Affinage

KL

Klotho · UniProt Q9UEF7

Round 2 corrected
Length
1012 aa
Mass
116.2 kDa
Annotated
2026-04-28
130 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

α-Klotho (KL) is a single-pass transmembrane protein that functions as an obligate non-enzymatic co-receptor for endocrine FGF23 signaling and as a secreted antagonist of multiple pro-fibrotic, pro-calcific, and pro-inflammatory pathways, thereby acting as a systemic suppressor of aging-related pathologies. The shed ectodomain simultaneously tethers FGFR1c and FGF23 into a ternary complex that governs renal phosphate and vitamin D homeostasis; loss-of-function mutations in mice cause a premature aging syndrome, and a human homozygous KL missense mutation (H193R) causes tumoral calcinosis with hyperphosphatemia (PMID:9363890, PMID:29342138, PMID:17710231). Secreted Klotho additionally binds the type-II TGF-β receptor to block TGF-β1 signaling and EMT, binds Wnt ligands to antagonize β-catenin–dependent transcription and fibrosis, and interacts with the IGF-1 receptor to suppress mitogenic signaling in cancer cells (PMID:21209102, PMID:23559584, PMID:18762812). Intracellular Klotho suppresses the senescence-associated secretory phenotype by binding and inhibiting RIG-I, while age-related epigenetic silencing of the KL promoter via H3K27me3 accumulation (due to reduced JMJD3 demethylase) underlies declining KL expression in renal tubules (PMID:21336305, PMID:32223380).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1997 High

    The foundational question of whether a single gene could coordinate mammalian aging-like phenotypes was answered when disruption of the klotho locus produced a syndrome resembling premature aging, establishing KL as a systemic aging suppressor.

    Evidence Homozygous loss-of-function mouse with comprehensive phenotypic characterization (lifespan, vascular, skeletal, skin, pulmonary defects)

    PMID:9363890

    Open questions at the time
    • Mechanism of action (endocrine vs. paracrine vs. enzymatic) unknown
    • Relevant ligands or signaling pathways not identified
    • Human relevance undemonstrated
  2. 1998 High

    Characterization of the human KL gene structure resolved how two protein forms (membrane-bound and secreted) arise from a single locus, establishing that the secreted isoform predominates and raising the question of distinct functions for each form.

    Evidence cDNA cloning and alternative splicing analysis of human KL

    PMID:9464267

    Open questions at the time
    • Functional distinction between transmembrane and secreted forms unresolved
    • Ectodomain shedding as an additional source of soluble Klotho not yet known
  3. 2004 High

    Detection of a 130 kDa Klotho protein in serum and CSF—larger than the splice-derived secreted form—revealed that ectodomain shedding from the membrane form is a major source of circulating Klotho, establishing it as a bona fide humoral factor.

    Evidence Immunoblotting with novel anti-Klotho antibodies in serum and cerebrospinal fluid

    PMID:15135068

    Open questions at the time
    • Identity of the sheddase(s) responsible unknown
    • Relative physiological contribution of shed vs. alternatively spliced secreted form unresolved
  4. 2006 High

    The central mechanistic question of how Klotho suppresses aging was substantially answered by the discovery that Klotho converts FGFR1c into a high-affinity FGF23 receptor, directly linking Klotho to phosphate and vitamin D homeostasis.

    Evidence Co-immunoprecipitation of Klotho–FGF23 from renal homogenates; forced expression restoring FGF23 signaling; in vivo antibody neutralization

    PMID:17086194

    Open questions at the time
    • Atomic-resolution structure of the ternary complex not yet available
    • Whether Klotho has additional co-receptor-independent functions remained open
  5. 2007 High

    A human loss-of-function mutation (H193R) causing tumoral calcinosis validated KL as essential for human FGF23 signaling and mineral homeostasis, while structural analysis of endocrine FGFs explained why Klotho co-receptorship evolved to compensate for reduced heparan sulfate affinity.

    Evidence Human H193R homozygous mutation with in vitro functional assays; crystal structures of FGF23/FGF19

    PMID:17339340 PMID:17710231

    Open questions at the time
    • Structural basis of Klotho–FGFR–FGF23 ternary interaction not yet solved
    • Whether H193R abolishes putative glycosidase activity or merely destabilizes the protein unclear
  6. 2008 High

    A human gain-of-function translocation elevating plasma Klotho caused hypophosphatemic rickets, establishing that both too little and too much Klotho disrupt mineral balance, while Klotho's interaction with the IGF-1 receptor revealed tumor-suppressive activity independent of FGF23.

    Evidence Human translocation with elevated circulating Klotho and FGF23; Co-IP of Klotho with IGF-1R in breast cancer cells with proliferation assays

    PMID:18308935 PMID:18762812

    Open questions at the time
    • Structural basis of Klotho–IGF-1R interaction unknown
    • Whether IGF-1R binding is direct or scaffold-mediated not resolved
    • In vivo tumor suppression by endogenous Klotho not demonstrated
  7. 2010 High

    Direct anti-calcific effects of Klotho on vascular smooth muscle cells, independent of systemic phosphate lowering, established the vasculature as a Klotho target tissue relevant to CKD-associated calcification.

    Evidence Klotho-overexpressing and haploinsufficient mice in CKD models; in vitro phosphate uptake and mineralization assays in VSMCs

    PMID:21115613 PMID:22492635

    Open questions at the time
    • Molecular target on VSMCs mediating phosphate uptake inhibition not identified
    • Whether vascular Klotho acts via FGF23-dependent or -independent mechanisms debated
  8. 2011 High

    Two previously unknown Klotho activities were discovered: secreted Klotho directly binds the TGF-β type-II receptor to block TGF-β1-induced EMT and fibrosis, while intracellular Klotho binds RIG-I to suppress the senescence-associated secretory phenotype, functionally separating extracellular from intracellular Klotho roles.

    Evidence Direct binding assays (Klotho–TGFβRII); Co-IP of intracellular Klotho–RIG-I; in vivo fibrosis and metastasis models; SASP cytokine measurement

    PMID:21209102 PMID:21336305

    Open questions at the time
    • Structural basis of Klotho–TGFβRII interaction unknown
    • Stoichiometry and affinity of Klotho–RIG-I interaction not defined
    • Whether intracellular Klotho pool is regulated independently of membrane/secreted forms unclear
  9. 2013 High

    Discovery that Klotho directly binds Wnt ligands (Wnt1, Wnt4, Wnt7a) to antagonize β-catenin signaling unified the anti-fibrotic effects of Klotho under a model in which it simultaneously blocks TGF-β and Wnt pathways converging on renal fibrosis.

    Evidence Direct binding assay of Klotho to Wnt ligands; β-catenin nuclear translocation assays; rescue in two CKD mouse models

    PMID:23559584

    Open questions at the time
    • Whether Klotho–Wnt binding is glycosidase-domain-dependent unknown
    • Relative contribution of Wnt vs. TGF-β antagonism to in vivo fibrosis protection not dissected
  10. 2018 High

    The crystal structure of the α-Klotho–FGFR1c–FGF23 ternary complex resolved the atomic mechanism: Klotho acts as a non-enzymatic scaffold tethering FGFR1c (via D3) and FGF23 (via its C-terminal tail), definitively ruling out glycosidase catalytic activity for the co-receptor function.

    Evidence X-ray crystallography of the 1:1:1 ternary complex at atomic resolution

    PMID:29342138

    Open questions at the time
    • Structure of full ternary signaling complex including heparan sulfate and dimerized receptors not solved
    • Whether KL1 and KL2 domains have residual enzymatic activity in other contexts remains debated
  11. 2020 High

    The mechanism of age-related KL silencing was elucidated: H3K27me3 accumulates at the KL promoter in aging kidneys due to reduced JMJD3 demethylase, with PRC2 inhibition restoring KL expression, providing a druggable epigenetic axis.

    Evidence ChIP-qPCR showing H3K27me3 at KL promoter; PRC2 inhibitor rescue of KL expression; aged mouse kidney validation

    PMID:32223380

    Open questions at the time
    • Whether other epigenetic marks (DNA methylation, H3K9me3) cooperate in KL silencing not addressed
    • Upstream signals driving JMJD3 decline with age not identified
    • Therapeutic window of PRC2 inhibition for KL restoration in CKD not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of Klotho's interactions with TGF-βRII and Wnt ligands, the identity of the sheddase(s) generating circulating Klotho, the relative in vivo contributions of FGF23-dependent versus FGF23-independent Klotho functions to aging suppression, and whether residual glycosidase activity exists in any physiological context.
  • No structural data for Klotho–TGFβRII or Klotho–Wnt complexes
  • Sheddase identity not established
  • In vivo genetic separation of co-receptor vs. anti-fibrotic functions not achieved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 2
Localization
GO:0005576 extracellular region 5 GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1430728 Metabolism 3 R-HSA-382551 Transport of small molecules 2 R-HSA-168256 Immune System 1 R-HSA-4839726 Chromatin organization 1
Partners
DDX58FGF23FGFR1IGF1RTGFBR2WNT1WNT4WNT7A
Complex memberships
FGF23–FGFR1c–αKlotho ternary complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Homozygous defect in klotho gene expression in mice causes a syndrome resembling premature aging, including short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema, establishing klotho as a suppressor of aging phenotypes. The gene encodes a membrane protein with sequence similarity to beta-glucosidase enzymes. Mouse knockout/loss-of-function genetics with phenotypic characterization Nature High 9363890
1998 The human KL gene is composed of 5 exons spanning ~50 kb on chromosome 13q12. Two transcripts arise from alternative RNA splicing: one encoding a membrane-bound form and one encoding a secreted form, with the secreted form predominating. cDNA cloning, gene structure analysis, alternative splicing characterization Biochemical and biophysical research communications High 9464267
2002 A functional KL variant termed KL-VS contains two amino acid substitutions (F352V and C370S) in complete linkage disequilibrium. In transient transfection assays, the V352 form reduces secreted klotho levels ~6-fold, while the S370 form increases extracellular levels ~2.9-fold. The double mutant shows intragenic complementation. F352V in the paralog cBGL1 eliminates beta-glucosidase activity, suggesting KL has catalytic activity relevant to this residue. Transient transfection assay measuring secreted protein levels; paralog mutagenesis with enzymatic assay Proceedings of the National Academy of Sciences of the United States of America High 11792841
2004 Secreted Klotho protein detected in serum and cerebrospinal fluid is 130 kDa, larger than the 70 kDa predicted from the transcript, indicating post-translational processing. Both secreted and membrane-bound Klotho form oligomeric complexes. Release involves post-translational cleavage (ectodomain shedding) from the membrane form. Immunoblotting with newly established anti-Klotho antibodies; detection in serum and CSF FEBS letters High 15135068
2006 Klotho converts canonical FGF receptors (specifically FGFR1(IIIc)) into a specific receptor for FGF23. Klotho binds FGF23 in renal homogenates; forced Klotho expression enables high-affinity FGF23 binding and restores FGF23 responsiveness in renal cell lines. Anti-Klotho monoclonal antibody injection in wild-type mice induces FGF23 incompetence. Thus Klotho is an essential co-receptor for FGF23 signaling. Co-immunoprecipitation/binding assay with renal homogenate; forced expression in cell lines; in vivo antibody neutralization Nature High 17086194
2007 Crystal structures of FGF19 and FGF23 reveal that the heparin-binding region between beta strands 10 and 12 diverges from paracrine FGFs, reducing heparan sulfate binding affinity and conferring endocrine function. Klotho/betaKlotho evolved as a compensatory mechanism for poor heparin/HS-mediated FGF receptor binding, enabling endocrine FGF signaling. X-ray crystallography of FGF19 alone and FGF23 in complex with sucrose octasulfate; structural comparison Molecular and cellular biology High 17339340
2007 A homozygous missense mutation H193R in human KL causes severe tumoral calcinosis with hyperphosphatemia and elevated FGF23. H193R maps to the base of the catalytic cleft of the KL1 glycosidase domain. Expression and secretion of H193R KL are markedly reduced in vitro, resulting in diminished ability of FGF23 to signal via its cognate FGF receptors. Human genetic study; structural mapping onto crystal structure homolog; in vitro expression and FGF23 signaling assay The Journal of clinical investigation High 17710231
2008 Klotho acts as a tumor suppressor in human breast cancer. Secreted klotho inhibits IGF-1 and insulin signaling pathways. Co-immunoprecipitation reveals an interaction between klotho and the IGF-1 receptor. Klotho overexpression also enhances FGF pathway activation by basic FGF in breast cancer cells, upregulating CCAAT/enhancer-binding protein beta. Co-immunoprecipitation; forced expression and siRNA knockdown with proliferation readouts; pathway activation by western blot Oncogene High 18762812
2008 A chromosomal translocation with a breakpoint adjacent to the alpha-Klotho locus causes markedly elevated plasma alpha-Klotho and beta-glucuronidase activity, leading to hypophosphatemic rickets and hyperparathyroidism. Circulating FGF23 is also markedly elevated, implicating alpha-Klotho in regulation of phosphate levels and parathyroid mass/function. Human genetic/clinical study; plasma Klotho and FGF23 measurement; beta-glucuronidase activity assay Proceedings of the National Academy of Sciences of the United States of America High 18308935
2009 Secreted Klotho protein has putative sialidase activity that modifies glycans on cell surfaces, potentially explaining its ability to regulate multiple ion channels and growth factors including insulin, IGF-1, and Wnt. Transmembrane and secreted Klotho forms have distinct functions collectively affecting aging. Review synthesizing biochemical data on Klotho glycosidase/sialidase activity and ion channel regulation Biochimica et biophysica acta Medium 19230844
2010 Klotho deficiency in chronic kidney disease (CKD) contributes to vascular calcification. In vitro, Klotho directly suppresses Na+-dependent phosphate uptake and phosphate-induced mineralization in vascular smooth muscle cells and preserves their differentiation. Klotho-overexpressing transgenic mice with CKD have less calcification; Klotho-haploinsufficient mice have severe calcification. This demonstrates a direct anti-calcific effect of Klotho on the vasculature beyond phosphaturia. Transgenic overexpression and haploinsufficiency mouse models of CKD; in vitro vascular smooth muscle cell phosphate uptake assays; histology Journal of the American Society of Nephrology : JASN High 21115613
2011 Secreted Klotho protein directly binds the type-II TGF-β receptor and inhibits TGF-β1 binding to cell surface receptors, thereby blocking TGF-β1 signaling. Klotho suppresses TGF-β1-induced epithelial-to-mesenchymal transition (EMT) in cultured cells. In vivo, secreted Klotho suppresses renal fibrosis in unilateral ureteral obstruction and inhibits cancer xenograft metastasis. Direct binding assay (secreted Klotho to TGF-β receptor); cell-based EMT assays; in vivo mouse models of fibrosis and metastasis The Journal of biological chemistry High 21209102
2011 Intracellular Klotho (not secreted form) interacts with RIG-I (retinoic-acid-inducible gene-I) and inhibits RIG-I-induced expression of IL-6 and IL-8. RIG-I is induced via the ATM-IRF1 axis in senescent cells and mediates the senescence-associated secretory phenotype (SASP). Thus, Klotho suppresses senescence-associated inflammation through direct interaction with RIG-I. Co-immunoprecipitation; siRNA knockdown; forced expression; SASP cytokine measurement in vitro and in vivo Nature cell biology High 21336305
2013 Klotho functions as an endogenous antagonist of Wnt/β-catenin signaling. Both full-length and secreted Klotho bind to multiple Wnt ligands (Wnt1, Wnt4, Wnt7a). Klotho blocks Wnt-triggered activation and nuclear translocation of β-catenin and expression of its target genes in tubular epithelial cells. TGF-β1 suppresses Klotho expression and activates β-catenin; Klotho overexpression abolishes TGF-β1 fibrogenic effects. In vivo secreted Klotho reduces renal fibrosis in two CKD mouse models. Direct binding assay (Klotho to Wnt ligands); β-catenin nuclear translocation assays; in vivo mouse CKD models with Klotho expression Journal of the American Society of Nephrology : JASN High 23559584
2015 Transmembrane alpha-Klotho protein expression in human tissues was systematically characterized. Strong expression was found in kidney tubules and arteries; liver showed no detectable signal. Expression was confirmed across multiple organ systems including arterial, epithelial, endocrine, reproductive, and neuronal tissues using parallel reaction monitoring mass spectrometry, immunohistochemistry, and western blotting. Immunohistochemistry; western blotting of whole tissues and primary cells; parallel reaction monitoring mass spectrometry (targeted proteomics) The Journal of clinical endocrinology and metabolism High 26280509
2018 Crystal structure of a 1:1:1 ternary complex of shed α-klotho extracellular domain, FGFR1c ligand-binding domain, and FGF23 reveals that α-klotho simultaneously tethers FGFR1c via its D3 domain and FGF23 via its C-terminal tail, implementing FGF23-FGFR1c proximity and conferring stability. The structure shows α-klotho functions as a non-enzymatic molecular scaffold, incompatible with glycosidase activity. Dimerization and receptor activation remain dependent on heparan sulfate. X-ray crystallography of ternary complex; structural analysis Nature High 29342138
2019 αKlotho and βKlotho are essential components of endocrine FGF receptor complexes required for high-affinity binding of FGF19, FGF21, and FGF23 to their cognate FGFRs. FGF23 from bone binds αKlotho-FGFR complexes (most abundantly in renal tubules) to regulate mineral metabolism. βKlotho forms complexes with FGFR4 for FGF19 signaling in hepatocytes and with FGFR1c for FGF21 signaling in adipocytes and hypothalamus. Review synthesizing crystal structure data, binding studies, and in vivo genetic evidence Nature reviews. Nephrology High 30455427
2020 KL gene expression is epigenetically regulated by H3K27 trimethylation (H3K27me3) at the KL promoter in renal tubule cells. H3K27me3 levels increase in aged kidneys, correlating with reduced JMJD3 demethylase expression. Inhibition of PRC2 (the H3K27 trimethyltransferase) decreases H3K27me3 levels and increases KL expression. ChIP-qPCR confirmed physical association of H3K27me3 with the KL promoter. KL deficiency impairs SGK1/FOXO3a signaling, upregulating p53 and p16. Chromatin immunoprecipitation (ChIP)-qPCR; PRC2 inhibitor treatment; KL promoter activity assay; western blot in aged and KL-mutant mouse kidneys Hypertension (Dallas, Tex. : 1979) High 32223380
2012 Vascular Klotho deficiency in CKD potentiates calcification through a Runx2 and myocardin-serum response factor-dependent pathway. Klotho knockdown in vascular cells abolishes FGF-23-mediated activation of p-ERK and p-AKT and cellular proliferative effects, demonstrating vascular cells are a Klotho-dependent target for FGF-23. Vitamin D receptor activators restore Klotho expression and confer FGF-23 responsiveness. Klotho knockdown (siRNA) in human aortic smooth muscle cells; signaling assays (p-ERK, p-AKT); human arterial organ culture; in vitro calcification assay Circulation High 22492635
2005 Klotho protein reduces H2O2- and etoposide-induced apoptosis in human umbilical vascular endothelial cells (HUVEC) and COS-1/Jurkat cells. Caspase-3 and caspase-9 activity is lower in Klotho-treated cells. Klotho also inhibits H2O2-induced premature cellular senescence, with decreased p53 and p21 expression. Klotho overexpression; caspase activity assay; senescence-associated beta-gal staining; western blot for p53 and p21 Biochemical and biophysical research communications High 16325773
2013 KL-6/MUC1 (in the context of pulmonary fibrosis) upregulates collagen type I and III expression in human lung fibroblasts in a dose-dependent manner, inhibits hepatocyte growth factor (HGF) production, and induces myofibroblast differentiation as measured by elevated alpha-SMA expression. These effects were demonstrated in the MRC-5 embryonic lung fibroblast cell line. Recombinant KL-6 treatment of MRC-5 cells; RT-PCR for collagen; ELISA for HGF and TGF-β1; flow cytometry for α-SMA European review for medical and pharmacological sciences Medium 24302189
2013 Anti-KL-6 antibody treatment in a bleomycin-induced pulmonary fibrosis mouse model reduces alveolar inflammatory leukocytes, hydroxyproline content, collagen type I expression, TGF-β1, and KL-6 levels, while upregulating HGF and inhibiting epithelial cell apoptosis (TUNEL staining). In vivo mouse bleomycin model; TUNEL staining; ELISA; qRT-PCR; pathological examination Experimental lung research Medium 23672275
2006 Anti-KL-6/MUC1 monoclonal antibody induces capping of MUC1 on the surface of breast cancer cells, facilitating E-cadherin-mediated cell-cell interaction and enhancing lymphokine-activated killer cell cytotoxicity. MUC1 capping restores surface adhesion molecules and tumor antigens, inhibiting tumor proliferation. Anti-KL-6 mAb treatment of breast cancer cell lines; MUC1 capping visualization; E-cadherin interaction assay; cytotoxicity assay Cancer science Medium 16630141
2011 KL-6/MUC1 knockdown in pancreatic ductal carcinoma cells (Panc-1 and Capan-1) increases E-cadherin and E-cadherin/β-catenin complex expression, decreases nuclear β-catenin, cyclin D1, and c-myc expression, and reduces cell invasive ability. This demonstrates that KL-6/MUC1 regulates pancreatic cancer cell proliferation, apoptosis, and invasion via the β-catenin pathway. siRNA knockdown; RT-PCR; western blot; immunoprecipitation; invasion assay; apoptosis assay Life sciences Medium 21466814
2023 FGF21 signals through an FGFR1-βKlotho (β-KL) cascade in cardiomyocytes to modulate angiogenesis and inflammation under diabetic/metabolic stress. Decreased expression and activity of FGFR1 and β-KL were found in human and mouse diabetic hearts. Reinforcing cardiac FGFR1 and β-KL expression alleviates pro-inflammatory response and endothelial dysfunction. Novel cardiomyocyte-derived anti-inflammatory and proangiogenic factors regulated by FGFR1-β-KL signaling were identified by proteomics. In vivo diabetic mouse model; human diabetic heart tissue; forced expression; proteomics; functional readouts of inflammation and angiogenesis Heliyon Medium 37123894

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 3043 9363890
2006 Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 1447 17086194
2010 Klotho deficiency causes vascular calcification in chronic kidney disease. Journal of the American Society of Nephrology : JASN 765 21115613
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
1998 Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochemical and biophysical research communications 556 9464267
2019 The Klotho proteins in health and disease. Nature reviews. Nephrology 550 30455427
2011 Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. The Journal of biological chemistry 472 21209102
2004 Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS letters 452 15135068
2007 Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Molecular and cellular biology 442 17339340
2018 α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Nature 388 29342138
2001 Severely reduced production of klotho in human chronic renal failure kidney. Biochemical and biophysical research communications 388 11162628
2002 Association of human aging with a functional variant of klotho. Proceedings of the National Academy of Sciences of the United States of America 372 11792841
2012 Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23. Circulation 352 22492635
2013 Loss of Klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling. Journal of the American Society of Nephrology : JASN 329 23559584
2007 A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. The Journal of clinical investigation 311 17710231
2012 Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respiratory investigation 310 22554854
2000 FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Molecular and cellular biology 286 10629055
2009 Klotho and aging. Biochimica et biophysica acta 263 19230844
2008 Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 262 18762812
2005 Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circulation research 233 15677572
2011 Klotho suppresses RIG-I-mediated senescence-associated inflammation. Nature cell biology 228 21336305
2011 Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF-23-klotho in chronic kidney disease. Journal of the American Society of Nephrology : JASN 220 21852584
2013 Klotho, phosphate and FGF-23 in ageing and disturbed mineral metabolism. Nature reviews. Nephrology 205 23774819
2009 Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients. Kidney international 200 19890272
2005 Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochemical and biophysical research communications 200 16325773
2003 KLOTHO allele status and the risk of early-onset occult coronary artery disease. American journal of human genetics 193 12669274
1999 Phospholipase C-gamma as a signal-transducing element. Experimental cell research 188 10579907
2020 Identification of Acinetobacter baumannii loci for capsular polysaccharide (KL) and lipooligosaccharide outer core (OCL) synthesis in genome assemblies using curated reference databases compatible with Kaptive. Microbial genomics 176 32118530
2015 α-Klotho Expression in Human Tissues. The Journal of clinical endocrinology and metabolism 173 26280509
2008 A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proceedings of the National Academy of Sciences of the United States of America 171 18308935
2003 Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. American journal of physiology. Lung cellular and molecular physiology 155 12959931
2006 Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases. Journal of internal medicine 136 17040248
2009 Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. The Journal of rheumatology 134 19286849
2000 Y chromosomal fertility factors kl-2 and kl-3 of Drosophila melanogaster encode dynein heavy chain polypeptides. Proceedings of the National Academy of Sciences of the United States of America 127 11069293
2008 ATRA and KL promote differentiation toward the meiotic program of male germ cells. Cell cycle (Georgetown, Tex.) 102 19098446
2004 Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis. The Journal of rheumatology 102 15170923
2010 Prescreening based on the presence of CT-scan abnormalities and biomarkers (KL-6 and SP-D) may reduce severe radiation pneumonitis after stereotactic radiotherapy. Radiation oncology (London, England) 86 20459699
2012 Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation. Blood 85 22279057
2005 Pharmacodynamics of the G-quadruplex-stabilizing telomerase inhibitor 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) in vitro: activity in human tumor cells correlates with telomere length and can be enhanced, or antagonized, with cytotoxic agents. Molecular pharmacology 76 16150933
2011 KL-6: a serological biomarker for interstitial lung disease in patients with polymyositis and dermatomyositis. Journal of internal medicine 74 21950266
2010 Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients. BMC pulmonary medicine 73 20158912
2011 Surfactant protein D and KL-6 serum levels in systemic sclerosis: correlation with lung and systemic involvement. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG 70 21796888
1998 Serum and bronchoalveolar fluid KL-6 levels in patients with pulmonary alveolar proteinosis. American journal of respiratory and critical care medicine 69 9769294
2015 The usefulness of KL-6 and SP-D for the diagnosis and management of chronic hypersensitivity pneumonitis. Respiratory medicine 64 26481343
2018 MUC1 aptamer-targeted DNA micelles for dual tumor therapy using doxorubicin and KLA peptide. Nanomedicine : nanotechnology, biology, and medicine 60 29317345
2009 The frequency of Klotho KL-VS polymorphism in a large Italian population, from young subjects to centenarians, suggests the presence of specific time windows for its effect. Biogerontology 60 19421891
2000 Serum KL-6 in adult patients with polymyositis and dermatomyositis. Rheumatology (Oxford, England) 60 10888708
2012 Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels. Respiratory medicine 57 22995277
2021 Serum KL-6, CA19-9, CA125 and CEA are Diagnostic Biomarkers for Rheumatoid Arthritis-Associated Interstitial Lung Disease in the Chinese Population. Rheumatology and therapy 56 33586127
1993 The kl-3 loop of the Y chromosome of Drosophila melanogaster binds a tektin-like protein. Genetics 54 8454204
2009 Differential cytokine/chemokines and KL-6 profiles in patients with different forms of tuberculosis. Cytokine 53 19570688
2008 Antitumor polycyclic acridines. 20. Search for DNA quadruplex binding selectivity in a series of 8,13-dimethylquino[4,3,2-kl]acridinium salts: telomere-targeted agents. Journal of medicinal chemistry 51 18247546
2023 Auto-Kla: a novel web server to discriminate lysine lactylation sites using automated machine learning. Briefings in bioinformatics 49 36869843
2005 Serum KL-6 and surfactant proteins A and D in pediatric interstitial lung disease. Chest 49 15654008
2001 Serum levels of KL-6 are useful biomarkers for severe radiation pneumonitis. Lung cancer (Amsterdam, Netherlands) 49 11557124
2021 KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease. Nature communications 43 34158479
2015 Enhanced antitumor effects of the BRBP1 compound peptide BRBP1-TAT-KLA on human brain metastatic breast cancer. Scientific reports 43 25619721
2010 Association of the functional KL-VS variant of Klotho gene with early-onset ischemic stroke. Biochemical and biophysical research communications 42 21093413
2019 Serum neopterin as well as ferritin, soluble interleukin-2 receptor, KL-6 and anti-MDA5 antibody titer provide markers of the response to therapy in patients with interstitial lung disease complicating anti-MDA5 antibody-positive dermatomyositis. Modern rheumatology 38 30449228
2014 Apoptosis inducing, conformationally constrained, dimeric peptide analogs of KLA with submicromolar cell penetrating abilities. Biomacromolecules 38 25188534
2023 Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma. Scientific reports 37 37903971
2020 Epigenetic Regulation of KL (Klotho) via H3K27me3 (Histone 3 Lysine [K] 27 Trimethylation) in Renal Tubule Cells. Hypertension (Dallas, Tex. : 1979) 35 32223380
2009 Clinicopathology of sialomucin: MUC1, particularly KL-6 mucin, in gastrointestinal, hepatic and pancreatic cancers. Bioscience trends 35 20103851
2004 Expression patterns of sialylated epitope recognized by KL-6 monoclonal antibody in ocular surface epithelium of normals and dry eye patients. Investigative ophthalmology & visual science 35 15223797
2023 Lysine lactylation (Kla) might be a novel therapeutic target for breast cancer. BMC medical genomics 34 37950222
2009 Potential-dependent membrane permeabilization and mitochondrial aggregation caused by anticancer polyarginine-KLA peptides. Archives of biochemistry and biophysics 34 19900399
1997 Comparative studies of circulating KL-6, type III procollagen N-terminal peptide and type IV collagen 7S in patients with interstitial pneumonitis and alveolar pneumonia. Respiratory medicine 33 9415357
2020 Lung ultrasound B-lines and serum KL-6 correlate with the severity of idiopathic inflammatory myositis-associated interstitial lung disease. Rheumatology (Oxford, England) 32 31794028
2018 Synergistic effect of the pro-apoptosis peptide kla-TAT and the cationic anticancer peptide HPRP-A1. Apoptosis : an international journal on programmed cell death 32 29397453
2004 Rational design, synthesis, and biological evaluation of bis(pyrimido[5,6,1-de]acridines) and bis(pyrazolo[3,4,5-kl]acridine-5-carboxamides) as new anticancer agents. Journal of medicinal chemistry 32 15456268
2001 The paralemmin protein family: identification of paralemmin-2, an isoform differentially spliced to AKAP2/AKAP-KL, and of palmdelphin, a more distant cytosolic relative. Biochemical and biophysical research communications 31 11478809
2013 Correlation between mass transfer coefficient kLa and relevant operating parameters in cylindrical disposable shaken bioreactors on a bench-to-pilot scale. Journal of biological engineering 30 24289110
2011 Ageing and long-term smoking affects KL-6 levels in the lung, induced sputum and plasma. BMC pulmonary medicine 30 21569324
2020 Serum KL-6 levels in pulmonary Langerhans' cell histiocytosis. European journal of clinical investigation 29 32307698
2011 Levels of surfactant proteins A and D and KL-6 are elevated in the induced sputum of chronic obstructive pulmonary disease patients: a sequential sputum analysis. Respiration; international review of thoracic diseases 29 21474912
2005 Studies on the cellular uptake of substance P and lysine-rich, KLA-derived model peptides. Journal of molecular recognition : JMR 29 15386618
2016 MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis. Orphanet journal of rare diseases 28 27108412
2018 Diagnostic value of KL-6 in idiopathic interstitial pneumonia. Journal of thoracic disease 26 30233844
2001 KL-6, surfactant protein A and D in bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis. Respiration; international review of thoracic diseases 26 11694811
2020 Bronchoalveolar lavage and serum KL-6 concentrations in chronic hypersensitivity pneumonitis: correlations with radiological and immunological features. Internal and emergency medicine 25 32078140
2011 Pneumocyte biomarkers KL-6 and surfactant protein D reflect the distinct findings of high-resolution computed tomography in nonspecific interstitial pneumonia. Respiration; international review of thoracic diseases 25 21555868
2021 Serial Measurements of Circulating KL-6, SP-D, MMP-7, CA19-9, CA-125, CCL18, and Periostin in Patients with Idiopathic Pulmonary Fibrosis Receiving Antifibrotic Therapy: An Exploratory Study. Journal of clinical medicine 24 34501312
2002 KL/KIT co-expression in mouse fetal oocytes. The International journal of developmental biology 24 12533025
2022 Efficacy and safety of KL-A167 in previously treated recurrent or metastatic nasopharyngeal carcinoma: a multicenter, single-arm, phase 2 study. The Lancet regional health. Western Pacific 23 36879786
2001 Synthesis, antitumor cytotoxicity, and DNA-binding of novel N-5,2-di(omega-aminoalkyl)-2,6-dihydropyrazolo[3,4,5-kl]acridine-5-carboxamides. Journal of medicinal chemistry 23 11563932
2021 Age-Related Tau Burden and Cognitive Deficits Are Attenuated in KLOTHO KL-VS Heterozygotes. Journal of Alzheimer's disease : JAD 21 33427737
2020 Serum SP-A and KL-6 levels can predict the improvement and deterioration of patients with interstitial pneumonia with autoimmune features. BMC pulmonary medicine 21 33267857
2019 Coadministration of kla peptide with HPRP-A1 to enhance anticancer activity. PloS one 20 31703065
2021 Baseline plasma KL-6 level predicts adverse outcomes in patients with idiopathic pulmonary fibrosis receiving nintedanib: a retrospective real-world cohort study. BMC pulmonary medicine 18 33992083
2022 YKL-40 and KL-6 Levels in Serum and Sputum of Patients Diagnosed With Hypersensitivity Pneumonitis. The journal of allergy and clinical immunology. In practice 17 35788062
2021 Association of serum KL-6 levels on COVID-19 severity: A cross-sectional study design with purposive sampling. Annals of medicine and surgery (2012) 17 34401147
2018 Establishment of a CFD-based kL a model in microtiter plates to support CHO cell culture scale-up during clone selection. Biotechnology progress 17 30281943
2009 Serum KL-6 as a novel disease marker in adolescent and adult cystic fibrosis. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG 17 19960788
2008 Drosophila melanogaster kl-3 and kl-5 Y-loops harbor triple-stranded nucleic acids. Journal of cell science 17 18430782
2006 The functional "KL-VS" variant of KLOTHO is not associated with type 2 diabetes in 5028 UK Caucasians. BMC medical genetics 17 16753056
2018 Cardol triene inhibits dengue infectivity by targeting kl loops and preventing envelope fusion. Scientific reports 16 30413789
2017 The KL-VS polymorphism of KLOTHO gene is protective against retinopathy incidence in patients with type 1 diabetes. Biochimica et biophysica acta. Molecular basis of disease 16 29247834
2012 The Diagnostic Value of the Interstitial Biomarkers KL-6 and SP-D for the Degree of Fibrosis in Combined Pulmonary Fibrosis and Emphysema. Pulmonary medicine 16 22530118
2006 Anti-tumor effect of the anti-KL-6/MUC1 monoclonal antibody through exposure of surface molecules by MUC1 capping. Cancer science 16 16630141
2021 The value of KL-6 in the diagnosis and assessment of interstitial lung disease. American journal of translational research 15 34540037
2018 Anti-KL-6/MUC1 monoclonal antibody reverses resistance to trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity by capping MUC1. Cancer letters 15 30389434
2016 Characterization of antimicrobial substance from Lactobacillus salivarius KL-D4 and its application as biopreservative for creamy filling. SpringerPlus 15 27462508
2013 Bleomycin-induced pulmonary fibrosis is attenuated by an antibody against KL-6. Experimental lung research 15 23672275
2013 KL-6 regulated the expression of HGF, collagen and myofibroblast differentiation. European review for medical and pharmacological sciences 15 24302189
2023 FGF21/FGFR1-β-KL cascade in cardiomyocytes modulates angiogenesis and inflammation under metabolic stress. Heliyon 14 37123894
2017 Specific hepatic stellate cell-penetrating peptide targeted delivery of a KLA peptide reduces collagen accumulation by inducing apoptosis. Journal of drug targeting 14 28447897
2009 Partitioning, dynamics, and orientation of lung surfactant peptide KL(4) in phospholipid bilayers. Biochimica et biophysica acta 14 19735643
2006 Simultaneous measurements of KL-6 and SP-D in patients undergoing thoracic radiotherapy. Medical oncology (Northwood, London, England) 14 16645232
2023 KL-6 levels in the connective tissue disease population: typical values and potential confounders-a retrospective, real-world study. Frontiers in immunology 13 37409133
2020 Krebs von den Lungen-6 (KL-6) is a pathophysiological biomarker of early-stage acute hypersensitivity pneumonitis among pigeon fanciers. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 13 32966647
2017 Anti-inflammatory activities and glycerophospholipids metabolism in KLA-stimulated RAW 264.7 macrophage cells by diarylheptanoids from the rhizomes of Alpinia officinarum. Biomedical chromatography : BMC 13 28906002
2011 Expression of KL-6/MUC1 in pancreatic cancer tissues and its potential involvement in tumor metastasis. Oncology reports 13 21617869
2014 Inhibition of KL-6/MUC1 glycosylation limits aggressive progression of pancreatic cancer. World journal of gastroenterology 12 25232251
2013 A novel lung injury animal model using KL-6-measurable human MUC1-expressing mice. Biochemical and biophysical research communications 12 23410752
2017 Impact of anti-tumor necrosis factor-α agents on serum levels of KL-6 and surfactant protein-D in patients with psoriasis. The Journal of dermatology 11 28370220
2011 Expression of KL-6/MUC1 in pancreatic ductal carcinoma and its potential relationship with β-catenin in tumor progression. Life sciences 11 21466814
2004 Detection of serum and intrahepatic KL-6 in anti-HCV positive patients with hepatocellular carcinoma. Hepatology research : the official journal of the Japan Society of Hepatology 11 15341771
2001 Domain and genomic sequence analysis of bdellin-KL, a leech-derived trypsin-plasmin inhibitor. Journal of biochemistry 11 11530020
2000 Diagnostic accuracy of KL-6 as a marker of amiodarone-induced pulmonary toxicity. Pacing and clinical electrophysiology : PACE 11 11139980
2024 KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults. Alzheimer's & dementia : the journal of the Alzheimer's Association 10 39030746
2022 AD-associated CSF biomolecular changes are attenuated in KL-VS heterozygotes. Alzheimer's & dementia (Amsterdam, Netherlands) 10 36505396
2018 Co-administration of kla-TAT peptide and iRGD to enhance the permeability on A549 3D multiple sphere cells and accumulation on xenograft mice. Chemical biology & drug design 10 29722179
2017 Pre-operative evaluation of circulating KL-6 levels as a biomarker for epithelial ovarian carcinoma and its correlation with tumor MUC1 expression. Oncology letters 10 28693233
2014 The association between KL polymorphism and prostate cancer risk in Korean patients. Molecular biology reports 10 25120167
2005 Usefulness of quantifying serum KL-6 levels in the follow-up of uveitic patients with sarcoidosis. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 10 16133026
2024 Research progress of KL-6 in respiratory system diseases. Critical reviews in clinical laboratory sciences 9 38773736
2024 Histone Lysine Lactylation (Kla)-induced BCAM Promotes OSCC Progression and Cis-Platinum Resistance. Oral diseases 9 39503345
2022 Expression of S100A9 and KL-6 in common interstitial lung diseases. Medicine 9 35512076