The ß-Glucuronidase Klotho Hydrolyzes and Activates the TRPV5 Channel

Chang, Qing; Hoefs, Susan; Kemp, Jennifer; Topala, Catalin N.; Bindels, René J. M.; Hoenderop, Joost G. J.

doi:10.1126/science.1114245

Cited by 570 publications

(502 citation statements)

References 19 publications

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“…Mechanisms implicated in its tumor suppressor activities include inhibition of insulin and IGF-1 signaling, modulation of FGF signaling, and inhibition of Wnt signaling (4,5,8,9,12,15,37). We noted a correlation between the ability to inhibit the IGF-1 pathway, interaction with the IGF-1R, and inhibition of proliferation.…”

Section: Discussionmentioning

confidence: 85%

“…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%

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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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Section: Discussionmentioning

confidence: 85%

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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“…The wide-ranging activity of klotho raises the possibility that regulation of Ca and phosphate metabolism is an Urinary P ↑ Urinary Ca ↓ essential feature of many systems of the body, not just those connected with the skeleton. Further information on this area of discussion is available (1,20,(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48) .…”

Section: Low Serum Calciummentioning

confidence: 99%

Elsie Widdowson Lecture 2006 Mining the depths: metabolic insights into mineral nutrition

Prentice

2007

Proc. Nutr. Soc.

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2006 marked the centenary of the birth of Dr Elsie Widdowson, a pioneer of nutrition science. One of the hallmarks of Elsie Widdowson's research was an integrative approach that recognised the importance of investigating the mechanisms underpinning a public health or clinical issue at all levels, looking into the physiology, comparative biology, intermediate metabolism and basic science. The theme of the present lecture, given in celebration of the work of Dr Widdowson, is mineral nutrition, with a particular focus on Ca, P and vitamin D. The contributions of Dr Widdowson to the early understanding of mineral nutrition are reviewed and the latest scientific findings in this rapidly-expanding field of research are presented.

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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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The ß-Glucuronidase Klotho Hydrolyzes and Activates the TRPV5 Channel

Cited by 570 publications

References 19 publications

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

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

Elsie Widdowson Lecture 2006 Mining the depths: metabolic insights into mineral nutrition

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

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