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Symbol KL contributors: mct - updated : 14-09-2018
HGNC name klotho
HGNC id 6344
  • an N terminal signal sequence
  • an extracellular domains with two internal repeats, each repeat sharing 20–40 p100 sequence identity to mammalian lactase glycosylceramidase, beta-glucosidase-like domain
  • a short intracellular domain
  • second hydrolase domain of Klotho interacts with sixth and seventh Ig domains of KDR and the third extracellular loop of TRPC1 (
  • C-terminal region is critical for Klotho specificity determination and interaction
  • conjugated GlycoP
    isoforms Precursor
    interspecies homolog to murine Kl (86.2pc)
    homolog to rattus Kl (84.8pc)
  • glycosyl hydrolase 1 family
  • Klotho subfamily
  • CATEGORY enzyme , secretory
        plasma membrane
  • type1 membrane protein
  • ADAM10 and ADAM17 are capable of shedding KL from the plasma membrane, and that insulin can stimulate KL shedding
  • basic FUNCTION
  • beta-glucosidase activity
  • may be involved in genetic regulation of common age-related diseases like osteoporosis and spondylosis
  • playing a crucial role in the regulation of renal stanniocalcin gene expression at least partly, through the control of circulating calcium and phosphate concentrations
  • activating a cell surface channel by hydrolysis of its extracellular N-linked oligosaccharides, as TRPV5
  • soluble isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling
  • regulating cellular senescence by repressing the p53/p21 pathway
  • fundamental roles in the regulation of calcium metabolism
  • involved in the inhibition of the insulin signaling pathway
  • functions as an aging-suppressor gene that extends life span when overexpressed and accelerates aging-like phenotypes when disrupted in mice
  • single-pass transmembrane protein that binds to multiple fibroblast growth factor (FGF) receptors and functions as a co-receptor for FGF23, a bone-derived hormone
  • can regulate multiple growth factor signaling pathways, including insulin/IGF1 and Wnt, and the activity of multiple ion channels
  • works as a hormonal factor to promote adipocyte differentiation in the early days, during the period of transient proliferation in the differentiation process, and may play an essential role in adipocyte differentiation
  • can be shed and act as a circulating hormone and is a putative tumor suppressor in breast cancer
  • key regulator of mineral homeostasis
  • associated with KDR/TRPC1 in causing cointernalization, and thus regulating TRPC1–mediated Ca2+ entry to maintain endothelial integrity
  • likely to be a kidney-derived vasoprotective protein
  • regulating KDR/TRPC1–mediated Ca2+ influx to maintain endothelial biological homeostasis
  • functions as an anti-ageing factor through the suppression of DDX58-mediated inflammation
  • renal KL controls mineral metabolism by directly modulating tubular reabsorption of phosphate and calcium and by acting as a co-receptor for the phosphaturic and vitamin D-regulating hormone FGF23
  • modulates the stress response in human senescent endothelial cells
  • has an important role in regulating ER stress and loss of KL is causally linked to ER stress-induced apoptosis
  • is a novel player in the retina, with a clear connection to photoreceptor cell death as well as with an influence on retinal organization
  • is an important regulator of retinal pigment epithelium (RPE) homeostasis
  • role for the antiaging hormone KL in the regulation of prenatal and postnatal hematopoiesis
  • functions as the obligatory co-receptor for fibroblast growth factor-23 (FGF23), a bone-derived phosphaturic hormone
  • KL expression may be modulated by skeletal muscle activity
  • circulating alpha-Klotho protects the lung against oxidative damage and apoptosis partly via increasing endogenous antioxidative capacity in pulmonary epithelia
  • KL functions include inhibition of local phosphate transport in vascular cells, phenotypic switches of vascular cellular elements into bone-forming cells, attenuation of matrix mineralization and calcification, and also preservation of endothelial functional properties and viability
  • is an important molecule in aging processes and its overexpression results in longevity
  • is an antiaging gene encoding a single-pass transmembrane protein, KL, which serves as an aging suppressor through a wide variety of mechanisms, such as antioxidation, antisenescence, antiautophagy
  • exerts its renal protection by targeted inhibition of renin-angiotensin system (RAS), a pathogenic pathway known to play a key role in the evolution and progression of hypertension and chronic kidney disorders
  • up-regulates the excitatory glutamate transporters SLC1A3 and SLC1A2 and thus participates in the regulation of neuronal excitation
  • is implicated in the process of angiogenesis of human dermal microvasculature
  • soluble KL plays a stimulatory role in cardiac myofibroblast growth and activity through FGF pathway
  • in proximal renal tubules, FGF23 suppresses phosphate reabsorption by a KL dependent activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and of serum/glucocorticoid-regulated kinase-1 (SGK1)
    metabolism carbohydrate
    signaling signal transduction
  • renal FGF23-KL signaling, which is disrupted in chronic kidney disease, is essential for homeostatic control of mineral metabolism
  • a component
    small molecule
  • vitamin D binding
  • can directly interact with FGF receptors as well as with FGF19 and FGF23
  • binds directly to KDR and TRPC1 and strengthens the association to promote their cointernalization (
  • interacts with DDX58 and this interaction inhibits DDX58-induced expression of IL6 and IL8
  • FGF23 binding to FGFR3 was enhanced in the presence of KL
  • is a novel, powerful regulator of the excitatory amino acid transporters SLC1A1, SLC1A6
  • KL and sialidase regulate TRPV5 membrane stabilization in a different manner
  • Klotho upregulates KCNQ1/KCNE1 channel activity by “mainly” enhancing channel protein abundance in the plasma cell membrane
  • KL expression was associated with expression of the non-sulfated B3GAT1 epitope
  • regulates diverse calcium and potassium ion channels, as well as several carriers including the Na(+)-coupled excitatory amino acid transporters (SLC1A1, SLC1A6, SLC34A1, SLC34A2)
  • Klotho protein up-regulates the activity of creatine transporter SLC6A8 by stabilizing the carrier protein in the cell membrane, an effect requiring beta-glucuronidase activity of KL protein
  • CDKN2A plays a previously unrecognized role in downregulating KL expression during ageing
  • MTOR signaling inhibition ameliorates vascular calcification via KL upregulation
  • DGKE regulated KL expression, at least partly via the transcription factor Krüppel-like factor (KLF15)
  • cell & other
    induced by statin
    inhibited by angiotensin II through the regulation of Ras homolog gene family, member A
    Other regulated by insulin (stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17)
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    down-regulated in renal cell carcinomas, hepatocellular carcinomas
    constitutional     --low  
    down-regulated in chronic renal failure kidney, and decrease in circulating Klotho may contribute to vascular lesions in the patients with chronic renal failure (
    constitutional       loss of function
    downregulates SIRT1 activity in arterial endothelial and smooth muscle cells
    constitutional     --over  
    in patients with diabetes and s-KL levels, but decreased with increasing albumin excretion
  • to early-onset coronary artery disease and atherosclerosis
  • to osteoporosis in postmenopausal women
  • to decreased longevity
  • to variation of BMD in male adults
  • to breast and ovarian cancers
  • Variant & Polymorphism SNP , other
  • associated with decreased longevity
  • G395A or C1818T increasing the risk of osteoporosis in postmenopausal women
  • allelic variants of Klotho constitute one of the genetic factors influencing BMD in male adults
  • KL-VS allele defined by the presence of 6 SNPs in exon 2 and flanking sequence impairs the trafficking and catalytic activity of KL
  • some SNPs are associated with sickle cell osteonecrosis
  • G395A is associated with blood pressure and C1818T is associated with glucose metabolism in Korean women
  • KLOTHO-V allele was associated with increased breast and ovarian cancers risk
  • Candidate gene DNA methylation markers of Gastric cancer (GC), which may serve as useful markers that may identify a distinct subset of GC
  • reduced serum KL concentrations and decreased vascular KL gene expression were associated with the presence and severity of coronary artery disease (CAD) independently of established cardiovascular risk factors
  • Therapy target
    might be a therapeutic target for preventing cardiovascular disease that complicates various diseases such as chronic kidney disease
  • transgenic mice
  • in klotho-null mice, the activity of calpain is elevated and the activity of its endogenous inhibitor is significantly decreased
  • klotho mice have a barely detectable amount of white adipose tissue, increased glucose tolerance and insulin sensitivity
  • overexpression of klotho in mice extends life span
  • mice heterozygously deficient for klotho gene showed blood flow recovery and impaired angiogenesis after ischemic hindlimb injury
  • Klotho-hypomorphic (Klotho(hm)) mice suffer from renal salt wasting and hypovolemia despite hyperaldosteronism
  • disruption of the Klotho gene in mice results in hypervitaminosis D and a syndrome resembling accelerated aging that includes osteopenia and vascular calcifications
  • in the mdx mouse model of DMD epigenetic silencing of Klotho during muscular dystrophy contributes substantially to lost regenerative capacity and increased fibrosis of dystrophic muscle during late progressive stages of the disease