Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1

Kuy, Seung; Ortega, Bernardo; Kurosu, Hiroshi; Rosenblatt, Kevin P.; Kuro‐o, Makoto; Huang, Chou Long

doi:10.1073/pnas.0803223105

Cited by 367 publications

(381 citation statements)

References 44 publications

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“…Whole-cell patch-clamp recording was performed using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster City, CA) as previously described. 26 siRNA-Mediated DGKE Targeting A pool of four siRNAs targeting different sequences of DGKE mRNA was purchased from Thermo Scientific (SMART pool L-011493-00-0005, anti-human DGKE NM_003647) and used according to the manufacturer's indications.…”

Section: Whole-cell Patch-clamp Electrophysiological Analysesmentioning

confidence: 99%

DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN

Özaltın

Li²,

Rauhauser³

et al. 2013

Journal of the American Society of Nephrology

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131

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Renal microangiopathies and membranoproliferative GN (MPGN) can manifest similar clinical presentations and histology, suggesting the possibility of a common underlying mechanism in some cases. Here, we performed homozygosity mapping and whole exome sequencing in a Turkish consanguineous family and identified DGKE gene variants as the cause of a membranoproliferative-like glomerular microangiopathy. Furthermore, we identified two additional DGKE variants in a cohort of 142 unrelated patients diagnosed with membranoproliferative GN. This gene encodes the diacylglycerol kinase DGK«, which is an intracellular lipid kinase that phosphorylates diacylglycerol to phosphatidic acid. Immunofluorescence confocal microscopy demonstrated that mouse and rat Dgk« colocalizes with the podocyte marker WT1 but not with the endothelial marker CD31. Patch-clamp experiments in human embryonic kidney (HEK293) cells showed that DGK« variants affect the intracellular concentration of diacylglycerol. Taken together, these results not only identify a genetic cause of a glomerular microangiopathy but also suggest that the phosphatidylinositol cycle, which requires DGKE, is critical to the normal function of podocytes.

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Section: Whole-cell Patch-clamp Electrophysiological Analysesmentioning

confidence: 99%

DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN

Özaltın

Li²,

Rauhauser³

et al. 2013

Journal of the American Society of Nephrology

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131

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“…The physiological function of klotho in the normal mammary gland has not been elucidated yet. In addition to its functions as a modulator of the FGF and IGF-1 pathways, klotho can activate calcium channels (TRPV5 and TRPV6) through modifying their glycans (Cha et al, 2008;Chang et al, 2005). Whereas TRPV5 is expressed in renal tubular cells, TRPV6 is expressed in the intestinal and mammary epithelial cells and is involved in transepithelial calcium transport (den Dekker et al, 2003).…”

Section: Klotho In Breast Cancer I Wolf Et Almentioning

confidence: 99%

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

et al. 2008

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Klotho is an anti-aging gene, which has been shown to inhibit the insulin and insulin-like growth factor 1 (IGF-1) pathways in mice hepatocytes and myocytes. As IGF-1 and insulin regulate proliferation, survival and metastasis of breast cancer, we studied klotho expression and activities in human breast cancer. Immunohistochemistry analysis of klotho expression in breast tissue arrays revealed high klotho expression in normal breast samples, but very low expression in breast cancer. In cancer samples, high klotho expression was associated with smaller tumor size and reduced KI67 staining. Forced expression of klotho reduced proliferation of MCF-7 and MDA-MB-231 breast cancer cells, whereas klotho silencing in MCF-7 cells, which normally express klotho, enhanced proliferation. Moreover, forced expression of klotho in these cells, or treatment with soluble klotho, inhibited the activation of IGF-1 and insulin pathways, and induced upregulation of the transcription factor CCAAT/enhancer-binding protein b, a breast cancer growth inhibitor that is negatively regulated by the IGF-1-AKT axis. Co-immunoprecipitation revealed an interaction between klotho and the IGF-1 receptor. Klotho is also a known modulator of the fibroblast growth factor (FGF) pathway, a pathway that inhibits proliferation of breast cancer cells. Studies in breast cancer cells revealed increased activation of the FGF pathway by basic FGF following klotho overexpression. Klotho did not affect activation of the epidermal growth factor pathway in breast cancer cells. These data suggest klotho as a potential tumor suppressor and identify it as an inhibitor of the IGF-1 pathway and activator of the FGF pathway in human breast cancer.

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“…Klotho is an essential cofactor for binding of FGF23 to the FGF receptor (FGFR; refs. 5,8), it modulates bFGF signaling (9, 10), inhibits the insulin and the insulin-like growth factor (IGF)-1 pathways (4,9), and regulates the activity of the transient receptor potential vanilloid type 5 (TRPV5) calcium channel (11,12). The common link between these diverse activities has not been elucidated yet.…”

Section: Introductionmentioning

confidence: 99%

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

Ligumsky

Rubinek

Merenbakh-Lamin

et al. 2015

Molecular Cancer Research

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Klotho is a transmembrane protein containing two internal repeats, KL1 and KL2, both displaying significant homology to members of the b-glycosidase family. Klotho is expressed in the kidney, brain, and various endocrine tissues, but can also be cleaved and act as a circulating hormone. Klotho is an essential cofactor for binding of fibroblast growth factor 23 (FGF23) to the FGF receptor and can also inhibit the insulin-like growth factor-1 (IGF-1) pathway. Data from a wide array of malignancies indicate klotho as a tumor suppressor; however, the structure-function relationships governing its tumor suppressor activities have not been deciphered. Here, the tumor suppressor activities of the KL1 and KL2 domains were examined. Overexpression of either klotho or KL1, but not of KL2, inhibited colony formation by MCF-7 and MDA-MB-231 cells. Moreover, in vivo administration of KL1 was not only well tolerated but significantly slowed tumor formation in nude mice. Further studies indicated that KL1, but not KL2, interacted with the IGF-1R and inhibited the IGF-1 pathway. Based on computerized structural modeling, klotho constructs were generated in which critical amino acids have been mutated. Interestingly, the mutated proteins retained their tumor suppressor activity but showed reduced ability to modulate FGF23 signaling. These data indicate differential activity of the klotho domains, KL1 and KL2, in breast cancer and reveal that the tumor suppressor activities of klotho can be dissected from its physiologic activities.Implications: These findings pave the way for a rational design of safe klotho-based molecules for the treatment of breast cancer.

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Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1

Cited by 367 publications

References 44 publications

DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN

DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

Tumor Suppressor Activity of Klotho in Breast Cancer Is Revealed by Structure–Function Analysis

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