KL encodes alpha-Klotho, a glycosylated type I single-pass transmembrane protein whose ectodomain consists of two tandem glycoside hydrolase family 1-like domains (KL1 and KL2) that lack the essential catalytic glutamates of active family members. Expressed mainly in kidney tubules, parathyroid gland and choroid plexus, alpha-Klotho binds the bone-derived hormone FGF23 and binds FGF receptors, principally FGFR1c, forming a ternary complex in which it acts as a non-enzymatic scaffold that converts FGFR1c into a high-affinity FGF23 receptor. FGF23-Klotho-FGFR signaling promotes renal phosphate excretion and suppresses 1,25-dihydroxyvitamin D synthesis; loss of human KL function causes hyperphosphatemic tumoral calcinosis. The ectodomain is shed from the cell surface and circulates in blood, urine and cerebrospinal fluid, where it can still serve as an FGF23 co-receptor, and a minor splice transcript encodes a KL1-only secreted form. Weak beta-glucuronidase activity has been reported in vitro but is contested, and the FGF23-independent hormonal effects attributed to soluble Klotho remain mechanistically unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003085 negative regulation of systemic arterial blood pressure | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer from rat Kl, whose annotation rests on intracerebroventricular klotho shRNA raising blood pressure during cold exposure. Reason: The rat source shows that brain Klotho knockdown potentiates cold-induced hypertension through endothelin-1 and sympathetic activation, a systemic and indirect effect. KL has no demonstrated molecular role within blood-pressure regulation; its established activity is FGF23 co-reception. The claim is not impossible physiologically but exceeds what is known about how the protein acts. Supporting Evidence: PMID:20086041 silencing of brain klotho increased ET1 production and the sympathetic nervous activity |
| GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: InterPro GH1-family mapping to O-glycosyl hydrolase activity. Reason: KL has two GH1-like domains but each lacks one catalytic glutamate. Weak beta-glucuronidase activity was reported for a mouse Klotho-Fc fusion, but the human ectodomain used for the crystal structure failed to hydrolyse glucuronidase or sialidase substrates, and the pocket loops are incompatible with canonical GH1 catalysis. The activity is contested and has no established physiological substrate, so the family-level catalytic term overstates what KL does. Supporting Evidence: file:human/KL/KL-uniprot.txt Contains 2 glycosyl hydrolase 1 regions. However, the first region lacks the essential Glu active site residue at position 239 PMID:29342138 Moreover, both KL domains lack one of the key catalytic glutamates deep within the putative catalytic pocket. PMID:29342138 Indeed, Ξ±Klothoecto failed to hydrolyze substrates for both sialidase and Ξ²-glucuronidase in vitro PMID:14701853 An enzymatic activity of Klotho was observed only with 4-methylumbelliferyl beta-D-glucuronide file:human/KL/KL-deep-research-falcon.md The weak in vitro glucuronidase activity may represent residual capacity rather than a physiologically significant function. |
| GO:0004566 beta-glucuronidase activity | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Beta-glucuronidase activity transferred from mouse Klotho, based on the Tohyama 2004 in vitro assay of a Klotho-Fc fusion. Reason: The mouse study detected activity only against an artificial 4-methylumbelliferyl glucuronide and, by competition, steroid glucuronides. The human alphaKlotho ectodomain failed to hydrolyse beta-glucuronidase substrates in the Chen 2018 study, and both KL domains lack a catalytic glutamate. The reported activity is weak, contested, and not linked to any physiological function; KL acts through FGF23 co-reception. It is retained as a reported, non-core in vitro activity rather than removed outright because a positive experimental report exists. Supporting Evidence: PMID:14701853 An enzymatic activity of Klotho was observed only with 4-methylumbelliferyl beta-D-glucuronide PMID:29342138 Indeed, Ξ±Klothoecto failed to hydrolyze substrates for both sialidase and Ξ²-glucuronidase in vitro PMID:29342138 Moreover, both KL domains lack one of the key catalytic glutamates deep within the putative catalytic pocket. file:human/KL/KL-deep-research-falcon.md The weak in vitro glucuronidase activity may represent residual capacity rather than a physiologically significant function. |
| GO:0004566 beta-glucuronidase activity | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Beta-glucuronidase activity transferred from mouse Klotho, based on the Tohyama 2004 in vitro assay of a Klotho-Fc fusion. Reason: The mouse study detected activity only against an artificial 4-methylumbelliferyl glucuronide and, by competition, steroid glucuronides. The human alphaKlotho ectodomain failed to hydrolyse beta-glucuronidase substrates in the Chen 2018 study, and both KL domains lack a catalytic glutamate. The reported activity is weak, contested, and not linked to any physiological function; KL acts through FGF23 co-reception. It is retained as a reported, non-core in vitro activity rather than removed outright because a positive experimental report exists. Supporting Evidence: PMID:14701853 An enzymatic activity of Klotho was observed only with 4-methylumbelliferyl beta-D-glucuronide PMID:29342138 Indeed, Ξ±Klothoecto failed to hydrolyze substrates for both sialidase and Ξ²-glucuronidase in vitro PMID:29342138 Moreover, both KL domains lack one of the key catalytic glutamates deep within the putative catalytic pocket. file:human/KL/KL-deep-research-falcon.md The weak in vitro glucuronidase activity may represent residual capacity rather than a physiologically significant function. |
| GO:0005104 fibroblast growth factor receptor binding | IBA GO_REF:0000033 | ACCEPT | Summary: KL binds FGF receptors, most importantly FGFR1c, as part of the FGF23 receptor complex. Reason: Co-precipitation shows Klotho binding to FGFR1c, FGFR3c and FGFR4, and the human ternary crystal structure shows the KL2 receptor-binding arm contacting FGFR1c. The IBA node PTN008498336 places this activity in the Klotho clade, and KL sits inside it. Supporting Evidence: PMID:16436388 Klotho binds to multiple FGFRs and functions as a cofactor necessary for FGF signaling activation by FGF23 PMID:16436388 FGF23 was pulled down with FGFR1c, -3c, and -4 only in the presence of Klotho PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005104 fibroblast growth factor receptor binding | IEA GO_REF:0000107 | ACCEPT | Summary: KL binds FGF receptors, most importantly FGFR1c, as part of the FGF23 receptor complex. Reason: Co-precipitation shows Klotho binding to FGFR1c, FGFR3c and FGFR4, and the human ternary crystal structure shows the KL2 receptor-binding arm contacting FGFR1c. The IBA node PTN008498336 places this activity in the Klotho clade, and KL sits inside it. Supporting Evidence: PMID:16436388 Klotho binds to multiple FGFRs and functions as a cofactor necessary for FGF signaling activation by FGF23 PMID:16436388 FGF23 was pulled down with FGFR1c, -3c, and -4 only in the presence of Klotho PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | EXP PMID:10631108 Establishment of the anti-Klotho monoclonal antibodies and d... | ACCEPT | Summary: Human Klotho detected by ELISA in the supernatant of transfected CHO cells. Reason: Direct detection of released human Klotho protein supports an extracellular pool; consistent with shedding and circulating Klotho. Supporting Evidence: PMID:10631108 we detected the human Klotho protein as low as 20 ng/ml in the supernatant of Chinese hamster ovary cells PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. |
| GO:0005576 extracellular region | EXP PMID:15135068 Secreted Klotho protein in sera and CSF: implication for pos... | ACCEPT | Summary: Secreted Klotho detected in human serum and cerebrospinal fluid. Reason: Direct experimental detection of circulating Klotho; the 130 kDa size indicates the shed ectodomain rather than the splice variant. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:15135068 Surprisingly the secreted Klotho was 130 kDa, in contrast to the 70 kDa predicted form |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Soluble alphaKlotho, produced mainly by ectodomain shedding, is present in serum, CSF and urine. Reason: Monoclonal antibodies detect secreted 130 kDa Klotho in human serum and cerebrospinal fluid, and human Klotho is released into culture supernatant. The shed ectodomain retains FGF23 co-receptor activity in trans, so the extracellular location is functionally relevant. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:10631108 we detected the human Klotho protein as low as 20 ng/ml in the supernatant of Chinese hamster ovary cells PMID:29342138 demonstrating that Ξ±Klothoecto can serve as a bona fide co-receptor to support FGF23 signaling in renal proximal tubules |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: Soluble alphaKlotho, produced mainly by ectodomain shedding, is present in serum, CSF and urine. Reason: Monoclonal antibodies detect secreted 130 kDa Klotho in human serum and cerebrospinal fluid, and human Klotho is released into culture supernatant. The shed ectodomain retains FGF23 co-receptor activity in trans, so the extracellular location is functionally relevant. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:10631108 we detected the human Klotho protein as low as 20 ng/ml in the supernatant of Chinese hamster ovary cells PMID:29342138 demonstrating that Ξ±Klothoecto can serve as a bona fide co-receptor to support FGF23 signaling in renal proximal tubules |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-109699 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-190268 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-191062 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2316434 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2400009 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654149 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654165 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654167 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654392 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654560 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654569 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654571 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654573 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654575 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654578 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654582 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654584 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654586 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654587 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654591 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654592 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654594 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654596 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654597 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654600 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654672 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654673 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654690 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5654692 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5656064 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-5672965 | ACCEPT | Summary: Reactome places KL in the extracellular region within FGF23-FGFR1c-Klotho signaling reactions. Reason: Correct for the gene: the shed and secreted forms of KL are extracellular and the soluble ectodomain can act as an FGF23 co-receptor. In these Reactome reactions KL is represented as the membrane-anchored co-receptor, so plasma membrane is the more precise location for the reaction context, but the extracellular annotation is independently well supported. Supporting Evidence: PMID:15135068 Newly established antibodies against Klotho allowed the detection of secreted Klotho, a candidate for the putative humoral factor, in sera and cerebrospinal fluid. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0005886 plasma membrane | EXP PMID:10631108 Establishment of the anti-Klotho monoclonal antibodies and d... | ACCEPT | Summary: 130 kDa Klotho detected in human and mouse kidney membrane fractions. Reason: Direct detection of Klotho in kidney membranes, consistent with the type I transmembrane topology and cell-surface co-receptor function. Supporting Evidence: PMID:10631108 KM2076 and KM2119 specifically recognized a 130 kDa Klotho protein in the mouse and human kidney membrane fractions file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane |
| GO:0005886 plasma membrane | EXP PMID:15135068 Secreted Klotho protein in sera and CSF: implication for pos... | ACCEPT | Summary: Membrane-bound Klotho characterized alongside the secreted form. Reason: The study analyses both membrane-bound and secreted Klotho and proposes release from the cell membrane by post-translational cleavage; plasma membrane is the site of the co-receptor function. Supporting Evidence: PMID:15135068 The secreted as well as the membrane-bound Klotho proteins were suggested to form oligomerized complex. file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Membrane-bound isoform 1 is a type I single-pass plasma-membrane protein. Reason: Kidney membrane fractions contain 130 kDa Klotho, UniProt records isoform 1 at the cell membrane with experimental evidence, and cell-surface KL converts FGFR1c into the FGF23 receptor. Supporting Evidence: PMID:10631108 KM2076 and KM2119 specifically recognized a 130 kDa Klotho protein in the mouse and human kidney membrane fractions file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS PMID:9464267 Identification of the human klotho gene and its two transcri... | ACCEPT | Summary: The human KL gene encodes a membrane-bound form via one of two transcripts. Reason: Consistent with the type I transmembrane topology of isoform 1 and its function as a cell-surface FGF23 co-receptor. Supporting Evidence: PMID:9464267 We have further identified two transcripts that encode a membrane or secreted protein. file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-109699 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-190268 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-191062 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2316434 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-2400009 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654149 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654165 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654167 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654392 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654560 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654569 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654571 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654573 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654575 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654578 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654582 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654584 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654586 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654587 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654591 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654592 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654594 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654596 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654597 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654600 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654672 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654673 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654690 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5654692 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5656064 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5672965 | ACCEPT | Summary: Reactome places membrane-bound KL at the plasma membrane in FGF23-FGFR1c-Klotho signaling reactions. Reason: Membrane-anchored KL forms the FGF23 receptor with FGFR1c at the cell surface. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | REMOVE | Summary: InterPro GH1-family mapping to carbohydrate metabolic process. Reason: KL has no demonstrated role in carbohydrate metabolism. The only reported chemistry is weak in vitro glucuronide hydrolysis, which the human ectodomain did not reproduce, and both GH1-like domains lack a catalytic glutamate. The family mapping assumes a conventional glycosidase, which KL is not; its physiological role is FGF23 co-reception. Supporting Evidence: PMID:29342138 Moreover, both KL domains lack one of the key catalytic glutamates deep within the putative catalytic pocket. PMID:29342138 Indeed, Ξ±Klothoecto failed to hydrolyze substrates for both sialidase and Ξ²-glucuronidase in vitro file:human/KL/KL-uniprot.txt Contains 2 glycosyl hydrolase 1 regions. However, the first region lacks the essential Glu active site residue at position 239 file:human/KL/KL-deep-research-falcon.md The weak in vitro glucuronidase activity may represent residual capacity rather than a physiologically significant function. |
| GO:0008422 beta-glucosidase activity | TAS PMID:9363890 Mutation of the mouse klotho gene leads to a syndrome resemb... | REMOVE | Summary: Beta-glucosidase activity asserted from sequence similarity in the original klotho discovery paper. Reason: The 1997 paper reports only sequence similarity to beta-glucosidases, not activity. When recombinant Klotho was later screened against a series of 4-methylumbelliferyl beta-glycosides, activity was seen only with the glucuronide, not glucosides, and the human ectodomain lacks catalytic glutamates in both GH1-like domains. Beta-glucosidase activity is therefore contradicted. Supporting Evidence: PMID:9363890 The gene encodes a membrane protein that shares sequence similarity with the beta-glucosidase enzymes. PMID:14701853 An enzymatic activity of Klotho was observed only with 4-methylumbelliferyl beta-D-glucuronide PMID:29342138 Moreover, both KL domains lack one of the key catalytic glutamates deep within the putative catalytic pocket. file:human/KL/KL-deep-research-falcon.md The weak in vitro glucuronidase activity may represent residual capacity rather than a physiologically significant function. |
| GO:0008543 fibroblast growth factor receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: KL is an integral component of the FGF23 receptor, making FGF23-FGFR1c signaling possible. Reason: KL binds FGF23 and FGFR1c and is required for FGF23-induced FGFR activation; the anti-Klotho antibody abolishes FGF23 function in vivo. KL does work in the pathway by forming the ligand-binding part of the receptor complex, so involvement in FGFR signaling is a core process. Consistent with the PAINT placement for the Klotho clade. Supporting Evidence: PMID:16436388 Klotho binds to multiple FGFRs and functions as a cofactor necessary for FGF signaling activation by FGF23 PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0014823 response to activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer from rat Kl, whose annotation is based on expression change after physical activity. Reason: This is an electronic transfer from a rat expression (IEP) annotation. A change in KL expression after the stimulus does not show that KL protein acts in the response, and there is no mechanistic evidence for this in human. KL function is FGF23 co-reception. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Apical membrane localization transferred from mouse Klotho. Reason: Mouse Klotho has experimental apical-membrane localization and UniProt carries it by similarity; plausible for polarized renal and choroid-plexus epithelia, but not verified for human and the general plasma membrane location is the core one. Supporting Evidence: file:human/KL/KL-uniprot.txt Apical cell membrane |
| GO:0016324 apical plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Apical membrane localization transferred from mouse Klotho. Reason: Mouse Klotho has experimental apical-membrane localization and UniProt carries it by similarity; plausible for polarized renal and choroid-plexus epithelia, but not verified for human and the general plasma membrane location is the core one. Supporting Evidence: file:human/KL/KL-uniprot.txt Apical cell membrane |
| GO:0017134 fibroblast growth factor binding | IBA GO_REF:0000033 | ACCEPT | Summary: KL directly binds endocrine FGFs, principally FGF23. Reason: Klotho binds FGF23 in renal homogenate and in the human ternary crystal structure, where KL1 and KL2 together form the FGF23-binding groove. The IBA is seeded by KL itself, which is expected, not circular. Supporting Evidence: PMID:17086194 Using a renal homogenate, we found that Klotho binds to FGF23. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0017134 fibroblast growth factor binding | IEA GO_REF:0000120 | ACCEPT | Summary: KL directly binds endocrine FGFs, principally FGF23. Reason: Klotho binds FGF23 in renal homogenate and in the human ternary crystal structure, where KL1 and KL2 together form the FGF23-binding groove. The IBA is seeded by KL itself, which is expected, not circular. Supporting Evidence: PMID:17086194 Using a renal homogenate, we found that Klotho binds to FGF23. PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. |
| GO:0017134 fibroblast growth factor binding | IPI PMID:18829467 C-terminal tail of FGF19 determines its specificity toward K... | ACCEPT | Summary: alphaKlotho binds FGF19 (and FGF23) in chimera binding studies. Reason: The abstract states that FGF19 binds both alpha- and betaKlotho and that the FGF23 C-terminal tail confers alphaKlotho-specific binding. FGF binding is correct; the physiologically important ligand for KL is FGF23. Supporting Evidence: PMID:18829467 We previously showed that FGF19 can bind to both alpha and betaKlotho PMID:18829467 a chimera with the FGF23 C-terminal tail interacts only with alphaKlotho |
| GO:0030501 positive regulation of bone mineralization | IMP PMID:12110410 Association of klotho gene polymorphism with bone density an... | MARK AS OVER ANNOTATED | Summary: Based on association of a KL microsatellite allele with bone density in postmenopausal women. Reason: The study is a genetic association of a non-coding CA-repeat polymorphism with bone density, with no association in the overall population and nominal subgroup associations. That does not show that KL acts in bone mineralization, or in which direction. KL affects the skeleton indirectly through FGF23-dependent phosphate and vitamin D control; human loss of KL causes hyperphosphatemia and ectopic calcification. The curated annotation reflects the paper, but the process claim goes beyond the evidence. Supporting Evidence: PMID:12110410 None of the genotypes was associated with bone density in the overall population PMID:17710231 loss-of-function mutations in human KL impair FGF23 bioactivity, underscoring the essential role of KL in FGF23-mediated phosphate and vitamin D homeostasis in humans |
| GO:0033280 response to vitamin D | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer from rat Kl, whose annotation is based on expression change in response to vitamin D. Reason: This is an electronic transfer from a rat expression (IEP) annotation. A change in KL expression after the stimulus does not show that KL protein acts in the response, and there is no mechanistic evidence for this in human. Vitamin D induces klotho expression as part of the FGF23 feedback loop, but KL itself acts upstream of vitamin D metabolism via FGF23 signaling rather than in the response to vitamin D. Supporting Evidence: PMID:17710231 loss-of-function mutations in human KL impair FGF23 bioactivity, underscoring the essential role of KL in FGF23-mediated phosphate and vitamin D homeostasis in humans |
| GO:0042421 norepinephrine biosynthetic process | IEA GO_REF:0000107 | REMOVE | Summary: Electronic transfer from rat Kl, where brain klotho knockdown raised plasma norepinephrine. Reason: KL performs no step of norepinephrine synthesis. The rat study measured increased plasma norepinephrine after intracerebroventricular klotho shRNA and attributed it to endothelin-1-driven sympathetic activation; that is an indirect systemic effect, not participation in the biosynthetic process. Supporting Evidence: PMID:20086041 Interestingly, KL-shRNA increased brain ET1 expression and plasma norepinephrine level |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: KL detected in urinary exosome proteomes. Reason: High-throughput detection in urinary vesicles is consistent with KL expression in renal and prostate epithelia and release into urine, but exosomal localization has no known functional role for KL. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: KL detected in urinary exosome proteomes. Reason: High-throughput detection in urinary vesicles is consistent with KL expression in renal and prostate epithelia and release into urine, but exosomal localization has no known functional role for KL. Supporting Evidence: PMID:23533145 Using expressed prostatic secretions in urine (EPS-urine), exosome preparations were characterized by a shotgun proteomics procedure. |
| GO:0071774 response to fibroblast growth factor | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic transfer from rat Kl expression data; in human, KL is part of the receptor that responds to FGF23. Reason: The rat source is an expression change, but the term is true for human KL for a different reason: fibroblast growth factor receptor signaling pathway (which KL carries by IBA) is a descendant of response to fibroblast growth factor. The precise term is the signaling pathway; this broader term is redundant but not wrong. Supporting Evidence: PMID:16436388 Klotho binds to multiple FGFRs and functions as a cofactor necessary for FGF signaling activation by FGF23 PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. |
| GO:1990776 response to angiotensin | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic transfer from rat Kl, whose annotation is based on expression change after angiotensin II. Reason: This is an electronic transfer from a rat expression (IEP) annotation. A change in KL expression after the stimulus does not show that KL protein acts in the response, and there is no mechanistic evidence for this in human. Supporting Evidence: file:human/KL/KL-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane |
| GO:0015026 coreceptor activity | IDA PMID:29342138 Ξ±-Klotho is a non-enzymatic molecular scaffold for FGF23 hor... | NEW | Summary: alphaKlotho binds FGF23 and FGFR1c and is required for FGF23 to activate FGFR1c; it cannot signal alone. Reason: Coreceptor activity (binding an extracellular messenger and cooperating with a nearby primary receptor to initiate a change in cell activity) describes KL exactly: it converts FGFR1c into a high-affinity FGF23 receptor, both membrane-bound and as the soluble ectodomain. This matches the core MF used for the paralog KLB. Fibroblast growth factor binding and FGF receptor binding already present describe the two halves of this activity. Supporting Evidence: PMID:29342138 The structure reveals that Ξ±Klotho serves as a non-enzymatic scaffold that simultaneously tethers FGFR1c and FGF23 to implement FGF23-FGFR1c proximity and hence stability. PMID:17086194 Thus, the concerted action of Klotho and FGFR1(IIIc) reconstitutes the FGF23 receptor. PMID:16436388 Klotho binds to multiple FGFRs and functions as a cofactor necessary for FGF signaling activation by FGF23 |
| GO:0055062 phosphate ion homeostasis | IMP PMID:17710231 A homozygous missense mutation in human KLOTHO causes severe... | NEW | Summary: Homozygous loss-of-function KL H193R causes hyperphosphatemic tumoral calcinosis by impairing FGF23 signaling. Reason: KL performs work in this process as the ligand-binding part of the FGF23 receptor in kidney, not merely as a required factor: FGF23 cannot engage FGFR1c without it. Comparator check: FGF23 carries phosphate ion homeostasis (IMP); FGFR1 and KLB do not, the latter because it serves other FGFs. The human disease phenotype is precisely loss of FGF23-dependent phosphate control. Supporting Evidence: PMID:17710231 loss-of-function mutations in human KL impair FGF23 bioactivity, underscoring the essential role of KL in FGF23-mediated phosphate and vitamin D homeostasis in humans PMID:17710231 This patient exhibited defects in mineral ion homeostasis with marked hyperphosphatemia |
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Download this section (compressed HTML)Q: Does alpha-Klotho retain any physiologically relevant glycosidase activity, reconciling the positive glucuronidase report for a mouse Klotho-Fc fusion with the negative result for the human ectodomain?
Q: Which binding partner mediates the FGF23-independent effects attributed to soluble Klotho, such as modulation of insulin/IGF1 signaling, Wnt signaling and TRPV5 or ROMK channel surface abundance, and do these involve glycan binding rather than hydrolysis?
Q: Is phosphate ion homeostasis an appropriate process term for KL given that FGF23 carries it but FGFR1 and KLB do not, or is the GO convention to place endocrine-outcome terms only on the hormone?
Q: What fraction of circulating Klotho arises from ADAM-mediated ectodomain shedding versus the KL1-only splice transcript, and does the splice product have measurable co-receptor activity?
Experiment: Assay purified, correctly glycosylated human alpha-Klotho ectodomain and the mouse Klotho-Fc construct side by side against 4-methylumbelliferyl glucuronide and steroid glucuronides with sensitive product detection, then test matched catalytic-site variants for FGF23 binding and FGFR1c activation in a Klotho-null cell line.
Hypothesis: Any glucuronidase activity of Klotho is separable from, and dispensable for, its FGF23 co-receptor function.
Type: Parallel enzymology and separation-of-function signaling assay
Experiment: Compare mice expressing only a non-sheddable membrane-anchored KL with mice expressing only the soluble ectodomain from a Klotho-null background, and measure FGF23-dependent phosphaturia, CYP27B1 and CYP24A1 expression and ERK activation in proximal tubule and in FGFR-positive, KL-negative tissues.
Hypothesis: The soluble shed ectodomain supports FGF23 signaling in vivo in tissues that lack membrane-bound KL.
Type: Allele-specific mouse genetics with endocrine readouts
Experiment: Perform proximity labeling and unbiased CRISPR screening for loss of soluble-Klotho responsiveness in cells lacking FGFRs, then validate candidate receptors by binding measurements and by testing whether KL variants that lose FGF23 co-receptor activity retain the FGF23-independent response.
Hypothesis: FGF23-independent effects of soluble Klotho require a distinct cell-surface receptor.
Type: Interaction proteomics plus genetic screen
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