Белки мембранных микродоменов и их участие в онкогенезе

Липидные рафты плазматических мембран формируются холестеролом, сфингомиелидами и гликосфинголипидами, а также различными белками. Эти микродомены участвуют в различных клеточных процессах, таких как перестройка мембраны, интернализация белков, передача сигналов, через них осуществляется проникновение вирусов внутрь клетки. Часть липидных рафтов стабилизирована специальными микродоменобразующими белками (МОБ). На сегодняшний день известно несколько семейств таких белков: кавеолины, SPFH- семейство, тетраспанины, галектины, которые не только поддерживают целостность микродоменов, но и формируют «сигналосомы» и, таким образом, являются регуляторами многих сигнальных путей. Участие различных классов МОБ необходимо для нормального функционирования комплексов ростовых факторов с их рецепторами, регуляции интегринов, факторов реорганизации клеточного скелета и внеклеточного матрикса, везикулярного транспорта и т. д. МОБ вовлечены практически во все аспекты жизнедеятельности клетки, однако до сих пор классы МОБ принято рассматривать отдельно друг от друга. В представленном обзоре проведен анализ участия МОБ разных семейств в общих сигнальных путях, ассоциированных с канцерогенезом.

1. Singer S. J., Nicolson G. L. The fluid mosaic model of the structure of cell membranes. Science 1972;175(4023): 720–31.

2. Stier A., Sackmann E. Spin labels as enzyme substrates. Heterogeneous lipid distribution in liver microsomal membranes. Biochim Biophys Acta 1973;311(3):400–8.

3. Edidin M. The state of lipid rafts: from model membranes to cells. Annu Rev Biophys Biomol Struct 2003;32:257–83.

4. Head B. P., Patel H. H., Insel P. A. Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta 2014;1838(2):532–45.

5. Nicolson G. L. Cell membrane fluidmosaic structure and cancer metastasis. Cancer Res 2015;75(7):1169–76.

6. Веснина Л. Э. Липидные рафты: роль в регуляции функционального состояния клеточных мембран. Актуальні проблеми сучасної медицини 2014;13(2(42):5–9. [Vesninа L. E. Lipid rafts: role in the regulation of the functional status of cellular membranes. Aktual’nye problemy suchsnoy meditsiny = Actual Problems Modern Medicine 2014;132 (42):5–9. (In Russ.)].

7. Martinez-Outschoorn U. E., Sotgia F., Lisanti M. P. Caveolae and signalling in cancer. Nat Rev Cancer 2015;15(4): 225–37.

8. Chavan T. S., Muratcioglu S., Marszalek R. et al. Plasma membrane regulates Ras signaling networks. Cellular logistics 2015;5(4):e1136374.

9. Nabi I. R., Shankar J., Dennis J. W. The galectin lattice at a glance. J Cell Sci 2015;128(13):2213–9.

10. Lajoie P., Goetz J. G., Dennis J. W. et al. Lattices, rafts, and scaffolds: domain regulation of receptor signaling at the plasma membrane. J Cell Biol 2009;185(3):381–5.

11. Bodin S., Planchon D., Rios Morris E. et al. Flotillins in intercellular adhesion – from cellular physiology to human diseases. J Cell Sci 2014;127(Pt 24): 5139–47.

12. Архипова К. А., Зборовская И. Б. Микродомен-образующие белки разных семейств в регуляции общих сигнальных путей клетки. Биологические мембраны 2012;29(6):387–99. [Аrkhipovа K. А., Zborovskaya I. B. Мicrodomain-forming proteins of different familites in the regulation of general signaling cellular pathways. Biologicheskie membrany = Biological Memnbranes 2012;29 (6):387–99. (In Russ.)].

13. Rocha-Perugini V., Sanchez-Madrid F., Martinez Del Hoyo G. Function and Dynamics of Tetraspanins during Antigen Recognition and Immunological Synapse Formation. Front Immunol 2015;6:653.

14. Mollinedo F., Gajate C. Lipid rafts as major platforms for signaling regulation in cancer. Adv Biol Regul 2015;57:130–46.

15. Villarroya-Beltri C., Baixauli F., Gutierrez-Vazquez C. et al. Sorting it out: regulation of exosome loading. Semin Cancer Biol 2014;28:3–13.

16. Iraci N., Leonardi T., Gessler F. et al. Focus on Extracellular Vesicles: Physiological Role and Signalling Properties of Extracellular Membrane Vesicles. Int J Mol Sci 2016;17(2):171.

17. Zhang H. G., Grizzle W. E. Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am J Pathol 2014;184(1):28–41.

18. Kirkham M., Nixon S. J., Howes M. T. et al. Evolutionary analysis and molecular dissection of caveola biogenesis. J Cell Sci 2008;121(Pt 12):2075–86.

19. Fernandez I., Ying Y., Albanesi J. et al. Mechanism of caveolin filament assembly. Proc Natl Acad Sci USA 2002;99(17):11193–8.

20. Williams T. M., Lisanti M. P. The caveolin proteins. Genome Biol 2004;5(3):214.

21. Bastiani M., Parton R. G. Caveolae at a glance. J Cell Sci 2010;123(Pt 22):3831–6.

22. Lisanti M. P., Scherer P. E., Tang Z. et al. Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis. Trends Cell Biol 1994;4(7):231–5.

23. Couet J., Sargiacomo M., Lisanti M. P. Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/ threonine kinase activities. J Biol Chem 1997;272(48):30429–38.

24. Roepstorff K., Thomsen P., Sandvig K. et al. Sequestration of epidermal growth factor receptors in non-caveolar lipid rafts inhibits ligand binding. J Biol Chem 2002;277(21):18954–60.

25. Matveev S. V., Smart E. J. Heterologous desensitization of EGF receptors and PDGF receptors by sequestration in caveolae. Am J Physiol Cell Physiol 2002;282(4):935–46.

26. Pike L. J. Growth factor receptors, lipid rafts and caveolae: an evolving story. Biochim Biophys Acta 2005;1746(3):260–73.

27. de Laurentiis A., Donovan L., Arcaro A. Lipid rafts and caveolae in signaling by growth factor receptors. Open Biochem J 2007;1:12–32.

28. Lee H., Volonte D., Galbiati F. et al. Constitutive and growth factor-regulated phosphorylation of caveolin-1 occurs at the same site(Tyr-14) in vivo: identification of a c- Src/Cav-1/Grb7 signaling cassette. Mol Endocrinol 2000;14(11):1750–75.

29. Engelman J. A., Zhang X. L., Razani B. et al. p42/44 MAP kinase-dependent and - independent signaling pathways regulate caveolin-1 gene expression. Activation of Ras- MAP kinase and protein kinase a signaling cascades transcriptionally down-regulates caveolin-1 promoter activity. J Biol Chem1999;274(45):32333–41.

30. Grande-Garcia A., Echarri A., de Rooij J. et al. Caveolin-1 regulates cell polarization and directional migration through Src kinase and Rho GTPases. J Cell Biol 2007; 177(4):683–94.

31. Beardsley A., Fang K., Mertz H. et al. Loss of caveolin-1 polarity impedes endothelial cell polarization and directional movement. J Biol Chem 2005;280(5): 3541–7.

32. Yu H., Shen H., Zhang Y. et al. CAV1 promotes HCC cell progression and metastasis through Wnt/beta-catenin pathway. PLoS One 2014, 9(9):e106451.

33. Brown G. T., Murray G. I. Current mechanistic insights into the roles of matrix metalloproteinases in tumour invasion and metastasis. J Pathol 2015;237(3):273–81.

34. Han F., Zhu H. G. Caveolin-1 regulating the invasion and expression of matrix metalloproteinase (MMPs) in pancreatic carcinoma cells. J Surg Res 2010;159(1): 443–50.

35. Aga M., Bradley J. M., Wanchu R. et al. Differential effects of caveolin-1 and -2 knockdown on aqueous outflow and altered extracellular matrix turnover in caveolinsilenced trabecular meshwork cells. Invest Ophthalmol Vis Sci 2014;55(9):5497–509.

36. Williams T. M., Medina F., Badano I. et al. Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo. Role of Cav-1 in cell invasiveness and matrix metalloproteinase(MMP-2/9) secretion. J Biol Chem 2004;279(49):51630–46.

37. Jia L., Wang S., Zhou H. et al. Caveolin-1 up-regulates CD147 glycosylation and the invasive capability of murine hepatocarcinoma cell lines. Int J Biochem Cell B 2006;38(9):1584–93.

38. Tang W., Hemler M. E. Caveolin-1 regulates matrix metalloproteinases-1 induction and CD147/EMMPRIN cell surface clustering. J Biol Chem 2004;279(12):11112–8.

39. Muramatsu T. Basigin(CD147), a multifunctional transmembrane glycoprotein with various binding partners. J Biochem 2016;159(5):481–90.

40. Andreu Z., Yanez-Mo M. Tetraspanins in extracellular vesicle formation and function. Front Immunol 2014;5:442.

41. Rivera-Milla E., Stuermer C. A., Malaga-Trillo E. Ancient origin of reggie (flotillin), reggie- like, and other lipid-raft proteins: convergent evolution of the SPFH domain. Cell Mol Life Sci 2006;63(3):343–57.

42. Browman D. T., Hoegg M. B., Robbins S. M. The SPFH domain-containing proteins: more than lipid raft markers. Trends Cell B 2007;17(8):394–402.

43. Stuermer C. A. The reggie/flotillin connection to growth. Trends Cell B 2010;20(1):6–13.

44. Chowdhury I., Thompson W. E., Thomas K. Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway. J Cell Physiol 2014;229(8):998–1004.

45. Solis G. P., Hulsbusch N., Radon Y. et al. Reggies/flotillins interact with Rab11a and SNX4 at the tubulovesicular recycling compartment and function in transferrin receptor and E- cadherin trafficking. Mol Biol Cell 2013;24(17):2689–702.

46. Koch J. C., Solis G. P., Bodrikov V. et al. Upregulation of reggie-1/flotillin-2 promotes axon regeneration in the rat optic nerve in vivo and neurite growth in vitro. Neurobiol Dis 2013;51:168–76.

47. Gomez V., Sese M., Santamaria A. et al. Regulation of aurora B kinase by the lipid raft protein flotillin-1. J Biol Chem 2010;285(27):20683–90.

48. Hazarika P., McCarty M. F., Prieto V. G. et al. Up-regulation of Flotillin-2 is associated with melanoma progression and modulates expression of the thrombin receptor protease activated receptor 1. Cancer Res 2004;64(20):7361–9.

49. Gallagher P. G., Romana M., Lieman J. H. et al. cDNA structure, tissue-specific expression, and chromosomal localization of the murine band 7.2b gene. Blood 1995;86(1):359–65.

50. Lapatsina L., Brand J., Poole K. et al. Stomatin-domain proteins. Eur J Cell Biol 2012;91(4):240–5.

51. Snyers L., Umlauf E., Prohaska R. Oligomeric nature of the integral membrane protein stomatin. J Biological Chem 1998;273(27):17221–6.

52. Umlauf E., Mairhofer M., Prohaska R. Characterization of the stomatin domain involved in homo-oligomerization and lipid raft association. J Biol Chem 2006;281(33):23349–56.

53. Chi H., Hu Y. H. Stomatin-like protein 2 of turbot Scopthalmus maximus: Gene cloning, expression profiling and immunoregulatory properties. Fish Shellfish immunol 2016;49:436–41.

54. Chang D., Ma K., Gong M. et al. SLP-2 overexpression is associated with tumour distant metastasis and poor prognosisin pulmonary squamous cell carcinoma. Biomarkers 2010;15(2):104–10.

55. Zhang L., Ding F., Cao W. et al. Stomatinlike protein 2 is overexpressed in cancer and involved in regulating cell growth and cell adhesion in human esophageal squamous cell carcinoma. Clin Cancer Res 2006;12(5):1639–46.

56. Cui Z., Zhang L., Hua Z. et al. Stomatin-like protein 2 is overexpressed and related to cell growth in human endometrial adenocarcinoma. Oncol Rep 2007; 17(4):829–33.

57. Cao W., Zhang B., Li J. et al. SLP-2 overexpression could serve as a prognostic factor in node positive and HER2 negative breast cancer. Pathology 2011;43(7):713–8.

58. Huang S., Tian H., Chen Z. et al. The evolution of vertebrate tetraspanins: gene loss, retention, and massive positive selection after whole genome duplications. BMC Evol Biol 2010;10:306.

59. Detchokul S., Williams E. D., Parker M. W. et al. Tetraspanins as regulators of the tumour microenvironment: implications for metastasis and therapeutic strategies. Br J Pharmacol 2014;171(24):5462–90.

60. Beckwith K. A., Byrd J. C., Muthusamy N. Tetraspanins as therapeutic targets in hematological malignancy: a concise review. Front Physiol 2015;6:91.

61. Levy S., Shoham T. Protein-protein interactions in the tetraspanin web. Physiology 2005;20:218–24.

62. Berditchevski F. Complexes of tetraspanins with integrins: more than meets the eye. J Cell Sci 2001;114(Pt 23):4143–51.

63. Kumari S., Devi G. t., Badana A. et al. CD151-A Striking Marker for Cancer Therapy. Biomark Cancer 2015;7:7–11.

64. Zhou P., Erfani S., Liu Z. et al. CD151-alpha3beta1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion. Oncotarget 2015;6(30): 29675–93.

65. Qin Y., Mohandessi S., Gordon L. et al. Regulation of FAK Activity by Tetraspan Proteins: Potential Clinical Implications in Cancer. Crit Rev Oncog 2015;20(5–6):391–405.

66. Stewart R. L., West D., Wang C. et al. Elevated integrin alpha6beta4 expression is associated with venous invasion and decreased overall survival in non-small cell lung cancer. Hum Pathol 2016;54:174–83.

67. Romanska H. M., Potemski P., Kusinska R. et al. Expression of CD151/ Tspan24 and integrin alpha 3 complex in aid of prognostication of HER2-negative highgrade ductal carcinoma in situ. Int J Clin Exp Pathol 2015;8(8):9471–8.

68. Ke A. W., Zhang P. F., Shen Y. H. et al. Generation and characterization of a tetraspanin CD151/integrin alpha6beta1- binding domain competitively binding monoclonal antibody for inhibition of tumor progression in HCC. Oncotarget 2016;7(5):6314–22.

69. Berditchevski F., Odintsova E. ErbB receptors and tetraspanins: Casting the net wider. Int J Biochem Cell B 2016;7(Pt A): 68–71.

70. Sadej R., Grudowska A., Turczyk L. et al. CD151 in cancer progression and metastasis: a complex scenario. Lab Invest 2014;94(1):41–51.

71. Hong I. K., Jin Y. J., Byun H. J. et al. Homophilic interactions of Tetraspanin CD151 up- regulate motility and matrix metalloproteinase-9 expression of human melanoma cells through adhesion-dependent c-Jun activation signaling pathways. J Biol Chem 2006;281(34):24279–92.

72. Miranti C. K. Controlling cell surface dynamics and signaling: how CD82/KAI1 suppresses metastasis. Cellular Signalling 2009;21(2):196–211.

73. Nazarenko I., Rana S., Baumann A. et al. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res 2010;70(4):1668–78.

74. Yue S., Mu W., Erb U. et al. The tetraspanins CD151 and Tspan8 are essential exosome components for the crosstalk between cancer initiating cells and their surrounding. Oncotarget 2015;6(4):2366–84.

75. Rana S., Zöller M. The Functional Importance of Tetraspanins in Exosomes Emerging Concepts of Tumor Exosomes- Mediated Cell-Cell Communication. Edited by Z.-H. Zhang. Springer Science + Business Media. New York, 2013. Pp. 69–106.

76. Sandfeld-Paulsen B., Jakobsen K. R., Baek R. et al. Exosomal Proteins as Diagnostic Biomarkers in Lung Cancer. J Thorac Oncol 2016.

77. Murayama Y., Shinomura Y., Oritani K. et al. The tetraspanin CD9 modulates epidermal growth factor receptor signaling in cancer cells. J Cell Physiol 2008;216(1):135–43.

78. Tejera E., Rocha-Perugini V., Lopez-Martin S. et al. CD81 regulates cell migration through its association with Rac GTPase. Mol Biol Cell 2013;24(3):261–73.

79. Lafleur M. A., Xu D., Hemler M. E. Tetraspanin proteins regulate membrane type- 1 matrix metalloproteinase-dependent pericellular proteolysis. Mol Biol Cell 2009;20(7):2030–40.

80. Seubert B., Cui H., Simonavicius N. et al. Tetraspanin CD63 acts as a pro-metastatic factor via beta-catenin stabilization. Int J Cancer 2015;136(10):2304–15.

81. Saito Y., Tachibana I., Takeda Y. et al. Absence of CD9 enhances adhesiondependent morphologic differentiation, survival, and matrix metalloproteinase-2 production in small cell lung cancer cells. Cancer Res 2006;66(19):9557–65.

82. Cao Z. Q., Guo X. L. The role of galectin-4 in physiology and diseases. Protein Cell 2016;7(5):314–24.

83. Wang L., Guo X. L. Molecular regulation of galectin-3 expression and therapeutic implication in cancer progression. Biomed Pharmacother 2016;78:165–71.

84. Timoshenko A. V. Towards molecular mechanisms regulating the expression of galectins in cancer cells under microenvironmental stress conditions. Cell Mol Life Sci 2015;2(22):4327–40.

85. Argueso P., Mauris J., Uchino Y. Galectin-3 as a regulator of the epithelial junction: Implications to wound repair and cancer. Tissue Barriers 2015;3(3):e1026505.

86. Demers M., Magnaldo T., Stрierre Y. A novel function for galectin-7: promoting tumorigenesis by up-regulating MMP-9 gene expression. Cancer Res 2005;65(12):5205–10.

87. Wu M. H., Hong T. M., Cheng H. W. et al. Galectin-1-mediated tumor invasion and metastasis, up-regulated matrix metalloproteinase expression, and reorganized actin cytoskeletons. Mol Cancer Res 2009;7(3):311–8.

88. Prudova A., auf dem Keller U., Butler G. S. et al. Multiplex N-terminome analysis of MMP- 2 and MMP-9 substrate degradomes by iTRAQ-TAILS quantitative proteomics. Mol Cell Proteomics 2010;9(5):894–911.

89. Ochieng J., Green B., Evans S. et al. Modulation of the biological functions of galectin-3 by matrix metalloproteinases. Biochim Biophys Acta 1998;1379(1):97–106.

90. Goetz J. G., Joshi B., Lajoie P. et al. Concerted regulation of focal adhesion dynamics by galectin-3 and tyrosinephosphorylated caveolin-1. J Cell B 2008;180(6):1261–75.

91. Bist A., Fielding C. J., Fielding P. E. p53 regulates caveolin gene transcription, cell cholesterol, and growth by a novel mechanism. Biochemistry 2000;39(8):1966–72.

92. Dumic J., Lauc G., Flogel M. Expression of galectin-3 in cells exposed to stress-roles of jun and NF-kappaB. Cell Physiol Biochem 2000;10(3):149–58.

93. Sasaki Y., Oshima Y., Koyama R. et al. Identification of flotillin-2, a major protein on lipid rafts, as a novel target of p53 family members. Mol Cancer Res 2008;6(3):395–406.

94. Banning A., Ockenga W., Finger F. et al. Transcriptional regulation of flotillins by the extracellularly regulated kinases and retinoid X receptor complexes. PloS One 2012;7(9):e45514.

95. Cao S., Fernandez-Zapico M. E., Jin D. et al. KLF11-mediated repression antagonizes Sp1/sterol-responsive element-binding protein-induced transcriptional activation of caveolin-1 in response to cholesterol signaling. J Biol Chem 2005;280(3):1901–10.

96. Wang J., Liu X., Ni P. et al. SP1 is required for basal activation and chromatin accessibility of CD151 promoter in liver cancer cells. Biochem Biophys Res Commun 2010;393(2):291–6.

97. Kathuria H., Cao Y. X., Ramirez M. I. et al. Transcription of the caveolin-1 gene is differentially regulated in lung type I epithelial and endothelial cell lines. A role for ETS proteins in epithelial cell expression. J Biol Chem 2004;279(29):30028–36.

98. Hoshino I., Matsubara H. MicroRNAs in cancer diagnosis and therapy: from bench to bedside. Surgery today 2013;43(5):467–78.

99. Butz H., Szabo P. M., Khella H. W. et al. miRNA-target network reveals miR-124 as a key miRNA contributing to clear cell renal cell carcinoma aggressive behaviour by targeting CAV1 and FLOT1. Oncotarget 2015;6(14):12543–57.

100. Sygitowicz G., Tomaniak M., Blaszczyk O. et al. Circulating microribonucleic acids miR-1, miR-21 and miR-208a in patients with symptomatic heart failure: Preliminary results. Arch Cardiovasc Dis 2015;108(12):634–42.

101. Gong H., Song L., Lin C. et al. Downregulation of miR-138 sustains NF-kappaB activation and promotes lipid raft formation in esophageal squamous cell carcinoma. Clin Cancer Res 2013;19(5):1083–93.

102. Wu L., Zhao Q., Zhu X. et al. A novel function of microRNA let-7d in regulation of galectin-3 expression in attention deficit hyperactivity disorder rat brain. Brain Pathol 2010;20(6):1042–54.

103. Kang M., Ren M. P., Zhao L. et al. miR-485-5p acts as a negative regulator in gastric cancer progression by targeting flotillin- 1. Am J Transl Res 2015;7(11):2212–22.

104. Yang F. Q., Zhang H. M., Chen S. J. et al. MiR-506 is down-regulated in clear cell renal cell carcinoma and inhibits cell growth and metastasis via targeting FLOT1. PloS One 2015;10(3):e0120258.

105. Liu R., Xie H., Luo C. et al. Identification of FLOT2 as a novel target for microRNA-34a in melanoma. J Cancer Res Clin Oncol 2015;141(6):993–1006.

106. Yang Q., Jiang W., Zhuang C. et al. microRNA-22 downregulation of galectin-9 influences lymphocyte apoptosis and tumor cell proliferation in liver cancer. Oncology reports 2015;34(4): 1771–8.

107. Huang X., Yuan T., Tschannen M. et al. Characterization of human plasma-derived exosomal RNAs by deep sequencing. BMC Genomics 2013;14:319.

108. Zhang L. Y., Liu M., Li X. et al. miR-490-3p modulates cell growth and epithelial to mesenchymal transition of hepatocellular carcinoma cells by targeting endoplasmic reticulum-Golgi intermediate compartment protein 3 (ERGIC3). J Biol Chem 2013;288(6): 4035–47.

109. Lin Q. H., Zhang K. D., Duan H. X. et al. ERGIC3, which is regulated by miR-203a, is a potential biomarker for non-small cell lung cancer. Cancer Sci 2015;106(10):1463–73.

110. Sandvig K., Torgersen M. L., Raa H. A. et al. Clathrin-independent endocytosis: from nonexisting to an extreme degree of complexity. Histochem Cell Biol 2008;129(3):267–76