Intracellular signaling of the aging suppressor protein klotho

Current Molecular Medicine

Volumn 15, Issue 1, 2015, Pages 27-37

  Sopjani, M ^a   Rinnerthaler, M ^b   Kruja, J ^c   Dermaku Sopjani M ^a  

^a UNIVERSITY OF PRISHTINA   (Serbia)

^b UNIVERSITY OF SALZBURG   (Austria)

^c University of Medicine   (Albania)

Author keywords

cAMP; Fibroblast growth factor (FGF); Insulin IGF 1; Klotho; p53 p21; PKC; PTH; Vitamin D; Wnt signaling pathway

Indexed keywords

ADENYLATE CYCLASE; CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE; DENTIN MATRIX PROTEIN 1; DIPEPTIDYL CARBOXYPEPTIDASE; FIBROBLAST GROWTH FACTOR 23; INSULIN; KLOTHO PROTEIN; PARATHYROID HORMONE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE C; PROTEIN P21; PROTEIN P53; RETINOIC ACID INDUCIBLE PROTEIN I; SOMATOMEDIN C; TRANSFORMING GROWTH FACTOR BETA; VITAMIN D; BETA GLUCURONIDASE; FIBROBLAST GROWTH FACTOR;

AGING; ARTICLE; GENE EXPRESSION; GENE OVEREXPRESSION; HOMEOSTASIS; HUMAN; INTRACELLULAR SIGNALING; KIDNEY FIBROSIS; KIDNEY FUNCTION; LONGEVITY; PREMATURE AGING; PROTEIN EXPRESSION; REGULATORY MECHANISM; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION; WNT SIGNALING PATHWAY; DEFICIENCY; GENETICS; PATHOPHYSIOLOGY; PHYSIOLOGY;

AGING, PREMATURE; FIBROBLAST GROWTH FACTORS; GLUCURONIDASE; HUMANS; INSULIN; INSULIN-LIKE GROWTH FACTOR I; LONGEVITY; TRANSFORMING GROWTH FACTOR BETA; WNT SIGNALING PATHWAY;

EID: 84922288806     PISSN: 15665240     EISSN: 18755666     Source Type: Journal    
DOI: 10.2174/1566524015666150114111258     Document Type: Article

References (108)

1. Razzaque MS, Sitara D, Taguchi T, St Arnaud R, Lanske B. Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. FASEB J 2006; 20: 720-722.
2. Tsujikawa H, Kurotaki Y, Fujimori T, Fukuda K, Nabeshima Y. Klotho, a gene related to a syndrome resembling human premature aging, functions in a negative regulatory circuit of vitamin D endocrine system. Mol Endocrinol 2003; 17: 2393-2403.
3. Wang Y, Sun Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage. Hypertension 2009; 54: 810-817.
4. Satoh M, Nagasu H, Morita Y, Yamaguchi TP, Kanwar YS, Kashihara N. Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling. Am J Physiol Renal Physiol 2012; 303: F1641-F1651.
5. Mochly-Rosen D, Das K, Grimes KV. Protein kinase C, an elusive therapeutic target? Nat Rev Drug Discov 2012; 11: 937-957.
6. Maekawa Y, Ishikawa K, Yasuda O, et al. Klotho suppresses TNF-alpha-induced expression of adhesion molecules in the endothelium and attenuates NF-kappaB activation. Endocrine 2009; 35: 341-346.
7. Rakugi H, Matsukawa N, Ishikawa K, et al. Anti-oxidative effect of Klotho on endothelial cells through cAMP activation. Endocrine 2007; 31: 82-87.
8. Dehvari N, Cedazo-Minguez A, Isacsson O, et al. Presenilin dependence of phospholipase C and protein kinase C signaling. J Neurochem 2007; 102: 848-857.
9. Semba RD, Cappola AR, Sun K, et al. Plasma klotho and cardiovascular disease in adults. J Am Geriatr Soc 2011; 59: 1596-1601.
10. Kuro-o M, Matsumura Y, Aizawa H, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390: 45-51.
11. Dermaku-Sopjani M, Kolgeci S, Abazi S, Sopjani M. Significance of the anti-aging protein Klotho. Mol Membr Biol 2013; 30: 369-385.
12. Hu MC, Shi M, Zhang J, Quinones H, Kuro-o M, Moe OW. Klotho deficiency is an early biomarker of renal ischemiareperfusion injury and its replacement is protective. Kidney Int 2010; 78: 1240-1251.
13. Dermaku-Sopjani M, Sopjani M, Saxena A, et al. Downregulation of NaPi-IIa and NaPi-IIb Na-coupled phosphate transporters by coexpression of Klotho. Cell Physiol Biochem 2011; 28: 251-258.
14. John GB, Cheng CY, Kuro-o M. Role of Klotho in aging, phosphate metabolism, and CKD. Am J Kidney Dis 2011; 58: 127-134.
15. Zacchia M, Capasso G. Dehydration: a new modulator of klotho expression. Am J Physiol Renal Physiol 2011; 301: F743-F744.
16. Kuro O. Klotho in health and disease. Curr Opin Nephrol Hypertens 2012; 21: 362-368.
17. Manya H, Akasaka-Manya K, Endo T. Klotho protein deficiency and aging. Geriatr Gerontol Int 2010; 10 Suppl 1: S80-S87.
18. Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice by the hormone Klotho. Science 2005; 309: 1829-1833.
19. Sopjani M, Alesutan I, Dermaku-Sopjani M, et al. Regulation of the Na+/K+ ATPase by Klotho. FEBS Lett 2011; 585: 1759-1764.
20. Almilaji A, Pakladok T, Munoz C, Elvira B, Sopjani M, Lang F. Upregulation of KCNQ1/KCNE1 K+ channels by Klotho. Channels (Austin) 2014; 8: 222-229.
21. Sopjani M, Alesutan I, Wilmes J, et al. Stimulation of Na+/K+ ATPase activity and Na+ coupled glucose transport by betacatenin. Biochem Biophys Res Commun 2010; 402: 467-470.
22. Dermaku-Sopjani M, Abazi S, Faggio C, Kolgeci J, Sopjani M. AMPK-sensitive cellular transport. J Biochem 2014; 155: 147-158.
23. Munoz C, Sopjani M, Dermaku-Sopjani M, Almilaji A, Foller M, Lang F. Downregulation of the osmolyte transporters SMIT and BGT1 by AMP-activated protein kinase. Biochem Biophys Res Commun 2012; 422: 358-362.
24. Foller M, Jaumann M, Dettling J, et al. AMP-activated protein kinase in BK-channel regulation and protection against hearing loss following acoustic overstimulation. FASEB J 2012; 26: 4243-4253.
25. Sopjani M, Alesutan I, Dermaku-Sopjani M, et al. Downregulation of Na+-coupled glutamate transporter EAAT3 and EAAT4 by AMP-activated protein kinase. J Neurochem 2010; 113: 1426-1435.
26. Dermaku-Sopjani M, Almilaji A, Pakladok T, et al. Downregulation of the Na-coupled phosphate transporter NaPi-IIa by AMP-activated protein kinase. Kidney Blood Press Res 2013; 37: 547-556.
27. Bhavsar SK, Hosseinzadeh Z, Brenner D, et al. Energysensitive regulation of Na+/K+-ATPase by Janus kinase 2. Am J Physiol Cell Physiol 2014; 306: C374-C384.
28. Hosseinzadeh Z, Sopjani M, Pakladok T, Bhavsar SK, Lang F. Downregulation of KCNQ4 by Janus kinase 2. J Membr Biol 2013; 246: 335-341.
29. Woudenberg-Vrenken TE, van der Eerden BC, van der Kemp AW, van Leeuwen JP, Bindels RJ, Hoenderop JG. Characterization of vitamin D-deficient klotho-/-mice: do increased levels of serum 1, 25(OH)2D3 cause disturbed calcium and phosphate homeostasis in klotho-/-mice? Nephrol Dial Transplant 2012; 27: 4061-4068.
30. Wang Y, Kuro O, Sun Z. Klotho gene delivery suppresses Nox2 expression and attenuates oxidative stress in rat aortic smooth muscle cells via the cAMP-PKA pathway. Aging Cell 2012; 11: 410-417.
31. Yamamoto M, Clark JD, Pastor JV, et al. Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem 2005; 280: 38029-38034.
32. Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A 2007; 104: 19796-19801.
33. Matsumura Y, Aizawa H, Shiraki-Iida T, Nagai R, Kuro-o M, Nabeshima Y. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem. Biophys Res Commun 1998; 242: 626-630.
34. Camilli TC, Xu M, O'Connell MP, et al. Loss of Klotho during melanoma progression leads to increased filamin cleavage, increased Wnt5A expression, and enhanced melanoma cell motility. Pigment Cell Melanoma Res 2011; 24: 175-186.
35. Kuro-o M. Disease model: human aging. Trends Mol Med 2001; 7: 179-181.
36. Doi S, Zou Y, Togao O, et al. Klotho inhibits transforming growth factor-beta1 (TGF-beta1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J Biol Chem 2011; 286: 8655-8665.
37. Li BS, Ma HX, Wang YJ, Wu P. [Klotho gene attenuates the progression of hypertension and heart damage in spontaneous hypertensive rats]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2012; 29: 662-668.
38. Hu MC, Shi M, Zhang J, et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J 2010; 24: 3438-3450.
39. Cha SK, Ortega B, Kurosu H, Rosenblatt KP, Kuro O, Huang CL. Removal of sialic acid involving Klotho causes cellsurface retention of TRPV5 channel via binding to galectin-1. Proc Natl Acad Sci U S A 2008; 105: 9805-9810.
40. Wolf I, Levanon-Cohen S, Bose S, et al. Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer. Oncogene 2008; 27: 7094-7105.
41. Bergwitz C, Juppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med 2010; 61: 91-104.
42. Imai M, Ishikawa K, Matsukawa N, et al. Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression. Endocrine 2004; 25: 229-234.
43. Ikushima M, Rakugi H, Ishikawa K, et al. Anti-apoptotic and anti-senescence effects of Klotho on vascular endothelial cells. Biochem Biophys Res Commun 2006; 339: 827-832.
44. Liu H, Fergusson MM, Castilho RM, et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 2007; 317: 803-806.
45. Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444: 770-774.
46. Faul C, Amaral AP, Oskouei B, et al. FGF23 induces left ventricular hypertrophy. J. Clin. Invest 2011; 121: 4393-4408.
47. Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006; 281: 6120-6123.
48. Itoh N, Ornitz DM. Evolution of the Fgf and Fgfr gene families. Trends Genet 2004; 20: 563-569.
49. Bai X, Miao D, Li J, Goltzman D, Karaplis AC. Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. Endocrinology 2004; 145: 5269-5279.
50. Ho HK, Pok S, Streit S, et al. Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alphafetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention. J Hepatol 2009; 50: 118-127.
51. Andrukhova O, Zeitz U, Goetz R, Mohammadi M, Lanske B, Erben RG. FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway. Bone 2012; 51: 621-628.
52. Sitara D, Kim S, Razzaque MS, et al. Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. PLoS Genet 2008; 4: e1000154.
53. Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD. Pathogenic role of Fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 2006; 291: E38-E49.
54. Liu S, Zhou J, Tang W, Menard R, Feng JQ, Quarles LD. Pathogenic role of Fgf23 in Dmp1-null mice. Am J Physiol Endocrinol Metab 2008; 295: E254-E261.
55. Sitara D, Razzaque MS, Hesse M, et al. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol 2004; 23: 421-432.
56. Shimada T, Urakawa I, Yamazaki Y, et al. FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. Biochem. Biophys Res Commun 2004; 314: 409-414.
57. Sitara D, Razzaque MS, St Arnaud R, et al. Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals. Am J Pathol 2006; 169: 2161-2170.
58. Fukumoto S, Yamashita T. Fibroblast growth factor-23 is the phosphaturic factor in tumor-induced osteomalacia and may be phosphatonin. Curr Opin Nephrol Hypertens 2002; 11: 385-389.
59. Perwad F, Zhang MY, Tenenhouse HS, Portale AA. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. Am J Physiol Renal Physiol 2007; 293: F1577-F1583.
60. Gattineni J, Bates C, Twombley K, et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol 2009; 297: F282-F291.
61. Borst O, Munzer P, Schmid E, et al. 1, 25(OH)2 vitamin D3-dependent inhibition of platelet Ca2+ signaling and thrombus formation in klotho-deficient mice. FASEB J 2014; 28: 2108-2119.
62. Shumilina E, Nurbaeva MK, Yang W, et al. Altered regulation of cytosolic Ca(2)(+) concentration in dendritic cells from klotho hypomorphic mice. Am J Physiol Cell Physiol 2013; 305: C70-C77.
63. Medici D, Razzaque MS, Deluca S, et al. FGF-23-Klotho signaling stimulates proliferation and prevents vitamin Dinduced apoptosis. J Cell Biol 2008; 182: 459-465.
64. Sugiura H, Yoshida T, Tsuchiya K, et al. Klotho reduces apoptosis in experimental ischaemic acute renal failure. Nephrol Dial Transplant 2005; 20: 2636-2645.
65. Koh N, Fujimori T, Nishiguchi S, et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochem. Biophys Res Commun 2001; 280: 1015-1020.
66. Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 2011; 22: 124-136.
67. Kenyon C. The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing. Philos. Trans R Soc Lond B Biol Sci 2011; 366: 9-16.
68. Schmid E, Yan J, Nurbaeva MK, et al. Decreased store operated Ca2+ entry in dendritic cells isolated from mice expressing PKB/SGK-resistant GSK3. PLoS One 2014; 9: e88637.
69. Mitobe M, Yoshida T, Sugiura H, Shirota S, Tsuchiya K, Nihei H. Oxidative stress decreases klotho expression in a mouse kidney cell line. Nephron Exp Nephrol 2005; 101: e67-e74.
70. Kops GJ, Dansen TB, Polderman PE, et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 2002; 419: 316-321.
71. Kokkinaki M, Abu-Asab M, Gunawardena N, et al. Klotho regulates retinal pigment epithelial functions and protects against oxidative stress. J Neurosci 2013; 33: 16346-16359.
72. Kuro-o M. Klotho as a regulator of oxidative stress and senescence. Biol Chem 2008; 389: 233-241.
73. Chen CD, Sloane JA, Li H, et al. The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci 2013; 33: 1927-1939.
74. Yang HC, Rossini M, Ma LJ, Zuo Y, Ma J, Fogo AB. Cells derived from young bone marrow alleviate renal aging. J Am Soc Nephrol 2011; 22: 2028-2036.
75. Kuang X, Chen YS, Wang LF, et al. Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer's disease mouse model. Neurobiol Aging 2014; 35: 169-178.
76. Xie B, Zhou J, Shu G, et al. Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: tumor suppressive role of klotho in gastric cancer. Cancer Cell Int 2013; 13: 18.
77. Shu G, Xie B, Ren F, et al. Restoration of klotho expression induces apoptosis and autophagy in hepatocellular carcinoma cells. Cell Oncol (Dordr) 2013; 36: 121-129.
78. Chen B, Wang X, Zhao W, Wu J. Klotho inhibits growth and promotes apoptosis in human lung cancer cell line A549. J Exp Clin Cancer Res 2010; 29: 99.
79. Abramovitz L, Rubinek T, Ligumsky H, et al. KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer. Clin Cancer Res 2011; 17: 4254-4266.
80. Liu F, Wu S, Ren H, Gu J. Klotho suppresses RIG-Imediated senescence-associated inflammation. Nat Cell Biol 2011; 13: 254-262.
81. Vonend O, Apel T, Amann K, et al. Modulation of gene expression by moxonidine in rats with chronic renal failure. Nephrol Dial Transplant 2004; 19: 2217-2222.
82. Zhang F, Kato BS, Gardner JP, Kimura M, Spector TD, Ahmadi KR. Lack of association between leukocyte telomere length and genetic variants in two ageing-related candidate genes. Mech Ageing Dev 2007; 128: 415-422.
83. Chen B, Ma X, Liu S, Zhao W, Wu J. Inhibition of lung cancer cells growth, motility and induction of apoptosis by Klotho, a novel secreted Wnt antagonist, in a dose-dependent manner. Cancer Biol Ther 2012; 13: 1221-1228.
84. de Oliveira RM. Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway. FEBS Lett 2006; 580: 5753-5758.
85. Sugiura H, Yoshida T, Shiohira S, et al. Reduced Klotho expression level in kidney aggravates renal interstitial fibrosis. Am J Physiol Renal Physiol 2012; 302: F1252-F1264.
86. Zhou L, Li Y, Zhou D, Tan RJ, Liu Y. Loss of Klotho contributes to kidney injury by derepression of Wnt/betacatenin signaling. J Am Soc Nephrol 2013; 24: 771-785.
87. Beckerman R, Prives C. Transcriptional regulation by p53. Cold Spring Harb Perspect Biol 2010; 2: a000935.
88. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 2005; 120: 513-522.
89. Miyauchi H, Minamino T, Tateno K, Kunieda T, Toko H, Komuro I. Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. EMBO J 2004; 23: 212-220.
90. Chen YJ, Hsiao PW, Lee MT, Mason JI, Ke FC, Hwang JJ. Interplay of PI3K and cAMP/PKA signaling, and rapamycinhypersensitivity in TGFbeta1 enhancement of FSHstimulated steroidogenesis in rat ovarian granulosa cells. J Endocrinol 2007; 192: 405-419.
91. Yang J, Matsukawa N, Rakugi H, et al. Upregulation of cAMP is a new functional signal pathway of Klotho in endothelial cells. Biochem Biophys Res Commun 2003; 301: 424-429.
92. Kim HJ, Chang H, Han SH, et al. Epigallocatechin-3-O-(3-Omethyl)-gallate-induced differentiation of human keratinocytes involves klotho-mediated regulation of protein kinase-cAMP responsive element-binding protein signaling. Int J Mol Sci 2014; 15: 5749-5761.
93. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298: 1912-1934.
94. Steinberg SF. Structural basis of protein kinase C isoform function. Physiol Rev 2008; 88: 1341-1378.
95. Garcia-Bermejo ML, Leskow FC, Fujii T, et al. Diacylglycerol (DAG)-lactones, a new class of protein kinase C (PKC) agonists, induce apoptosis in LNCaP prostate cancer cells by selective activation of PKCalpha. J Biol Chem 2002; 277: 645-655.
96. Raikwar NS, Liu KZ, Thomas CP. Protein kinase C regulates FLT1 abundance and stimulates its cleavage in vascular endothelial cells with the release of a soluble PlGF/VEGF antagonist. Exp Cell Res 2013; 319: 2578-2587.
97. Avila E, Diaz L, Barrera D, et al. Regulation of Vitamin D hydroxylases gene expression by 1, 25-dihydroxyvitamin D3 and cyclic AMP in cultured human syncytiotrophoblasts. J Steroid Biochem Mol Biol 2007; 103: 90-96.
98. Imura A, Tsuji Y, Murata M, et al. alpha-Klotho as a regulator of calcium homeostasis. Science 2007; 316: 1615-1618.
99. Alexander RT, Woudenberg-Vrenken TE, Buurman J, et al. Klotho prevents renal calcium loss. J Am Soc Nephrol 2009; 20: 2371-2379.
100. Kawaguchi H, Manabe N, Miyaura C, Chikuda H, Nakamura K, Kuro-o M. Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting lowturnover osteopenia. J Clin Invest 1999; 104: 229-237.
101. Xie B, Chen J, Liu B, Zhan J. Klotho acts as a tumor suppressor in cancers. Pathol Oncol Res 2013; 19: 611-617.
102. Mehi SJ, Maltare A, Abraham CR, King GD. MicroRNA-339 and microRNA-556 regulate Klotho expression in vitro. Age (Dordr) 2014; 36: 141-149.
103. Ell B, Mercatali L, Ibrahim T, et al. Tumor-Induced Osteoclast miRNA Changes as Regulators and Biomarkers of Osteolytic Bone Metastasis. Cancer Cell 2013; 24: 542-556.
104. Hackl M, Brunner S, Fortschegger K, et al. miR-17, miR-19b, miR-20a, and miR-106a are down-regulated in human aging. Aging Cell 2010; 9: 291-296.
105. Fang Y, Ginsberg C, Seifert M, et al. CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD-Mineral and Bone Disorder. J Am Soc Nephrol 2014; 25: 1760-1773.
106. Anour R, Andrukhova O, Ritter E, Zeitz U, Erben RG. Klotho lacks a vitamin D independent physiological role in glucose homeostasis, bone turnover, and steady-state PTH secretion in vivo. PLoS One 2012; 7: e31376.
107. Zhu Y, Xu L, Zhang J, et al. Klotho suppresses tumor progression via inhibiting PI3K/Akt/GSK3beta/Snail signaling in renal cell carcinoma. Cancer Sci 2013; 104: 663-671.
108. Chen L, Liu H, Liu J, et al. Klotho endows hepatoma cells with resistance to anoikis via VEGFR2/PAK1 activation in hepatocellular carcinoma. PLoS One 2013; 8: e58413.