Chonnam Med J.  2017 Jan;53(1):28-36. 10.4068/cmj.2017.53.1.28.

Versatile Functions of Caveolin-1 in Aging-related Diseases

• Nguyen KC
• Cho KA

• KMID: 2367337
• DOI: http://doi.org/10.4068/cmj.2017.53.1.28

Abstract

Caveolin-1 (Cav-1) is a trans-membrane protein that is a major component of the caveolae structure on the plasma membrane. Cav-1 is involved in the regulation of various cellular processes, including cell growth, differentiation, endocytosis, and in particular it has been implied in cellular senescence. Here we review current knowledge about Cav-1 in cellular signaling and discuss the role of Cav-1 in aging-related diseases.

Keyword

Caveolin 1; Caveolae; Cell Aging; Endocytosis

MeSH Terms

Caveolae
Caveolin 1*
Cell Aging
Cell Membrane
Endocytosis
Caveolin 1

Reference

1. Thomas CM, Smart EJ. Caveolae structure and function. J Cell Mol Med. 2008; 12:796–809.

2. Liu P, Rudick M, Anderson RG. Multiple functions of caveolin-1. J Biol Chem. 2002; 277:41295–41298.

3. Anderson RG. The caveolae membrane system. Annu Rev Biochem. 1998; 67:199–225.

4. Boscher C, Nabi IR. Caveolin-1: role in cell signaling. In : Jasmin JF, Frank PG, Lisanti MP, editors. Caveolins and Caveolae. New York: Springer;2012. p. 29–50.

5. Parton RG, Simons K. The multiple faces of caveolae. Nat Rev Mol Cell Biol. 2007; 8:185–194.

6. Schlegel A, Lisanti MP. A molecular dissection of caveolin-1 membrane attachment and oligomerization Two separate regions of the caveolin-1 C-terminal domain mediate membrane binding and oligomer/oligomer interactions in vivo. J Biol Chem. 2000; 275:21605–21617.

7. Razani B, Woodman SE, Lisanti MP. Caveolae: from cell biology to animal physiology. Pharmacol Rev. 2002; 54:431–467.

8. Sowa G, Pypaert M, Sessa WC. Distinction between signaling mechanisms in lipid rafts vs. caveolae. Proc Natl Acad Sci U S A. 2001; 98:14072–14077.

9. Patel HH, Murray F, Insel PA. Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol. 2008; 48:359–391.

10. Low JY, Nicholson HD. Epigenetic modifications of caveolae associated proteins in health and disease. BMC Genet. 2015; 16:71.

11. Quest AF, Gutierrez-Pajares JL, Torres VA. Caveolin-1: an ambiguous partner in cell signalling and cancer. J Cell Mol Med. 2008; 12:1130–1150.

12. van Helmond ZK, Miners JS, Bednall E, Chalmers KA, Zhang Y, Wilcock GK, et al. Caveolin-1 and -2 and their relationship to cerebral amyloid angiopathy in Alzheimer's disease. Neuropathol Appl Neurobiol. 2007; 33:317–327.

13. Williams TM, Lisanti MP. The caveolin proteins. Genome Biol. 2004; 5:214.

14. Yun JH, Park SJ, Jo A, Kang JL, Jou I, Park JS, et al. Caveolin-1 is involved in reactive oxygen species-induced SHP-2 activation in astrocytes. Exp Mol Med. 2011; 43:660–668.

15. Stahlhut M, van Deurs B. Identification of filamin as a novel ligand for caveolin-1: evidence for the organization of caveolin-1-associated membrane domains by the actin cytoskeleton. Mol Biol Cell. 2000; 11:325–337.

16. González-Muñoz E, López-Iglesias C, Calvo M, Palacín M, Zorzano A, Camps M. Caveolin-1 loss of function accelerates glucose transporter 4 and insulin receptor degradation in 3T3-L1 adipocytes. Endocrinology. 2009; 150:3493–3502.

17. Miyawaki-Shimizu K, Predescu D, Shimizu J, Broman M, Predescu S, Malik AB. siRNA-induced caveolin-1 knockdown in mice increases lung vascular permeability via the junctional pathway. Am J Physiol Lung Cell Mol Physiol. 2006; 290:L405–L413.

18. Parton RG, del Pozo MA. Caveolae as plasma membrane sensors, protectors and organizers. Nat Rev Mol Cell Biol. 2013; 14:98–112.

19. Wang XM, Kim HP, Nakahira K, Ryter SW, Choi AM. The heme oxygenase-1/carbon monoxide pathway suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1. J Immunol. 2009; 182:3809–3818.

20. Pike LJ. Growth factor receptors, lipid rafts and caveolae: an evolving story. Biochim Biophys Acta. 2005; 1746:260–273.

21. Gratton JP, Bernatchez P, Sessa WC. Caveolae and caveolins in the cardiovascular system. Circ Res. 2004; 94:1408–1417.

22. Smith RM, Harada S, Smith JA, Zhang S, Jarett L. Insulin-induced protein tyrosine phosphorylation cascade and signalling molecules are localized in a caveolin-enriched cell membrane domain. Cell Signal. 1998; 10:355–362.

23. Lajoie P, Nabi IR. Lipid rafts, caveolae, and their endocytosis. In : Kwang WJ, editor. International Review of Cell and Molecular Biology. AmsterdamL: Academic Press;2010. p. 135–163.

24. Bastiani M, Parton RG. Caveolae at a glance. J Cell Sci. 2010; 123:3831–3836.

25. Quest AF, Leyton L, Párraga M. Caveolins, caveolae, and lipid rafts in cellular transport, signaling, and disease. Biochem Cell Biol. 2004; 82:129–144.

26. Cheng JPX, Nichols BJ. Caveolae: one function or many? Trends Cell Biol. 2016; 26:177–189.

27. Levine TB, Levine AB. Metabolic Syndrome and Cardiovascular Disease. New York: John Wiley & Sons;2012.

28. Jasmin JF, Frank PG, Lisanti MP. Caveolins and caveolae: roles in signaling and disease mechanisms. New York: Springer;2012.

29. Lin YC, Lin CH, Kuo CY, Yang VC. ABCA1 modulates the oligomerization and Golgi exit of caveolin-1 during HDL-mediated cholesterol efflux in aortic endothelial cells. Biochem Biophys Res Commun. 2009; 382:189–195.

30. Boettcher JP, Kirchner M, Churin Y, Kaushansky A, Pompaiah M, Thorn H, et al. Tyrosine-phosphorylated caveolin-1 blocks bacterial uptake by inducing Vav2-RhoA-mediated cytoskeletal rearrangements. PLoS Biol. 2010; 8:DOI: 10.1371/journal.pbio.1000457.

31. Schlegel A, Arvan P, Lisanti MP. Caveolin-1 binding to endoplasmic reticulum membranes and entry into the regulated secretory pathway are regulated by serine phosphorylation. Protein sorting at the level of the endoplasmic reticulum. J Biol Chem. 2001; 276:4398–4408.

32. Qin H, Bollag WB. The caveolin-1 scaffolding domain peptide decreases phosphatidylglycerol levels and inhibits calcium-induced differentiation in mouse keratinocytes. PLoS One. 2013; 8:e80946.

33. Collins BM, Davis MJ, Hancock JF, Parton RG. Structure-based reassessment of the caveolin signaling model: do caveolae regulate signaling through caveolin-protein interactions? Dev Cell. 2012; 23:11–20.

34. Byrne DP, Dart C, Rigden DJ. Evaluating caveolin interactions: do proteins interact with the caveolin scaffolding domain through a widespread aromatic residue-rich motif? PLoS One. 2012; 7:e44879.

35. Le Lay S, Rodriguez M, Jessup W, Rentero C, Li Q, Cartland S, et al. Caveolin-1-mediated apolipoprotein A-I membrane binding sites are not required for cholesterol efflux. PLoS One. 2011; 6:e23353.

36. Joshi B, Bastiani M, Strugnell SS, Boscher C, Parton RG, Nabi IR. Phosphocaveolin-1 is a mechanotransducer that induces caveola biogenesis via Egr1 transcriptional regulation. J Cell Biol. 2012; 199:425–435.

37. Cameron PL, Ruffin JW, Bollag R, Rasmussen H, Cameron RS. Identification of caveolin and caveolin-related proteins in the brain. J Neurosci. 1997; 17:9520–9535.

38. Chen Z, Bakhshi FR, Shajahan AN, Sharma T, Mao M, Trane A, et al. Nitric oxide-dependent Src activation and resultant caveolin-1 phosphorylation promote eNOS/caveolin-1 binding and eNOS inhibition. Mol Biol Cell. 2012; 23:1388–1398.

39. Chen X, Whiting C, Borza C, Hu W, Mont S, Bulus N, et al. Integrin alpha1beta1 regulates epidermal growth factor receptor activation by controlling peroxisome proliferator-activated receptor gamma-dependent caveolin-1 expression. Mol Cell Biol. 2010; 30:3048–3058.

40. Lajoie P, Partridge EA, Guay G, Goetz JG, Pawling J, Lagana A, et al. Plasma membrane domain organization regulates EGFR signaling in tumor cells. J Cell Biol. 2007; 179:341–356.

41. Labrecque L, Nyalendo C, Langlois S, Durocher Y, Roghi C, Murphy G, et al. Src-mediated tyrosine phosphorylation of caveolin-1 induces its association with membrane type 1 matrix metalloproteinase. J Biol Chem. 2004; 279:52132–52140.

42. Schlegel A, Wang C, Katzenellenbogen BS, Pestell RG, Lisanti MP. Caveolin-1 potentiates estrogen receptor alpha (ERalpha) signaling. caveolin-1 drives ligand-independent nuclear translocation and activation of ERalpha. J Biol Chem. 1999; 274:33551–33556.

43. Zhang X, Ling MT, Wang Q, Lau CK, Leung SC, Lee TK, et al. Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial-mesenchymal transition and resistance to apoptosis in prostate cancer cells. J Biol Chem. 2007; 282:33284–33294.

44. Lu Z, Ghosh S, Wang Z, Hunter T. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell. 2003; 4:499–515.

45. Williams TM, Lisanti MP. Caveolin-1 in oncogenic transformation, cancer, and metastasis. Am J Physiol Cell Physiol. 2005; 288:C494–C506.

46. Lim JS, Nguyen KC, Nguyen CT, Jang IS, Han JM, Fabian C, et al. Flagellin-dependent TLR5/caveolin-1 as a promising immune activator in immunosenescence. Aging Cell. 2015; 14:907–915.

47. Scherer PE, Lisanti MP, Baldini G, Sargiacomo M, Mastick CC, Lodish HF. Induction of caveolin during adipogenesis and association of GLUT4 with caveolin-rich vesicles. J Cell Biol. 1994; 127:1233–1243.

48. Yamamoto M, Okumura S, Oka N, Schwencke C, Ishikawa Y. Downregulation of caveolin expression by cAMP signal. Life Sci. 1999; 64:1349–1357.

49. Park WY, Cho KA, Park JS, Kim DI, Park SC. Attenuation of EGF signaling in senescent cells by caveolin. Ann N Y Acad Sci. 2001; 928:79–84.

50. Park DS, Razani B, Lasorella A, Schreiber-Agus N, Pestell RG, Iavarone A, et al. Evidence that Myc isoforms transcriptionally repress caveolin-1 gene expression via an INR-dependent mechanism. Biochemistry. 2001; 40:3354–3362.

51. Bist A, Fielding PE, Fielding CJ. Two sterol regulatory element-like sequences mediate up-regulation of caveolin gene transcription in response to low density lipoprotein free cholesterol. Proc Natl Acad Sci U S A. 1997; 94:10693–10698.

52. Boopathi E, Gomes CM, Goldfarb R, John M, Srinivasan VG, Alanzi J, et al. Transcriptional repression of Caveolin-1 (CAV1) gene expression by GATA-6 in bladder smooth muscle hypertrophy in mice and human beings. Am J Pathol. 2011; 178:2236–2251.

53. van den Heuvel AP, Schulze A, Burgering BM. Direct control of caveolin-1 expression by FOXO transcription factors. Biochem J. 2005; 385:795–802.

54. Verma M, Srivastava S. Epigenetics in cancer: implications for early detection and prevention. Lancet Oncol. 2002; 3:755–763.

55. Deb M, Sengupta D, Kar S, Rath SK, Roy S, Das G, et al. Epigenetic drift towards histone modifications regulates CAV1 gene expression in colon cancer. Gene. 2016; 581:75–84.

56. Park WY, Park JS, Cho KA, Kim DI, Ko YG, Seo JS, et al. Up-regulation of caveolin attenuates epidermal growth factor signaling in senescent cells. J Biol Chem. 2000; 275:20847–20852.

57. Cho KA, Ryu SJ, Oh YS, Park JH, Lee JW, Kim HP, et al. Morphological adjustment of senescent cells by modulating caveolin-1 status. J Biol Chem. 2004; 279:42270–42278.

58. Cho KA, Ryu SJ, Park JS, Jang IS, Ahn JS, Kim KT, et al. Senescent phenotype can be reversed by reduction of caveolin status. J Biol Chem. 2003; 278:27789–27795.

59. Volonte D, Zhang K, Lisanti MP, Galbiati F. Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts. Mol Biol Cell. 2002; 13:2502–2517.

60. Head BP, Peart JN, Panneerselvam M, Yokoyama T, Pearn ML, Niesman IR, et al. Loss of caveolin-1 accelerates neurodegeneration and aging. PLoS One. 2010; 5:e15697.

61. Volonte D, Kahkonen B, Shapiro S, Di Y, Galbiati F. Caveolin-1 expression is required for the development of pulmonary emphysema through activation of the ATM-p53-p21 pathway. J Biol Chem. 2009; 284:5462–5466.

62. Lee JA, Choi DI, Choi JY, Kim SO, Cho KA, Lee JB, et al. Methyl-β-cyclodextrin up-regulates collagen I expression in chronologically-aged skin via its anti-caveolin-1 activity. Oncotarget. 2015; 6:1942–1953.

63. Powter EE, Coleman PR, Tran MH, Lay AJ, Bertolino P, Parton RG, et al. Caveolae control the anti-inflammatory phenotype of senescent endothelial cells. Aging Cell. 2015; 14:102–111.

64. de Magalhães JP. How ageing processes influence cancer. Nat Rev Cancer. 2013; 13:357–365.

65. Williams TM, Lisanti MP. Caveolin-1 in oncogenic transformation, cancer, and metastasis. Am J Physiol Cell Physiol. 2005; 288:C494–C506.

66. Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Caveolae and signalling in cancer. Nat Rev Cancer. 2015; 15:225–237.

67. Boscher C, Nabi IR. Caveolin-1: role in cell signaling. In : Jasmin JF, Frank PG, Lisanti MP, editors. Caveolins and Caveolae: Roles in Signaling and Disease Mechanisms. New York, NY: Springer;2012. p. 29–50.

68. Yang G, Truong LD, Timme TL, Ren C, Wheeler TM, Park SH, et al. Elevated expression of caveolin is associated with prostate and breast cancer. Clin Cancer Res. 1998; 4:1873–1880.

69. Li L, Ittmann MM, Ayala G, Tsai MJ, Amato RJ, Wheeler TM, et al. The emerging role of the PI3-K-Akt pathway in prostate cancer progression. Prostate Cancer Prostatic Dis. 2005; 8:108–118.

70. Gunasekaran U, Gannon M. Type 2 diabetes and the aging pancreatic beta cell. Aging (Albany NY). 2011; 3:565–575.

71. Cohen AW, Razani B, Wang XB, Combs TP, Williams TM, Scherer PE, et al. Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Am J Physiol Cell Physiol. 2003; 285:C222–C235.

72. Razani B, Combs TP, Wang XB, Frank PG, Park DS, Russell RG, et al. Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J Biol Chem. 2002; 277:8635–8647.

73. Oh YS, Khil LY, Cho KA, Ryu SJ, Ha MK, Cheon GJ, et al. A potential role for skeletal muscle caveolin-1 as an insulin sensitivity modulator in ageing-dependent non-obese type 2 diabetes: studies in a new mouse model. Diabetologia. 2008; 51:1025–1034.

74. Oh YS, Lee TS, Cheon GJ, Jang IS, Jun HS, Park SC. Modulation of insulin sensitivity and caveolin-1 expression by orchidectomy in a nonobese type 2 diabetes animal model. Mol Med. 2011; 17:4–11.

75. Mahavadi S, Nalli A, Kumar D, Bhattacharya S, Zhou R, Grider J, et al. Increased expression of caveolin-1 is associated with up-regulation of the RhoA/Rho kinase pathway and smooth muscle contraction in diabetes (1110.11). FASEB J. 2014; 28.

76. Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, et al. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science. 2001; 293:2449–2452.

77. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999; 340:115–126.

78. Frank PG, Woodman SE, Park DS, Lisanti MP. Caveolin, caveolae, and endothelial cell function. Arterioscler Thromb Vasc Biol. 2003; 23:1161–1168.

79. Fernández-Hernando C, Yu J, Dávalos A, Prendergast J, Sessa WC. Endothelial-specific overexpression of caveolin-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol. 2010; 177:998–1003.

80. Razani B, Combs TP, Wang XB, Frank PG, Park DS, Russell RG, et al. Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J Biol Chem. 2002; 277:8635–8647.

81. Frank PG. Endothelial caveolae and caveolin-1 as key regulators of atherosclerosis. Am J Pathol. 2010; 177:544–546.

82. Lim JS, Shin M, Kim HJ, Kim KS, Choy HE, Cho KA. Caveolin-1 mediates Salmonella invasion via the regulation of SopE-dependent Rac1 activation and actin reorganization. J Infect Dis. 2014; 210:793–802.

83. Gavazzi G, Krause KH. Ageing and infection. Lancet Infect Dis. 2002; 2:659–666.

84. Lim JS, Choy HE, Park SC, Han JM, Jang IS, Cho KA. Caveolae-mediated entry of Salmonella typhimurium into senescent nonphagocytotic host cells. Aging Cell. 2010; 9:243–251.

85. Simionescu N, Siminoescu M, Palade GE. Permeability of muscle capillaries to small heme-peptides. Evidence for the existence of patent transendothelial channels. J Cell Biol. 1975; 64:586–607.

86. Kiss AL, Botos E. Endocytosis via caveolae: alternative pathway with distinct cellular compartments to avoid lysosomal degradation? J Cell Mol Med. 2009; 13:1228–1237.

87. Gruenberg J, van der Goot FG. Mechanisms of pathogen entry through the endosomal compartments. Nat Rev Mol Cell Biol. 2006; 7:495–504.

88. Pang H, Le PU, Nabi IR. Ganglioside GM1 levels are a determinant of the extent of caveolae/raft-dependent endocytosis of cholera toxin to the Golgi apparatus. J Cell Sci. 2004; 117:1421–1430.

89. Ferrari A, Pellegrini V, Arcangeli C, Fittipaldi A, Giacca M, Beltram F. Caveolae-mediated internalization of extracellular HIV-1 tat fusion proteins visualized in real time. Mol Ther. 2003; 8:284–294.

90. Schubert W, Frank PG, Razani B, Park DS, Chow CW, Lisanti MP. Caveolae-deficient endothelial cells show defects in the uptake and transport of albumin in vivo. J Biol Chem. 2001; 276:48619–48622.

91. Tomassian T, Humphries LA, Liu SD, Silva O, Brooks DG, Miceli MC. Caveolin-1 orchestrates TCR synaptic polarity, signal specificity, and function in CD8 T cells. J Immunol. 2011; 187:2993–3002.

92. Ohnuma K, Uchiyama M, Yamochi T, Nishibashi K, Hosono O, Takahashi N, et al. Caveolin-1 triggers T-cell activation via CD26 in association with CARMA1. J Biol Chem. 2007; 282:10117–10131.

93. Medina FA, Williams TM, Sotgia F, Tanowitz HB, Lisanti MP. A novel role for caveolin-1 in B lymphocyte function and the development of thymus-independent immune responses. Cell Cycle. 2006; 5:1865–1871.

94. Medina FA, de Almeida CJ, Dew E, Li J, Bonuccelli G, Williams TM, et al. Caveolin-1-deficient mice show defects in innate immunity and inflammatory immune response during Salmonella enterica serovar Typhimurium infection. Infect Immun. 2006; 74:6665–6674.

95. Lei MG, Morrison DC. Differential expression of caveolin-1 in lipopolysaccharide-activated murine macrophages. Infect Immun. 2000; 68:5084–5089.

96. Lim JS, Nguyen KC, Han JM, Jang IS, Fabian C, Cho KA. Direct Regulation of TLR5 Expression by Caveolin-1. Mol Cells. 2015; 38:1111–1117.

97. Escriche M, Burgueño J, Ciruela F, Canela EI, Mallol J, Enrich C, et al. Ligand-induced caveolae-mediated internalization of A1 adenosine receptors: morphological evidence of endosomal sorting and receptor recycling. Exp Cell Res. 2003; 285:72–90.

98. Liu L, Xu HX, Wang WQ, Wu CT, Chen T, Qin Y, et al. Cavin-1 is essential for the tumor-promoting effect of caveolin-1 and enhances its prognostic potency in pancreatic cancer. Oncogene. 2014; 33:2728–2736.

99. Yang G, Xu H, Li Z, Li F. Interactions of caveolin-1 scaffolding and intramembrane regions containing a CRAC motif with cholesterol in lipid bilayers. Biochim Biophys Acta. 2014; 1838:2588–2599.

100. Engelman JA, Chu C, Lin A, Jo H, Ikezu T, Okamoto T, et al. Caveolin-mediated regulation of signaling along the p42/44 MAP kinase cascade in vivo. A role for the caveolin-scaffolding domain. FEBS Lett. 1998; 428:205–211.

101. Sato M, Hutchinson DS, Halls ML, Furness SG, Bengtsson T, Evans BA, et al. Interaction with caveolin-1 modulates G protein coupling of mouse β3-adrenoceptor. J Biol Chem. 2012; 287:20674–20688.

102. Calizo RC, Scarlata S. A role for G-proteins in directing G-protein-coupled receptor-caveolae localization. Biochemistry. 2012; 51:9513–9523.

103. Shen J, Lee W, Li Y, Lau CF, Ng KM, Fung ML, et al. Interaction of caveolin-1, nitric oxide, and nitric oxide synthases in hypoxic human SK-N-MC neuroblastoma cells. J Neurochem. 2008; 107:478–487.

104. Kabayama K, Sato T, Saito K, Loberto N, Prinetti A, Sonnino S, et al. Dissociation of the insulin receptor and caveolin-1 complex by ganglioside GM3 in the state of insulin resistance. Proc Natl Acad Sci U S A. 2007; 104:13678–13683.

105. Sato Y, Sagami I, Shimizu T. Identification of caveolin-1-interacting sites in neuronal nitric-oxide synthase. Molecular mechanism for inhibition of NO formation. J Biol Chem. 2004; 279:8827–8836.

106. Volonte D, Liu Z, Musille PM, Stoppani E, Wakabayashi N, Di YP, et al. Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence. Mol Biol Cell. 2013; 24:1852–1862.

107. Li L, Ren C, Yang G, Goltsov AA, Tabata K, Thompson TC. Caveolin-1 promotes autoregulatory, Akt-mediated induction of cancer-promoting growth factors in prostate cancer cells. Mol Cancer Res. 2009; 7:1781–1791.

108. Mercier I, Jasmin JF, Lisanti MP. Caveolins in Cancer Pathogenesis, Prevention and Therapy. New York: Springer;2011.

109. Razani B, Lisanti MP. Two distinct caveolin-1 domains mediate the functional interaction of caveolin-1 with protein kinase A. Am J Physiol Cell Physiol. 2001; 281:C1241–C1250.

110. Jiao J, Garg V, Yang B, Elton TS, Hu K. Protein kinase C-epsilon induces caveolin-dependent internalization of vascular adenosine 5'-triphosphate-sensitive K+ channels. Hypertension. 2008; 52:499–506.

111. Conde-Perez A, Gros G, Longvert C, Pedersen M, Petit V, Aktary Z, et al. A caveolin-dependent and PI3K/AKT-independent role of PTEN in β-catenin transcriptional activity. Nat Commun. 2015; 6:8093.

112. Senetta R, Stella G, Pozzi E, Sturli N, Massi D, Cassoni P. Caveolin-1 as a promoter of tumour spreading: when, how, where and why. J Cell Mol Med. 2013; 17:325–336.

113. Razani B, Zhang XL, Bitzer M, von Gersdorff G, Böttinger EP, Lisanti MP. Caveolin-1 regulates transforming growth factor (TGF)-beta/SMAD signaling through an interaction with the TGF-beta type I receptor. J Biol Chem. 2001; 276:6727–6738.

114. Lim JS, Nguyen KC, Han JM, Jang IS, Fabian C, Cho KA. Direct Regulation of TLR5 Expression by Caveolin-1. Mol Cells. 2015; 38:1111–1117.

115. Czikora I, Feher A, Lucas R, Fulton DJ, Bagi Z. Caveolin-1 prevents sustained angiotensin II-induced resistance artery constriction and obesity-induced high blood pressure. Am J Physiol Heart Circ Physiol. 2015; 308:H376–H385.

116. Tahir SA, Park S, Thompson TC. Caveolin-1 regulates VEGF-stimulated angiogenic activities in prostate cancer and endothelial cells. Cancer Biol Ther. 2009; 8:2286–2296.

117. Hehlgans S, Cordes N. Caveolin-1: an essential modulator of cancer cell radio-and chemoresistance. Am J Cancer Res. 2011; 1:521–530.

118. Chiu WT, Lee HT, Huang FJ, Aldape KD, Yao J, Steeg PS, et al. Caveolin-1 upregulation mediates suppression of primary breast tumor growth and brain metastases by stat3 inhibition. Cancer Res. 2011; 71:4932–4943.

119. Suprynowicz FA, Disbrow GL, Krawczyk E, Simic V, Lantzky K, Schlegel R. HPV-16 E5 oncoprotein upregulates lipid raft components caveolin-1 and ganglioside GM1 at the plasma membrane of cervical cells. Oncogene. 2008; 27:1071–1078.

120. Park J, Bae E, Lee C, Yoon SS, Chae YS, Ahn KS, et al. RNA interference-directed caveolin-1 knockdown sensitizes SN12CPM6 cells to doxorubicin-induced apoptosis and reduces lung metastasis. Tumour Biol. 2010; 31:643–650.

121. Diaz-Valdivia N, Bravo D, Huerta H, Henriquez S, Gabler F, Vega M, et al. Enhanced caveolin-1 expression increases migration, anchorage-independent growth and invasion of endometrial adenocarcinoma cells. BMC Cancer. 2015; 15:463.

122. Chatterjee M, Ben-Josef E, Thomas DG, Morgan MA, Zalupski MM, Khan G, et al. Caveolin-1 is associated with tumor progression and confers a multi-modality resistance phenotype in pancreatic cancer. Sci Rep. 2015; 5:10867.

123. Yang G, Goltsov AA, Ren C, Kurosaka S, Edamura K, Logothetis R, et al. Caveolin-1 upregulation contributes to c-Myc-induced high-grade prostatic intraepithelial neoplasia and prostate cancer. Mol Cancer Res. 2012; 10:218–229.

124. Thompson TC, Tahir SA, Li L, Watanabe M, Naruishi K, Yang G, et al. The role of caveolin-1 in prostate cancer: clinical implications. Prostate Cancer Prostatic Dis. 2010; 13:6–11.