Ras-superfamily small GTPase (RGK family) that is transiently induced in mitogen-stimulated T cells, localizes to the cytosolic face of the plasma membrane, is phosphorylated on tyrosine residues, and negatively regulates cell proliferation when deregulated [PMID:7912851]. Its crystal structure reveals a canonical G-domain fold with unusually low nucleotide affinity (micromolar range) and elevated intrinsic GTPase activity, both governed by its distinctive N- and C-terminal extensions and a bulky DXWEX motif in switch II [PMID:17107948]. Ca²⁺/calmodulin binds the C-terminal extension at nanomolar affinity and inhibits GTP binding, directly coupling calcium signaling to GEM's nucleotide cycle [PMID:8810259]. GEM also acts as a negative regulator of the Rho–Rho kinase cytoskeletal pathway, inducing cell elongation when overexpressed [PMID:15087445].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"The discovery of GEM established a new Ras-superfamily GTPase that is mitogen-inducible in T cells, membrane-associated, tyrosine-phosphorylated, and growth-suppressive when constitutively expressed, answering whether mitogenic signaling engages novel GTP-binding proteins with anti-proliferative feedback capacity.\",\n      \"evidence\": \"Molecular cloning, GTP-binding assays, tyrosine phosphorylation detection, subcellular fractionation, and overexpression/proliferation assays in 3T3 cells\",\n      \"pmids\": [\"7912851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No GEF, GAP, or effector identified\",\n        \"Mechanism by which GEM suppresses proliferation unknown\",\n        \"Physiological relevance of tyrosine phosphorylation not determined\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstration that Ca²⁺/calmodulin binds the GEM C-terminal extension at ~1 nM affinity and inhibits GTP loading established a direct regulatory link between calcium signaling and GEM's nucleotide cycle, answering how second-messenger pathways might modulate this atypical GTPase.\",\n      \"evidence\": \"Fluorescence spectrometry with dansyl-CaM, gel-shift, CaM overlay on GST fusions, W269G mutagenesis, and GTP-binding inhibition assays in vitro\",\n      \"pmids\": [\"8810259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo relevance of CaM-mediated GTP-binding inhibition not shown\",\n        \"Whether CaM regulation affects GEM localization or effector engagement is unknown\",\n        \"No structural detail of the GEM–CaM complex\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placing GEM as a negative regulator of the Rho–Rho kinase cytoskeletal pathway answered the question of which downstream signaling axis mediates GEM's effects on cell shape, and revealed functional antagonism between GEM and the microtubule-associated protein tau.\",\n      \"evidence\": \"Overexpression in CHO cells with morphology readout, co-expression epistasis with tau domain mutants, co-IP, and mRNA profiling of tau-knockout mouse brain\",\n      \"pmids\": [\"15087445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct biochemical interaction between GEM and Rho or Rho kinase demonstrated\",\n        \"Findings based on overexpression in a single cell type\",\n        \"Endogenous loss-of-function data for GEM's role in cytoskeletal regulation lacking\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The 2.1 Å crystal structure of the GEM G-domain with Mg·GDP explained the unusually low nucleotide affinity and high intrinsic GTPase activity through structural features in the DXWEX motif and the regulatory N- and C-terminal extensions, resolving why RGK-family GTPases differ biochemically from classical Ras proteins.\",\n      \"evidence\": \"X-ray crystallography, fluorescence-based nucleotide binding assays, GTPase activity measurements, and truncation mutant analysis\",\n      \"pmids\": [\"17107948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure of full-length GEM including the CaM-binding C-terminal region not resolved\",\n        \"No structure of GEM in complex with an effector or regulator\",\n        \"Whether GEM cycles between GTP/GDP states in vivo or is constitutively nucleotide-free remains unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological effectors of GEM, the identity of upstream GEFs/GAPs if any, the in vivo significance of tyrosine phosphorylation, and whether GEM functions primarily through Rho pathway inhibition or voltage-gated calcium channel regulation (as reported for other RGK members) remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct effector identified\",\n        \"No GEF or GAP characterized for GEM\",\n        \"Loss-of-function phenotype in animal models not established in the available timeline\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CALM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway section — those should be Reactome IDs, not GO terms. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"GEM is a Ras-superfamily small GTPase (RGK family) that is transiently induced in mitogen-stimulated T cells, localizes to the cytosolic face of the plasma membrane, is phosphorylated on tyrosine residues, and negatively regulates cell proliferation when deregulated [PMID:7912851]. Its crystal structure reveals a canonical G-domain fold with unusually low nucleotide affinity (micromolar range) and elevated intrinsic GTPase activity, both governed by its distinctive N- and C-terminal extensions and a bulky DXWEX motif in switch II [PMID:17107948]. Ca²⁺/calmodulin binds the C-terminal extension at nanomolar affinity and inhibits GTP binding, directly coupling calcium signaling to GEM's nucleotide cycle [PMID:8810259]. GEM also acts as a negative regulator of the Rho–Rho kinase cytoskeletal pathway, inducing cell elongation when overexpressed [PMID:15087445].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"The discovery of GEM established a new Ras-superfamily GTPase that is mitogen-inducible in T cells, membrane-associated, tyrosine-phosphorylated, and growth-suppressive when constitutively expressed, answering whether mitogenic signaling engages novel GTP-binding proteins with anti-proliferative feedback capacity.\",\n      \"evidence\": \"Molecular cloning, GTP-binding assays, tyrosine phosphorylation detection, subcellular fractionation, and overexpression/proliferation assays in 3T3 cells\",\n      \"pmids\": [\"7912851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No GEF, GAP, or effector identified\",\n        \"Mechanism by which GEM suppresses proliferation unknown\",\n        \"Physiological relevance of tyrosine phosphorylation not determined\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstration that Ca²⁺/calmodulin binds the GEM C-terminal extension at ~1 nM affinity and inhibits GTP loading established a direct regulatory link between calcium signaling and GEM's nucleotide cycle, answering how second-messenger pathways might modulate this atypical GTPase.\",\n      \"evidence\": \"Fluorescence spectrometry with dansyl-CaM, gel-shift, CaM overlay on GST fusions, W269G mutagenesis, and GTP-binding inhibition assays in vitro\",\n      \"pmids\": [\"8810259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo relevance of CaM-mediated GTP-binding inhibition not shown\",\n        \"Whether CaM regulation affects GEM localization or effector engagement is unknown\",\n        \"No structural detail of the GEM–CaM complex\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Placing GEM as a negative regulator of the Rho–Rho kinase cytoskeletal pathway answered the question of which downstream signaling axis mediates GEM's effects on cell shape, and revealed functional antagonism between GEM and the microtubule-associated protein tau.\",\n      \"evidence\": \"Overexpression in CHO cells with morphology readout, co-expression epistasis with tau domain mutants, co-IP, and mRNA profiling of tau-knockout mouse brain\",\n      \"pmids\": [\"15087445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct biochemical interaction between GEM and Rho or Rho kinase demonstrated\",\n        \"Findings based on overexpression in a single cell type\",\n        \"Endogenous loss-of-function data for GEM's role in cytoskeletal regulation lacking\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The 2.1 Å crystal structure of the GEM G-domain with Mg·GDP explained the unusually low nucleotide affinity and high intrinsic GTPase activity through structural features in the DXWEX motif and the regulatory N- and C-terminal extensions, resolving why RGK-family GTPases differ biochemically from classical Ras proteins.\",\n      \"evidence\": \"X-ray crystallography, fluorescence-based nucleotide binding assays, GTPase activity measurements, and truncation mutant analysis\",\n      \"pmids\": [\"17107948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structure of full-length GEM including the CaM-binding C-terminal region not resolved\",\n        \"No structure of GEM in complex with an effector or regulator\",\n        \"Whether GEM cycles between GTP/GDP states in vivo or is constitutively nucleotide-free remains unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological effectors of GEM, the identity of upstream GEFs/GAPs if any, the in vivo significance of tyrosine phosphorylation, and loss-of-function phenotypes in animal models remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct effector identified\",\n        \"No GEF or GAP characterized for GEM\",\n        \"Loss-of-function phenotype in animal models not established in the available timeline\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CALM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"GEM is a mitogen-induced, immediate-early RGK-family GTPase that localizes to the cytosolic face of the plasma membrane, is phosphorylated on tyrosine, and participates in receptor-mediated signal transduction in T cells and fibroblasts [PMID:7912851]. Its G domain binds GDP and GTP with unusually low (micromolar) affinity owing to a distinctive DXWEX motif in switch II that distorts the phosphate-binding site, and its intrinsic GTPase activity is modulated by N- and C-terminal extensions, as revealed by a 2.1 Å crystal structure [PMID:17107948]. Ca²⁺/calmodulin binds the C-terminal extension with ~1 nM affinity and inhibits GTP loading, directly coupling calcium signaling to GEM nucleotide cycling [PMID:8810259]. GEM also functions as a negative regulator of the Rho–Rho kinase cytoskeletal pathway, inducing cell elongation that is indirectly antagonized by the microtubule-binding activity of tau [PMID:15087445].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of GEM as a mitogen-induced GTPase established the existence of a Ras-related protein linking mitogenic receptor signaling to cell proliferation control.\",\n      \"evidence\": \"Molecular cloning from stimulated human T cells, subcellular fractionation, tyrosine phosphorylation assay, and overexpression-induced growth arrest in 3T3 fibroblasts\",\n      \"pmids\": [\"7912851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream effectors of GEM signaling were not identified\",\n        \"The kinase responsible for GEM tyrosine phosphorylation is unknown\",\n        \"Whether GEM acts in the GTP- or GDP-bound state for its anti-proliferative effect was not resolved\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstration that Ca²⁺/calmodulin binds the C-terminal extension and inhibits GTP loading revealed a direct regulatory link between calcium signaling and GEM nucleotide cycling.\",\n      \"evidence\": \"Fluorescence titration with dansyl-CaM, W269G point mutant ablating binding, [³²P]CaM overlay, and GTP-binding inhibition assays with recombinant GST-GEM\",\n      \"pmids\": [\"8810259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological consequences of CaM-mediated GTP-loading inhibition in cells were not tested\",\n        \"Whether CaM binding affects GEM localization or effector interactions is unknown\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that GEM overexpression induces cell elongation through inhibition of the Rho–Rho kinase pathway provided the first defined cytoskeletal effector axis for this GTPase, and revealed an indirect antagonism by tau through microtubule binding.\",\n      \"evidence\": \"Transcriptomic profiling of tau-KO mouse brain, overexpression in CHO cells, co-expression rescue with tau and MAPs, direct binding assay (negative)\",\n      \"pmids\": [\"15087445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The direct molecular target through which GEM inhibits Rho–Rho kinase signaling was not identified\",\n        \"Reliance on overexpression in a single cell type limits generalizability\",\n        \"Whether endogenous GEM levels are sufficient to modulate cytoskeletal organization in neurons or T cells is untested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The 2.1 Å crystal structure of the GEM G domain explained the biochemical basis for its unusually low nucleotide affinity and showed how the N- and C-terminal extensions regulate GTPase activity, providing a structural framework for understanding RGK-family divergence from classical Ras.\",\n      \"evidence\": \"X-ray crystallography of truncated GEM·Mg·GDP complex, nucleotide-binding and GTPase activity assays with truncation mutants\",\n      \"pmids\": [\"17107948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of full-length GEM or GEM bound to an effector or calmodulin is available\",\n        \"Whether the GTP-bound conformation differs sufficiently to act as a classical switch remains unresolved\",\n        \"The structural basis of membrane association is not captured in the truncated construct\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct effector(s) mediating GEM's anti-proliferative and cytoskeletal functions, and the in vivo physiological roles of GEM in immune cells and neurons, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No GEM effector protein has been identified by direct binding\",\n        \"Loss-of-function studies (knockout, knockdown) in physiologically relevant cell types are lacking\",\n        \"Regulation of GEM by upstream kinases is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CALM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to correct the pathway entry. Let me fix that — I accidentally included a malformed term_id. Let me re-output:\n\n```json\n{\n  \"mechanistic_narrative\": \"GEM is a mitogen-induced, immediate-early RGK-family GTPase that localizes to the cytosolic face of the plasma membrane, is phosphorylated on tyrosine, and participates in receptor-mediated signal transduction in T cells and fibroblasts [PMID:7912851]. Its G domain binds GDP and GTP with unusually low (micromolar) affinity owing to a distinctive DXWEX motif in switch II that distorts the phosphate-binding site, and its intrinsic GTPase activity is modulated by N- and C-terminal extensions, as revealed by a 2.1 Å crystal structure [PMID:17107948]. Ca²⁺/calmodulin binds the C-terminal extension with ~1 nM affinity and inhibits GTP loading, directly coupling calcium signaling to GEM nucleotide cycling [PMID:8810259]. GEM also functions as a negative regulator of the Rho–Rho kinase cytoskeletal pathway, inducing cell elongation that is indirectly antagonized by the microtubule-binding activity of tau [PMID:15087445].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of GEM as a mitogen-induced GTPase established the existence of a Ras-related protein linking mitogenic receptor signaling to cell proliferation control.\",\n      \"evidence\": \"Molecular cloning from stimulated human T cells, subcellular fractionation, tyrosine phosphorylation assay, and overexpression-induced growth arrest in 3T3 fibroblasts\",\n      \"pmids\": [\"7912851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream effectors of GEM signaling were not identified\",\n        \"The kinase responsible for GEM tyrosine phosphorylation is unknown\",\n        \"Whether GEM acts in the GTP- or GDP-bound state for its anti-proliferative effect was not resolved\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstration that Ca²⁺/calmodulin binds the C-terminal extension and inhibits GTP loading revealed a direct regulatory link between calcium signaling and GEM nucleotide cycling.\",\n      \"evidence\": \"Fluorescence titration with dansyl-CaM, W269G point mutant ablating binding, [³²P]CaM overlay, and GTP-binding inhibition assays with recombinant GST-GEM\",\n      \"pmids\": [\"8810259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological consequences of CaM-mediated GTP-loading inhibition in cells were not tested\",\n        \"Whether CaM binding affects GEM localization or effector interactions is unknown\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that GEM overexpression induces cell elongation through inhibition of the Rho–Rho kinase pathway provided the first defined cytoskeletal effector axis for this GTPase, and revealed an indirect antagonism by tau through microtubule binding.\",\n      \"evidence\": \"Transcriptomic profiling of tau-KO mouse brain, overexpression in CHO cells, co-expression rescue with tau and MAPs, direct binding assay (negative)\",\n      \"pmids\": [\"15087445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The direct molecular target through which GEM inhibits Rho–Rho kinase signaling was not identified\",\n        \"Reliance on overexpression in a single cell type limits generalizability\",\n        \"Whether endogenous GEM levels are sufficient to modulate cytoskeletal organization in neurons or T cells is untested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The 2.1 Å crystal structure of the GEM G domain explained the biochemical basis for its unusually low nucleotide affinity and showed how the N- and C-terminal extensions regulate GTPase activity, providing a structural framework for understanding RGK-family divergence from classical Ras.\",\n      \"evidence\": \"X-ray crystallography of truncated GEM·Mg·GDP complex, nucleotide-binding and GTPase activity assays with truncation mutants\",\n      \"pmids\": [\"17107948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of full-length GEM or GEM bound to an effector or calmodulin is available\",\n        \"Whether the GTP-bound conformation differs sufficiently to act as a classical switch remains unresolved\",\n        \"The structural basis of membrane association is not captured in the truncated construct\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct effector(s) mediating GEM's anti-proliferative and cytoskeletal functions, and the in vivo physiological roles of GEM in immune cells and neurons, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No GEM effector protein has been identified by direct binding\",\n        \"Loss-of-function studies (knockout, knockdown) in physiologically relevant cell types are lacking\",\n        \"Regulation of GEM by upstream kinases is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CALM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}