Affinage

INS

Insulin · UniProt P01308

Round 2 corrected
Length
110 aa
Mass
12.0 kDa
Annotated
2026-04-28
130 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Insulin is a peptide hormone encoded by the INS gene that serves as the master regulator of glucose homeostasis through receptor-mediated signaling in muscle, fat, liver, bone, and brain. Preproinsulin folds in the endoplasmic reticulum, assembles into zinc hexamers for regulated secretory storage, and is processed to mature insulin; missense mutations that disrupt folding cause ER stress and permanent neonatal diabetes (PMID:9631292, PMID:17855560). Upon secretion, insulin binds its receptor tyrosine kinase to activate the PI3K/PKB(Akt) cascade, which inhibits GSK3 to promote glycogen synthesis, suppresses NFκB-driven inflammation, and—in osteoblasts—stimulates osteocalcin activation to coordinate systemic glucose metabolism (PMID:8524413, PMID:11443198, PMID:20655470). INS transcription is regulated by the upstream VNTR/IDDM2 locus, where class III alleles drive higher thymic INS expression that promotes immune self-tolerance and protects against type 1 diabetes (PMID:7773291, PMID:9054944).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1980 High

    Determining the genomic organization of human INS—two introns interrupting the coding sequence and upstream regulatory elements—established the physical framework needed to study its transcriptional regulation and processing.

    Evidence DNA sequencing and comparison with rat insulin gene

    PMID:6243748

    Open questions at the time
    • Functional roles of intronic sequences not yet defined
    • Upstream regulatory elements only identified, not functionally tested
  2. 1995 High

    Two key mechanistic questions were resolved: (1) the IDDM2 susceptibility locus was mapped directly to the INS VNTR, linking allelic variation to transcriptional output and type 1 diabetes risk, and (2) insulin's metabolic signaling cascade was ordered—PI3K activates PKB/Akt, which inhibits GSK3 independently of MAPK pathways—explaining how insulin drives glycogen synthesis.

    Evidence Cross-match haplotype/LD mapping with in vivo INS mRNA quantification; in vivo kinase assays with PI3-kinase inhibitors and pharmacological blockade of parallel pathways

    PMID:7773291 PMID:8524413

    Open questions at the time
    • Mechanism by which VNTR alleles alter transcription not yet identified
    • Cell-type-specific differences in PI3K/Akt vs. MAPK usage not resolved
    • Identity of tissues where VNTR-driven INS expression confers disease protection unknown
  3. 1997 High

    The discovery of INS expression in human fetal thymus—at levels controlled by VNTR class—provided a mechanistic explanation for the dominant protective effect of class III alleles: higher thymic insulin promotes central immune tolerance to insulin.

    Evidence RT-PCR quantification of INS mRNA in fetal thymus stratified by VNTR genotype

    PMID:9054944

    Open questions at the time
    • Direct demonstration of tolerogenic T-cell deletion in response to thymic insulin not shown
    • Contribution of thymic INS expression relative to peripheral tolerance mechanisms unclear
  4. 1998 High

    The biosynthetic pathway from preproinsulin to stored mature hormone was consolidated: ER folding, proinsulin assembly into zinc hexamers, and regulated secretory granule maturation explained how beta cells produce and store active insulin.

    Evidence Structural, chemical, and genetic analyses including transgenic animals and transfected cells

    PMID:9631292

    Open questions at the time
    • Specific chaperones governing proinsulin folding in the ER not fully catalogued
    • Mechanisms controlling hexamer-to-monomer conversion upon secretion not resolved
  5. 1998 High

    Identification of insulin as a physiological competitive substrate of insulin-degrading enzyme (IDE) revealed a clearance mechanism with implications for amyloid-beta metabolism, since insulin competitively blocks IDE-mediated Aβ degradation.

    Evidence Purification of IDE from conditioned medium, competitive substrate assay, immunodepletion

    PMID:9830016

    Open questions at the time
    • In vivo relevance of insulin–Aβ competition for IDE not established
    • Relative contribution of IDE versus other insulin-degrading pathways not quantified
  6. 2000 Medium

    The mechanistic link between the VNTR and INS transcription was advanced by showing that ILPR repeats form G-quartet DNA structures whose stability correlates with transcriptional activity, providing a structural basis for allele-specific regulation.

    Evidence In vitro G-quartet formation assays combined with transcription reporter assays

    PMID:11070077

    Open questions at the time
    • G-quartet formation demonstrated only in vitro; in vivo evidence lacking
    • Trans-acting factors recognizing G-quartets at the ILPR not identified
  7. 2001 High

    The downstream signaling network was elaborated: insulin receptor activation branches into PI3K/Akt (glucose uptake, glycogen synthesis) and Ras/MAPK (gene expression) arms, and insulin was shown to exert direct anti-inflammatory effects via NFκB suppression and IκB induction in human mononuclear cells.

    Evidence Biochemical pathway analysis with receptor mutagenesis; controlled human insulin infusion with nuclear NFκB quantification and ROS/cytokine measurements

    PMID:11443198 PMID:11742412

    Open questions at the time
    • Molecular mechanism of NFκB suppression by insulin not fully delineated
    • Tissue-specific versus systemic contribution of anti-inflammatory insulin signaling unclear
  8. 2002 High

    The functional significance of insulin receptor isoforms was established: IR-A/IGF-IR hybrid receptors respond to insulin, IGF-I, and IGF-II, whereas IR-B hybrids respond primarily to IGF-I, explaining how receptor isoform expression dictates tissue-specific responses to circulating ligands.

    Evidence Cotransfection of IR isoforms with IGF-IR in R(−) cells, ligand binding, substrate phosphorylation, and proliferation/migration assays

    PMID:12138094

    Open questions at the time
    • Relative abundance of hybrid receptor types in normal human tissues not quantified
    • Downstream signaling specificity of hybrid versus homodimeric receptors not fully mapped
  9. 2006 Medium

    A second functional IDDM2 variant was identified: the IVS1-6A/T (−23HphI) SNP controls alternative splicing of INS intron 1, with the A allele producing longer 5′ leader mRNAs that yield more proinsulin, linking splicing regulation to disease-associated variation in insulin output.

    Evidence Minigene splicing reporter in multiple cell lines with proinsulin secretion measurement

    PMID:16380501

    Open questions at the time
    • Effect size in primary beta cells not confirmed
    • Interaction between −23HphI splicing effect and VNTR-mediated transcriptional regulation not dissected
  10. 2007 High

    Human genetics directly linked INS coding mutations to permanent neonatal diabetes: ten heterozygous preproinsulin mutations disrupt protein folding, cause ER stress, and kill beta cells—mirroring the Akita mouse—establishing misfolded proinsulin as a monogenic diabetes mechanism.

    Evidence Linkage analysis, candidate gene sequencing, structural modeling; corroboration with Akita and Munich mouse models

    PMID:17855560

    Open questions at the time
    • Quantitative relationship between ER stress burden and beta-cell death threshold not determined
    • Potential for pharmacological chaperone rescue not tested
  11. 2010 High

    A novel endocrine circuit was uncovered: insulin signaling in osteoblasts promotes osteoclastic bone resorption, which decarboxylates and activates osteocalcin; active osteocalcin then feeds back to enhance whole-body glucose homeostasis, extending insulin's role beyond classical metabolic tissues.

    Evidence Osteoblast-specific insulin receptor knockout mice with osteocalcin carboxylation assays and glucose homeostasis measurements

    PMID:20655470

    Open questions at the time
    • Quantitative contribution of bone-derived osteocalcin to systemic glucose control in humans not established
    • Whether the insulin–osteocalcin axis is dysregulated in human diabetes not shown
  12. 2021 Medium

    The molecular basis of insulin resistance was integrated: lipid intermediates (ceramide, diacylglycerol) accumulate and impair the IR→IRS→Akt cascade, with adipose tissue dysfunction serving as a primary driver that propagates resistance to muscle, liver, and other tissues.

    Evidence Synthesis of human genetics, mouse models, and lipid intermediate measurements

    PMID:34285405

    Open questions at the time
    • Relative contributions of individual lipid species to signaling node inhibition not fully resolved
    • Therapeutic targets within the ceramide pathway not validated in humans

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the precise ER chaperone network governing proinsulin folding, the in vivo role of G-quartet structures at the VNTR, the mechanistic basis of insulin's NFκB suppression, and whether pharmacological chaperones can rescue misfolded-proinsulin neonatal diabetes.
  • Proinsulin ER folding chaperones incompletely identified
  • In vivo evidence for G-quartet-mediated transcriptional regulation absent
  • Molecular mechanism of insulin-driven NFκB suppression unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3 GO:0005783 endoplasmic reticulum 2 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-392499 Metabolism of proteins 2
Partners
AKT1BGLAPGSK3BIDEIGF1RINSRPIK3CA
Complex memberships
Zinc-insulin hexamer

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1980 The human insulin gene (INS) contains two intervening sequences (introns): one within the 5'-untranslated region and one interrupting the C-peptide-encoding region, establishing the pre-mRNA structure and identifying potential regulatory regions upstream of the gene. DNA sequencing and comparison with rat insulin gene Nature High 6243748
1995 IDDM2 susceptibility to type 1 diabetes maps to within the insulin gene VNTR minisatellite itself; allelic variation at the VNTR correlates with levels of INS transcription in the pancreas in vivo, implicating transcriptional regulation as the disease mechanism. Cross-match haplotype analysis, linkage disequilibrium mapping, in vivo INS mRNA quantification by allele Nature genetics High 7773291
1995 Insulin inhibits glycogen synthase kinase-3 (GSK3) in vivo through protein kinase B (PKB/Akt), independently of MAPKAP kinase-1 and p70S6K; this places PKB downstream of PI 3-kinase in the insulin signaling cascade leading to GSK3 inhibition and glycogen synthesis. In vivo kinase assays with PI 3-kinase inhibitors, immunoprecipitation kinase assays, pharmacological blockade of parallel pathways Nature High 8524413
1997 Insulin (INS) is expressed in human fetal thymus, and class III VNTR alleles at IDDM2 are associated with 2- to 3-fold higher INS mRNA levels in thymus compared to class I alleles, suggesting that thymic INS expression promotes immune tolerance and explains the dominant protective effect of class III alleles against type 1 diabetes. RT-PCR quantification of INS mRNA in fetal thymus tissues stratified by VNTR genotype Nature genetics High 9054944
1998 Insulin-degrading enzyme (IDE) is the principal extracellular protease capable of degrading secreted amyloid beta-protein (Aβ); insulin competitively inhibits IDE-mediated Aβ degradation, and IDE immunodepletion removes Aβ-degrading activity from conditioned medium, establishing insulin as a physiological competitive substrate of IDE. Purification of IDE from conditioned medium, competitive inhibition assay with insulin, immunodepletion with anti-IDE antibody, CSF identification The Journal of biological chemistry High 9830016
1998 Insulin is synthesized as preproinsulin with an N-terminal signal sequence and a C-peptide connecting the A and B chains; proinsulin folds in the ER and assembles into zinc-containing hexamers, and these assembly states are exploited during progression through the regulated secretory pathway to mature insulin storage as microcrystals. Structural, chemical, and genetic analyses; transgenic animal and transfected cell experiments Current opinion in structural biology High 9631292
2000 The insulin-linked polymorphic region (ILPR/IDDM2) upstream of the human INS gene forms G-quartet DNA structures in vitro; the ability to form inter- and intramolecular G-quartets correlates with transcriptional activity of the insulin gene, with single nucleotide differences affecting both G-quartet formation and transcriptional output. G-quartet formation assays, designed high-activity ILPR repeats, transcription reporter assays Proceedings of the National Academy of Sciences of the United States of America Medium 11070077
2001 Insulin signaling activates a complex network downstream of the insulin receptor including the PI 3-kinase/Akt pathway controlling glucose uptake and glycogen synthesis, and the Ras/MAPK pathway controlling gene expression; tissues such as muscle, fat, and liver exhibit insulin resistance when these pathways are attenuated. Biochemical pathway analysis, receptor mutagenesis, downstream kinase assays across multiple cell types Nature High 11742412
2001 Acute insulin infusion in obese subjects suppresses intranuclear NFκB and increases IκB in mononuclear cells, reduces reactive oxygen species generation and p47phox (NADPH oxidase subunit), and lowers plasma sICAM-1, MCP-1, and PAI-1, demonstrating a direct anti-inflammatory signaling action of insulin. Controlled human infusion study with nuclear NFκB quantification, ROS assay, cytokine measurement; dextrose and saline controls The Journal of clinical endocrinology and metabolism Medium 11443198
2002 Insulin/IGF-I hybrid receptors containing the IR-A isoform (Hybrid-Rs-A) bind and are activated by IGF-I, IGF-II, and insulin, leading to activation of the IGF-IR beta-subunit and the IGF-IR-specific substrate CrkII; hybrid receptors containing IR-B are activated with high affinity only by IGF-I, establishing that the IR isoform determines the signaling specificity and biological responses (proliferation, migration) of hybrid receptors. Cotransfection of IR-A or IR-B with IGF-IR in R(-) cells, ligand binding assays, substrate phosphorylation, proliferation/migration assays The Journal of biological chemistry High 12138094
2006 The INS intronic variant IVS1-6A/T (-23HphI) is a key functional SNP that controls alternative splicing of INS intron 1 through differential recognition of its 3' splice site; the A allele increases production of mature transcripts with a long 5' leader, and these extended mRNAs generate more proinsulin in culture supernatants, establishing -23HphI as a functional IDDM2 variant affecting INS expression via splicing. Minigene reporter splicing assay in multiple cell lines, proinsulin secretion measurement, expressed sequence tag analysis Diabetes Medium 16380501
2007 Ten heterozygous mutations in the human INS gene cause permanent neonatal diabetes; the mutations are in critical regions of preproinsulin and are predicted to prevent normal protein folding, leading to endoplasmic reticulum stress and beta cell death, analogous to the Akita mouse model (Ins2 mutation). Linkage analysis, candidate gene sequencing, structural modeling of preproinsulin folding; comparison with Akita/Munich mouse models Proceedings of the National Academy of Sciences of the United States of America High 17855560
2009 Insulin prevents pathogenic binding of Aβ oligomers (ADDLs) to hippocampal synapses and protects against ADDL-induced loss of surface insulin receptors, oxidative stress, and synaptic spine deterioration; this protection requires insulin receptor tyrosine kinase activity and works through IR signaling-dependent downregulation of ADDL binding sites, not ligand competition. Hippocampal neuron culture, ADDL binding assay, spine imaging, IR kinase inhibition, CaMKII/CK2 inhibitors Proceedings of the National Academy of Sciences of the United States of America Medium 19188609
2010 Insulin signaling in osteoblasts is required for whole-body glucose homeostasis; insulin acts in osteoblasts to increase osteocalcin activity by promoting osteoclastic bone resorption (which occurs at acidic pH sufficient to decarboxylate and thereby activate osteocalcin), establishing a feed-forward endocrine loop in which insulin in osteoblasts activates a bone-derived hormone that in turn promotes glucose metabolism. Osteoblast-specific insulin receptor knockout mice, osteocalcin carboxylation assays, glucose homeostasis measurements, bone resorption manipulation Cell High 20655470
2021 Insulin resistance arises from perturbation of the intracellular signaling cascade downstream of the insulin receptor (IR, IRS proteins, AKT), caused by accumulation of lipid intermediates including ceramide; adipose tissue plays a key initiating role by releasing lipids and circulating factors that promote insulin resistance in muscle, liver, and other organs. Genetic and biochemical studies integrating human genetics, mouse models, and lipid intermediate measurements Nature reviews. Molecular cell biology Medium 34285405

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 4366 8524413
2001 Insulin signalling and the regulation of glucose and lipid metabolism. Nature 3784 11742412
2017 YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell research 1488 28106072
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature genetics 1382 19430480
1995 Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science (New York, N.Y.) 1182 7716547
2007 Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature genetics 1174 17554260
1994 A genome-wide search for human type 1 diabetes susceptibility genes. Nature 1167 8072542
2009 Eukaryotic stress granules: the ins and outs of translation. Molecular cell 1166 20064460
1986 Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucose. Cell 1137 3518947
2002 Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 1074 12086926
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2010 Insulin signaling in osteoblasts integrates bone remodeling and energy metabolism. Cell 857 20655470
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1998 Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. The Journal of biological chemistry 681 9830016
2011 The outs and the ins of sphingosine-1-phosphate in immunity. Nature reviews. Immunology 676 21546914
1997 Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nature genetics 659 9054944
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1995 Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nature genetics 628 7773291
1999 Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation. The Journal of biological chemistry 626 10383393
2001 Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? The Journal of clinical endocrinology and metabolism 588 11443198
2004 Checking on DNA damage in S phase. Nature reviews. Molecular cell biology 584 15459660
2008 Genotype score in addition to common risk factors for prediction of type 2 diabetes. The New England journal of medicine 580 19020323
2004 The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. The Biochemical journal 569 15005655
2008 Shared and distinct genetic variants in type 1 diabetes and celiac disease. The New England journal of medicine 566 19073967
2009 Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proceedings of the National Academy of Sciences of the United States of America 538 19188609
1994 The ins and outs of Raf kinases. Trends in biochemical sciences 492 7855890
2004 The ins and outs of lysophosphatidic acid signaling. BioEssays : news and reviews in molecular, cellular and developmental biology 474 15273989
2021 The aetiology and molecular landscape of insulin resistance. Nature reviews. Molecular cell biology 464 34285405
1980 Sequence of the human insulin gene. Nature 457 6243748
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1996 Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. The Journal of biological chemistry 423 8702995
2007 A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 422 17632545
2007 Insulin gene mutations as a cause of permanent neonatal diabetes. Proceedings of the National Academy of Sciences of the United States of America 416 17855560
2009 The ins and outs of leukocyte integrin signaling. Annual review of immunology 413 19302044
1998 The role of assembly in insulin's biosynthesis. Current opinion in structural biology 406 9631292
2002 Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. The Journal of biological chemistry 393 12138094
2008 Ins and outs of major facilitator superfamily antiporters. Annual review of microbiology 380 18537473
2003 The ins and outs of fibronectin matrix assembly. Journal of cell science 363 12857786
1997 The ins and outs of notch signaling. Molecular and cellular neurosciences 327 9245493
1994 The ins and outs of the transmembrane 4 superfamily. Immunology today 325 7531445
2005 The ins and outs of DNA transfer in bacteria. Science (New York, N.Y.) 320 16322448
2015 The ins and outs of the striatum: role in drug addiction. Neuroscience 319 26116518
2009 The 'ins' and 'outs' of flavonoid transport. Trends in plant science 309 20006535
2004 The ins and outs of E-cadherin trafficking. Trends in cell biology 306 15308209
2006 The ins and outs of cytochrome P450s. Biochimica et biophysica acta 300 16920266
2001 The ins and outs of calreticulin: from the ER lumen to the extracellular space. Trends in cell biology 286 11306273
1991 Perspectives in S-100 protein biology. Review article. Cell calcium 276 1769063
2008 Ins and outs of ADF/cofilin activity and regulation. European journal of cell biology 268 18499298
2007 The ins and outs of the plant cell cycle. Nature reviews. Molecular cell biology 267 17643126
2005 The ins and outs of sphingolipid synthesis. Trends in cell biology 267 15953549
2018 The enigmatic endosome - sorting the ins and outs of endocytic trafficking. Journal of cell science 258 29980602
2000 The ins and outs of DNA fingerprinting the infectious fungi. Clinical microbiology reviews 247 10756003
2003 The ins and outs of aquaporin-2 trafficking. American journal of physiology. Renal physiology 236 12676734
2015 The ins and outs of mitochondrial calcium. Circulation research 228 25999421
2014 Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombe. Nature 217 25307058
2017 The ins and outs of endoplasmic reticulum-controlled lipid biosynthesis. EMBO reports 215 29074503
2006 The ins and outs of MYC regulation by posttranslational mechanisms. The Journal of biological chemistry 213 16987807
2004 The ins and outs of mitochondrial dysfunction in NASH. Diabetes & metabolism 205 15223984
2015 The ins and outs of RND efflux pumps in Escherichia coli. Frontiers in microbiology 195 26113845
2011 The ins and outs of HIV-1 Tat. Traffic (Copenhagen, Denmark) 195 21951552
2004 Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 174 15220214
2012 Calreticulin in the immune system: ins and outs. Trends in immunology 161 22959412
2008 T cell trafficking in allergic asthma: the ins and outs. Annual review of immunology 152 18304002
2003 The ins and outs of leptin receptor activation. FEBS letters 149 12829235
1999 The ins and outs of HIV Rev. Archives of biochemistry and biophysics 143 10328811
2011 The ins and outs of pertussis toxin. The FEBS journal 141 21740523
2014 SPASM and twitch domains in S-adenosylmethionine (SAM) radical enzymes. The Journal of biological chemistry 133 25477505
2002 The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1. Diabetes 128 12031988
2016 The ins and outs of muscle stem cell aging. Skeletal muscle 123 26783424
2008 The ins and outs of GPR30: a transmembrane estrogen receptor. The Journal of steroid biochemistry and molecular biology 123 18406603
2000 Sip2p and its partner snf1p kinase affect aging in S. cerevisiae. Genes & development 120 10921902
2001 The ins and outs of nucleosome assembly. Current opinion in genetics & development 119 11250135
2010 The ins and outs of cholesterol in the vertebrate retina. Journal of lipid research 118 20861164
1998 The ins and outs of peptide signaling. Trends in microbiology 114 9717218
2020 From Synthesis to Utilization: The Ins and Outs of Mitochondrial Heme. Cells 101 32121449
2016 The "ins and outs" of complement-driven immune responses. Immunological reviews 100 27782335
2008 The ins and outs of syntenin, a multifunctional intracellular adaptor protein. Journal of cell science 99 18434645
2020 Cu Homeostasis in Bacteria: The Ins and Outs. Membranes 98 32962054
2019 Principles of meiotic chromosome assembly revealed in S. cerevisiae. Nature communications 97 31641121
2003 The ins, outs and roundabouts of malaria. Trends in parasitology 94 12763426
2000 Unusual DNA structure of the diabetes susceptibility locus IDDM2 and its effect on transcription by the insulin promoter factor Pur-1/MAZ. Proceedings of the National Academy of Sciences of the United States of America 94 11070077
2014 Flowers under pressure: ins and outs of turgor regulation in development. Annals of botany 91 25288632
2022 Ins and outs of AlphaFold2 transmembrane protein structure predictions. Cellular and molecular life sciences : CMLS 90 35034173
2020 Regulation of coenzyme A levels by degradation: the 'Ins and Outs'. Progress in lipid research 88 32234503
1994 The ins and outs of programmed cell death during C. elegans development. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 87 7846120
1998 The ins and outs of a molecular chaperone machine. Trends in biochemical sciences 85 9584617
2017 The Ins and Outs of Aurora B Inner Centromere Localization. Frontiers in cell and developmental biology 84 29312936
2016 The Ins and Outs of Anthrax Toxin. Toxins 84 26978402
2003 The outs and ins of bacterial type IV secretion substrates. Trends in microbiology 82 14607070
2018 The ins and outs of iron: Escorting iron through the mammalian cytosol. Free radical biology & medicine 80 30321701
2015 The ins and outs of lncRNA structure: How, why and what comes next? Biochimica et biophysica acta 80 26325022
2016 The Ins and Outs of Lipid Flip-Flop. Accounts of chemical research 79 27959517
2005 "Ins and outs" of seven-transmembrane receptor signalling to ERK. Trends in endocrinology and metabolism: TEM 79 15620546
2000 The ins and outs of EBV infection. Trends in microbiology 77 10754578
2002 Multivesicular bodies and multivesicular endosomes: the "ins and outs" of endosomal traffic. Science's STKE : signal transduction knowledge environment 76 12122203
2004 The ins and outs of Wingless signaling. Trends in cell biology 75 14729180
2011 The ins and outs of cellular Ca(2+) transport. Current opinion in plant biology 74 21865080
2018 The ins and outs of vesicular monoamine transporters. The Journal of general physiology 73 29666153
1997 Protein transports: the nonclassical ins and outs. Current biology : CB 73 9115389
2006 Encoding the ins and outs of circadian pacemaking. Journal of biological rhythms 71 17107937
2000 Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21. Human molecular genetics 71 10814711
2012 The INs and OUTs of pattern recognition receptors at the cell surface. Current opinion in plant biology 70 22664220
2008 lnterleukin-16: the ins and outs of regulating T-cell activation. Critical reviews in immunology 69 19265505
2011 The ins and outs of Mycobacterium tuberculosis protein export. Tuberculosis (Edinburgh, Scotland) 68 22192870
2020 Transporter engineering in microbial cell factories: the ins, the outs, and the in-betweens. Current opinion in biotechnology 57 32927362
2001 The HLA-DPB1--associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1. Diabetes 57 11334427
2003 The ins and outs of STAT1 nuclear transport. Science's STKE : signal transduction knowledge environment 55 12915721
2021 Ins and outs of cadmium-induced carcinogenesis: Mechanism and prevention. Cancer treatment and research communications 54 33865114
2022 The ins and outs of Bacillus proteases: activities, functions and commercial significance. FEMS microbiology reviews 53 34410368
2020 The ins and outs of host-microsporidia interactions during invasion, proliferation and exit. Cellular microbiology 50 32748538
2011 The ins and outs of hematopoietic stem cells: studies to improve transplantation outcomes. Stem cell reviews and reports 50 21140298
2006 Variants in the human insulin gene that affect pre-mRNA splicing: is -23HphI a functional single nucleotide polymorphism at IDDM2? Diabetes 49 16380501
2015 The Ins and Outs of B Cells in Multiple Sclerosis. Frontiers in immunology 48 26594215
2014 The ins and outs of serine integrase site-specific recombination. Current opinion in structural biology 48 24509164
1999 Expression, processing, and secretion of the neuroendocrine VGF peptides by INS-1 cells. Endocrinology 47 10433233
2021 The Ins and Outs of RAS Effector Complexes. Biomolecules 46 33562401
2009 Roles of human AND-1 in chromosome transactions in S phase. The Journal of biological chemistry 44 19439411
2014 The ins and outs of fibroblast growth factor receptor signalling. Clinical science (London, England : 1979) 43 24780002
2008 Expression and function of alphabeta1 integrins in pancretic beta (INS-1) cells. Journal of cell communication and signaling 43 19023675
2006 MEF immortalization to investigate the ins and outs of mutagenesis. Carcinogenesis 42 16777987
2006 The genomic repertoire for cell cycle control and DNA metabolism in S. purpuratus. Developmental biology 42 17078944
2009 The ins and outs of Na(+) bioenergetics in Acetobacterium woodii. Biochimica et biophysica acta 41 19167341
1994 The ins and outs of protein splicing elements. Molecular microbiology 40 8065257
2017 Survivin and autoimmunity; the ins and outs. Immunology letters 39 29155234
2019 Enzyme-fusion strategies for redirecting and improving carotenoid synthesis in S. cerevisiae. Metabolic engineering communications 38 30723675
2004 hIan5: the human ortholog to the rat Ian4/Iddm1/lyp is a new member of the Ian family that is overexpressed in B-cell lymphoid malignancies. Genes and immunity 37 14724691
2004 The ins and outs of RNAi in mammalian cells. Current pharmaceutical biotechnology 36 15544492
2023 Asymmetric distribution of parental H3K9me3 in S phase silences L1 elements. Nature 35 37938774