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Aberrant expression and functions of protocadherins in human malignant tumors

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Tumor Biology

Abstract

Protocadherins (PCDHs) are a group of transmembrane proteins belonging to the cadherin superfamily and are subdivided into “clustered” and “non-clustered” groups. PCDHs vary in both structure and interaction partners and thus regulate multiple biological responses in complex and versatile patterns. Previous researches showed that PCDHs regulated the development of brain and were involved in some neuronal diseases. Recently, studies have revealed aberrant expression of PCDHs in various human malignant tumors. The down-regulation or absence of PCDHs in malignant cells has been associated with cancer progression. Further researches suggest that PCDHs may play major functions as tumor suppressor by inhibiting the proliferation and metastasis of cancer cells. In this review, we focus on the altered expression of PCDHs and their roles in the development of cancer progression. We also discuss the potential mechanisms, by which PCDHs are aberrantly expressed, and its implications in regulating cancers.

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References

  1. Takeichi M. Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling. Nat Rev Mol Cell Biol. 2014;15:397–410.

    Article  CAS  PubMed  Google Scholar 

  2. Suzuki ST. Protocadherins and diversity of the cadherin superfamily. J Cell Sci. 1996;109(Pt 11):2609–11.

    CAS  PubMed  Google Scholar 

  3. Sano K, Tanihara H, Heimark RL, Obata S, Davidson M, St JT, et al. Protocadherins: a large family of cadherin-related molecules in central nervous system. EMBO J. 1993;12:2249–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Frank M, Kemler R. Protocadherins. Curr Opin Cell Biol. 2002;14:557–62.

    Article  CAS  PubMed  Google Scholar 

  5. Hulpiau P, van Roy F. Molecular evolution of the cadherin superfamily. Int J Biochem Cell Biol. 2009;41:349–69.

    Article  CAS  PubMed  Google Scholar 

  6. Boggon TJ, Murray J, Chappuis-Flament S, Wong E, Gumbiner BM, Shapiro L. C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science. 2002;296:1308–13.

    Article  CAS  PubMed  Google Scholar 

  7. Patel SD, Chen CP, Bahna F, Honig B, Shapiro L. Cadherin-mediated cell-cell adhesion: sticking together as a family. Curr Opin Struct Biol. 2003;13:690–8.

    Article  CAS  PubMed  Google Scholar 

  8. Morishita H, Umitsu M, Murata Y, Shibata N, Udaka K, Higuchi Y, et al. Structure of the cadherin-related neuronal receptor/protocadherin-alpha first extracellular cadherin domain reveals diversity across cadherin families. J Biol Chem. 2006;281:33650–63.

    Article  CAS  PubMed  Google Scholar 

  9. Morishita H, Yagi T. Protocadherin family: diversity, structure, and function. Curr Opin Cell Biol. 2007;19:584–92.

    Article  CAS  PubMed  Google Scholar 

  10. Kim SY, Yasuda S, Tanaka H, Yamagata K, Kim H. Non-clustered protocadherin. Cell Adhes Migr. 2011;5:97–105.

    Article  Google Scholar 

  11. Takagi J. Structural basis for ligand recognition by RGD (Arg-Gly-Asp)-dependent integrins. Biochem Soc Trans. 2004;32:403–6.

    Article  CAS  PubMed  Google Scholar 

  12. Mutoh T, Hamada S, Senzaki K, Murata Y, Yagi T. Cadherin-related neuronal receptor 1 (CNR1) has cell adhesion activity with beta1 integrin mediated through the RGD site of CNR1. Exp Cell Res. 2004;294:494–508.

    Article  CAS  PubMed  Google Scholar 

  13. Yagi T. Molecular codes for neuronal individuality and cell assembly in the brain. Front Mol Neurosci. 2012;5:45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ribich S, Tasic B, Maniatis T. Identification of long-range regulatory elements in the protocadherin-alpha gene cluster. Proc Natl Acad Sci U S A. 2006;103:19719–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tasic B, Nabholz CE, Baldwin KK, Kim Y, Rueckert EH, Ribich SA, et al. Promoter choice determines splice site selection in protocadherin alpha and gamma pre-mRNA splicing. Mol Cell. 2002;10:21–33.

    Article  CAS  PubMed  Google Scholar 

  16. Kaneko R, Kato H, Kawamura Y, Esumi S, Hirayama T, Hirabayashi T, et al. Allelic gene regulation of Pcdh-alpha and Pcdh-gamma clusters involving both monoallelic and biallelic expression in single Purkinje cells. J Biol Chem. 2006;281:30551–60.

    Article  CAS  PubMed  Google Scholar 

  17. Hirano K, Kaneko R, Izawa T, Kawaguchi M, Kitsukawa T, Yagi T. Single-neuron diversity generated by Protocadherin-beta cluster in mouse central and peripheral nervous systems. Front Mol Neurosci. 2012;5:90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Esumi S, Kakazu N, Taguchi Y, Hirayama T, Sasaki A, Hirabayashi T, et al. Monoallelic yet combinatorial expression of variable exons of the protocadherin-alpha gene cluster in single neurons. Nat Genet. 2005;37:171–6.

    Article  CAS  PubMed  Google Scholar 

  19. Zipursky SL, Sanes JR. Chemoaffinity revisited: dscams, protocadherins, and neural circuit assembly. Cell. 2010;143:343–53.

    Article  CAS  PubMed  Google Scholar 

  20. Lefebvre JL, Kostadinov D, Chen WV, Maniatis T, Sanes JR. Protocadherins mediate dendritic self-avoidance in the mammalian nervous system. Nature. 2012;488:517–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wu Q, Maniatis T. A striking organization of a large family of human neural cadherin-like cell adhesion genes. Cell. 1999;97:779–90.

    Article  CAS  PubMed  Google Scholar 

  22. Hayashi S, Takeichi M. Emerging roles of protocadherins: from self-avoidance to enhancement of motility. J Cell Sci 2015.

  23. Rubinstein R, Thu CA, Goodman KM, Wolcott HN, Bahna F, Mannepalli S, et al. Molecular logic of neuronal self-recognition through protocadherin domain interactions. Cell. 2015;163:629–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Thu CA, Chen WV, Rubinstein R, Chevee M, Wolcott HN, Felsovalyi KO, et al. Single-cell identity generated by combinatorial homophilic interactions between alpha, beta, and gamma protocadherins. Cell. 2014;158:1045–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hirayama T, Yagi T. Clustered protocadherins and neuronal diversity. Prog Mol Biol Transl Sci. 2013;116:145–67.

    Article  CAS  PubMed  Google Scholar 

  26. Wu Q, Zhang T, Cheng JF, Kim Y, Grimwood J, Schmutz J, et al. Comparative DNA sequence analysis of mouse and human protocadherin gene clusters. Genome Res. 2001;11:389–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Golan-Mashiach M, Grunspan M, Emmanuel R, Gibbs-Bar L, Dikstein R, Shapiro E. Identification of CTCF as a master regulator of the clustered protocadherin genes. Nucleic Acids Res. 2012;40:3378–91.

    Article  CAS  PubMed  Google Scholar 

  28. Yokota S, Hirayama T, Hirano K, Kaneko R, Toyoda S, Kawamura Y, et al. Identification of the cluster control region for the protocadherin-beta genes located beyond the protocadherin-gamma cluster. J Biol Chem. 2011;286:31885–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Phillips JE, Corces VG. CTCF: master weaver of the genome. Cell. 2009;137:1194–211.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hirayama T, Tarusawa E, Yoshimura Y, Galjart N, Yagi T. CTCF is required for neural development and stochastic expression of clustered Pcdh genes in neurons. Cell Rep. 2012;2:345–57.

    Article  CAS  PubMed  Google Scholar 

  31. Victoria-Acosta G, Vazquez-Santillan K, Jimenez-Hernandez L, Munoz-Galindo L, Maldonado V, Martinez-Ruiz GU, et al. Epigenetic silencing of the XAF1 gene is mediated by the loss of CTCF binding. Sci Rep. 2015;5:14838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Walker CJ, Miranda MA, O’Hern MJ, McElroy JP, Coombes KR, Bundschuh R, et al. Patterns of CTCF and ZFHX3 mutation and associated outcomes in endometrial cancer. J Natl Cancer Inst. 2015;107.

  33. Katainen R, Dave K, Pitkanen E, Palin K, 0000000246216128 AO, Kivioja T, et al. CTCF/cohesin-binding sites are frequently mutated in cancer. Nat Genet. 2015;47:818–21.

    Article  CAS  PubMed  Google Scholar 

  34. Zou Y, Huang MZ, Liu FY, Yang BC, Wang LQ, Wang F, et al. Absence of and hotspot mutations in patients with various subtypes of ovarian carcinomas. Biomed Rep. 2015;3:33–7.

    PubMed  Google Scholar 

  35. Remeseiro S, Cuadrado A, Gomez-Lopez G, Pisano DG, Losada A. A unique role of cohesin-SA1 in gene regulation and development. EMBO J. 2012;31:2090–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Monahan K, Rudnick ND, Kehayova PD, Pauli F, Newberry KM, Myers RM, et al. Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of protocadherin-alpha gene expression. Proc Natl Acad Sci U S A. 2012;109:9125–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tan YP, Li S, Jiang XJ, Loh W, Foo YK, Loh CB, et al. Regulation of protocadherin gene expression by multiple neuron-restrictive silencer elements scattered in the gene cluster. Nucleic Acids Res. 2010;38:4985–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kehayova P, Monahan K, Chen W, Maniatis T. Regulatory elements required for the activation and repression of the protocadherin-alpha gene cluster. Proc Natl Acad Sci U S A. 2011;108:17195–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Majumder S. REST in good times and bad: roles in tumor suppressor and oncogenic activities. Cell Cycle. 2006;5:1929–35.

    Article  CAS  PubMed  Google Scholar 

  40. Wagoner MP, Gunsalus KT, Schoenike B, Richardson AL, Friedl A, Roopra A. The transcription factor REST is lost in aggressive breast cancer. PLoS Genet. 2010;6:e1000979.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Huang Z, Bao S. Ubiquitination and deubiquitination of REST and its roles in cancers. FEBS Lett. 2012;586:1602–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Robertson KD, Wolffe AP. DNA methylation in health and disease. Nat Rev Genet. 2000;1:11–9.

    Article  CAS  PubMed  Google Scholar 

  43. Kawaguchi M, Toyama T, Kaneko R, Hirayama T, Kawamura Y, Yagi T. Relationship between DNA methylation states and transcription of individual isoforms encoded by the protocadherin-alpha gene cluster. J Biol Chem. 2008;283:12064–75.

    Article  CAS  PubMed  Google Scholar 

  44. Toyoda S, Kawaguchi M, Kobayashi T, Tarusawa E, Toyama T, Okano M, et al. Developmental epigenetic modification regulates stochastic expression of clustered protocadherin genes, generating single neuron diversity. Neuron. 2014;82:94–108.

    Article  CAS  PubMed  Google Scholar 

  45. Novak P, Jensen T, Oshiro MM, Watts GS, Kim CJ, Futscher BW. Agglomerative epigenetic aberrations are a common event in human breast cancer. Cancer Res. 2008;68:8616–25.

    Article  CAS  PubMed  Google Scholar 

  46. Miyamoto K, Fukutomi T, Akashi-Tanaka S, Hasegawa T, Asahara T, Sugimura T, et al. Identification of 20 genes aberrantly methylated in human breast cancers. Int J Cancer. 2005;116:407–14.

    Article  CAS  PubMed  Google Scholar 

  47. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vincent A, Omura N, Hong SM, Jaffe A, Eshleman J, Goggins M. Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma. Clin Cancer Res. 2011;17:4341–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Waha A, Guntner S, Huang TH, Yan PS, Arslan B, Pietsch T, et al. Epigenetic silencing of the protocadherin family member PCDH-gamma-A11 in astrocytomas. Neoplasia. 2005;7:193–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Shi H, Guo J, Duff DJ, Rahmatpanah F, Chitima-Matsiga R, Al-Kuhlani M, et al. Discovery of novel epigenetic markers in non-Hodgkin’s lymphoma. Carcinogenesis. 2007;28:60–70.

    Article  CAS  PubMed  Google Scholar 

  51. Dallosso AR, Hancock AL, Szemes M, Moorwood K, Chilukamarri L, Tsai HH, et al. Frequent long-range epigenetic silencing of protocadherin gene clusters on chromosome 5q31 in Wilms’ tumor. PLoS Genet. 2009;5:e1000745.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Dallosso AR, Oster B, Greenhough A, Thorsen K, Curry TJ, Owen C, et al. Long-range epigenetic silencing of chromosome 5q31 protocadherins is involved in early and late stages of colorectal tumorigenesis through modulation of oncogenic pathways. Oncogene. 2012;31:4409–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Severson PL, Tokar EJ, Vrba L, Waalkes MP, Futscher BW. Agglomerates of aberrant DNA methylation are associated with toxicant-induced malignant transformation. Epilepsia. 2012;7:1238–48.

    CAS  Google Scholar 

  54. Yu JS, Koujak S, Nagase S, Li CM, Su T, Wang X, et al. PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer. Oncogene. 2008;27:4657–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang D, Zhao W, Liao X, Bi T, Li H, Che X. Frequent silencing of protocadherin 8 by promoter methylation, a candidate tumor suppressor for human gastric cancer. Oncol Rep. 2012;28:1785–91.

    CAS  PubMed  Google Scholar 

  56. Lin YL, Wang YL, Ma JG, Li WP. Clinical significance of protocadherin 8 (PCDH8) promoter methylation in non-muscle invasive bladder cancer. J Exp Clin Cancer Res. 2014;33:68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Leshchenko VV, Kuo PY, Shaknovich R, Yang DT, Gellen T, Petrich A, et al. Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood. 2010;116:1025–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yu B, Yang H, Zhang C, Wu Q, Shao Y, Zhang J, et al. High-resolution melting analysis of PCDH10 methylation levels in gastric, colorectal and pancreatic cancers. Neoplasma. 2010;57:247–52.

    Article  CAS  PubMed  Google Scholar 

  59. Yu J, Cheng YY, Tao Q, Cheung KF, Lam CN, Geng H, et al. Methylation of protocadherin 10, a novel tumor suppressor, is associated with poor prognosis in patients with gastric cancer. Gastroenterology. 2009;136:640–51.e1.

    Article  CAS  PubMed  Google Scholar 

  60. Heitzer E, Artl M, Filipits M, Resel M, Graf R, Weissenbacher B, et al. Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1. Mod Pathol. 2014;27:906–15.

    Article  CAS  PubMed  Google Scholar 

  61. Danese E, Minicozzi AM, Benati M, Montagnana M, Paviati E, Salvagno GL, et al. Epigenetic alteration: new insights moving from tissue to plasma—the example of PCDH10 promoter methylation in colorectal cancer. Br J Cancer. 2013;109:807–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Deng J, Liang H, Ying G, Dong Q, Zhang L, Yu J, et al. Clinical significance of the methylated cytosine-phosphate-guanine sites of protocadherin-10 promoter for evaluating the prognosis of gastric cancer. J Am Coll Surg. 2014;219:904–13.

    Article  PubMed  Google Scholar 

  63. Ying J, Li H, Seng TJ, Langford C, Srivastava G, Tsao SW, et al. Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation. Oncogene. 2006;25:1070–80.

    Article  CAS  PubMed  Google Scholar 

  64. Narayan G, Scotto L, Neelakantan V, Kottoor SH, Wong AH, Loke SL, et al. Protocadherin PCDH10, involved in tumor progression, is a frequent and early target of promoter hypermethylation in cervical cancer. Genes Chromosom Cancer. 2009;48:983–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Harada H, Miyamoto K, Yamashita Y, Taniyama K, Mihara K, Nishimura M, et al. Prognostic signature of protocadherin 10 methylation in curatively resected pathological stage I non-small-cell lung cancer. Cancer Med. 2015.

  66. Cheung HH, Lee TL, Davis AJ, Taft DH, Rennert OM, Chan WY. Genome-wide DNA methylation profiling reveals novel epigenetically regulated genes and non-coding RNAs in human testicular cancer. Br J Cancer. 2010;102:419–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ying J, Gao Z, Li H, Srivastava G, Murray PG, Goh HK, et al. Frequent epigenetic silencing of protocadherin 10 by methylation in multiple haematologic malignancies. Br J Haematol. 2007;136:829–32.

    Article  CAS  PubMed  Google Scholar 

  68. Haruki S, Imoto I, Kozaki K, Matsui T, Kawachi H, Komatsu S, et al. Frequent silencing of protocadherin 17, a candidate tumour suppressor for esophageal squamous cell carcinoma. Carcinogenesis. 2010;31:1027–36.

    Article  CAS  PubMed  Google Scholar 

  69. Hu X, Sui X, Li L, Huang X, Rong R, Su X, et al. Protocadherin 17 acts as a tumour suppressor inducing tumour cell apoptosis and autophagy, and is frequently methylated in gastric and colorectal cancers. J Pathol. 2013;229:62–73.

    Article  CAS  PubMed  Google Scholar 

  70. Imoto I, Izumi H, Yokoi S, Hosoda H, Shibata T, Hosoda F, et al. Frequent silencing of the candidate tumor suppressor PCDH20 by epigenetic mechanism in non-small-cell lung cancers. Cancer Res. 2006;66:4617–26.

    Article  CAS  PubMed  Google Scholar 

  71. Gendrel AV, Tang YA, Suzuki M, Godwin J, Nesterova TB, Greally JM, et al. Epigenetic functions of smchd1 repress gene clusters on the inactive X chromosome and on autosomes. Mol Cell Biol. 2013;33:3150–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chen K, Hu J, Moore DL, Liu R, Kessans SA, Breslin K, et al. Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation. Proc Natl Acad Sci U S A 2015.

  73. Leong HS, Chen K, Hu Y, Lee S, Corbin J, Pakusch M, et al. Epigenetic regulator Smchd1 functions as a tumor suppressor. Cancer Res. 2013;73:1591–9.

    Article  CAS  PubMed  Google Scholar 

  74. Bamford S, Dawson E, Forbes S, Clements J, Pettett R, Dogan A, et al. The COSMIC (catalogue of somatic mutations in cancer) database and website. Br J Cancer. 2004;91:355–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Article  PubMed  Google Scholar 

  76. Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, et al. A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell. 2003;114:635–45.

    Article  CAS  PubMed  Google Scholar 

  77. Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, et al. ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation. Proc Natl Acad Sci U S A. 2005;102:9182–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Marambaud P, Robakis NK. Genetic and molecular aspects of Alzheimer’s disease shed light on new mechanisms of transcriptional regulation. Genes Brain Behav. 2005;4:134–46.

    Article  CAS  PubMed  Google Scholar 

  79. Bonn S, Seeburg PH, Schwarz MK. Combinatorial expression of alpha- and gamma-protocadherins alters their presenilin-dependent processing. Mol Cell Biol. 2007;27:4121–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Asad M, Wong MK, Tan TZ, Choolani M, Low J, Mori S, et al. FZD7 drives in vitro aggressiveness in Stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway. Cell Death Dis. 2014;5:e1346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wang C, Tao B, Li S, Li B, Wang X, Hu G, et al. Characterizing the role of PCDH9 in the regulation of glioma cell apoptosis and invasion. J Mol Neurosci. 2014;52:250–60.

    Article  CAS  PubMed  Google Scholar 

  82. Zhu P, Lv J, Yang Z, Guo L, Zhang L, Li M, et al. Protocadherin 9 inhibits epithelial-mesenchymal transition and cell migration through activating GSK-3beta in hepatocellular carcinoma. Biochem Biophys Res Commun. 2014;452:567–74.

    Article  CAS  PubMed  Google Scholar 

  83. Xu Y, Yang Z, Yuan H, Li Z, Li Y, Liu Q, et al. PCDH10 inhibits cell proliferation of multiple myeloma via the negative regulation of the Wnt/beta-catenin/BCL-9 signaling pathway. Oncol Rep. 2015;34:747–54.

    CAS  PubMed  Google Scholar 

  84. Jao TM, Tsai MH, Lio HY, Weng WT, Chen CC, Tzeng ST, et al. Protocadherin 10 suppresses tumorigenesis and metastasis in colorectal cancer and its genetic loss predicts adverse prognosis. Int J Cancer. 2014;135:2593–603.

    Article  CAS  PubMed  Google Scholar 

  85. Zhao Y, Yang Y, Trovik J, Sun K, Zhou L, Jiang P, et al. A novel wnt regulatory axis in endometrioid endometrial cancer. Cancer Res. 2014;74:5103–17.

    Article  CAS  PubMed  Google Scholar 

  86. Chen T, Long B, Ren G, Xiang T, Li L, Wang Z, et al. Protocadherin20 acts as a tumor suppressor gene: epigenetic inactivation in nasopharyngeal carcinoma. J Cell Biochem. 2015.

  87. Wu, JC, Wang FZ, Tsai ML, Lo CY, Badmaev V, Ho CT, et al. Se-Allylselenocysteine induces autophagy by modulating the AMPK/mTOR signaling pathway and epigenetic regulation of PCDH17 in human colorectal adenocarcinoma cells. Mol Nutr Food Res 2015.

  88. Dang Z, Shangguan J, Zhang C, Hu P, Ren Y, Lv Z, et al. Loss of protocadherin-17 (PCDH-17) promotes metastasis and invasion through hyperactivation of EGFR/MEK/ERK signaling pathway in hepatocellular carcinoma. Tumour Biol 2015.

  89. Chen MW, Vacherot F, De La Taille A, Gil-Diez-De-Medina S, Shen R, Friedman RA, et al. The emergence of protocadherin-PC expression during the acquisition of apoptosis-resistance by prostate cancer cells. Oncogene. 2002;21:7861–71.

    Article  CAS  PubMed  Google Scholar 

  90. Terry S, Maille P, Baaddi H, Kheuang L, Soyeux P, Nicolaiew N, et al. Cross modulation between the androgen receptor axis and protocadherin-PC in mediating neuroendocrine transdifferentiation and therapeutic resistance of prostate cancer. Neoplasia. 2013;15:761–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Terry S, Queires L, Gil-Diez-de-Medina S, Chen MW, de la Taille A, Allory Y, et al. Protocadherin-PC promotes androgen-independent prostate cancer cell growth. Prostate. 2006;66:1100–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yang X, Chen MW, Terry S, Vacherot F, Chopin DK, Bemis DL, et al. A human- and male-specific protocadherin that acts through the wnt signaling pathway to induce neuroendocrine transdifferentiation of prostate cancer cells. Cancer Res. 2005;65:5263–71.

    Article  CAS  PubMed  Google Scholar 

  93. Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, et al. Genes that mediate breast cancer metastasis to the brain. Nature. 2009;459:1005–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Li AM, Tian AX, Zhang RX, Ge J, Sun X, Cao XC. Protocadherin-7 induces bone metastasis of breast cancer. Biochem Biophys Res Commun. 2013;436:486–90.

    Article  CAS  PubMed  Google Scholar 

  95. Du W, Liu X, Fan G, Zhao X, Sun Y, Wang T, et al. From cell membrane to the nucleus: an emerging role of E-cadherin in gene transcriptional regulation. J Cell Mol Med. 2014;18:1712–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Han MH, Lin C, Meng S, Wang X. Proteomics analysis reveals overlapping functions of clustered protocadherins. Mol Cell Proteomics. 2010;9:71–83.

    Article  CAS  PubMed  Google Scholar 

  97. Wilker EW, van Vugt MA, Artim SA, Huang PH, Petersen CP, Reinhardt HC, et al. 14-3-3sigma controls mitotic translation to facilitate cytokinesis. Nature. 2007;446:329–32.

    Article  CAS  PubMed  Google Scholar 

  98. Urano T, Saito T, Tsukui T, Fujita M, Hosoi T, Muramatsu M, et al. Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth. Nature. 2002;417:871–5.

    Article  CAS  PubMed  Google Scholar 

  99. Kohmura N, Senzaki K, Hamada S, Kai N, Yasuda R, Watanabe M, et al. Diversity revealed by a novel family of cadherins expressed in neurons at a synaptic complex. Neuron. 1998;20:1137–51.

    Article  CAS  PubMed  Google Scholar 

  100. Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, et al. Proteogenomic characterization of human colon and rectal cancer. Nature. 2014;513:382–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Vanhalst K, Kools P, Staes K, van Roy F, Redies C. Delta-Protocadherins: a gene family expressed differentially in the mouse brain. Cell Mol Life Sci. 2005;62:1247–59.

    Article  CAS  PubMed  Google Scholar 

  102. Heggem MA, Bradley RS. The cytoplasmic domain of Xenopus NF-protocadherin interacts with TAF1/set. Dev Cell. 2003;4:419–29.

    Article  CAS  PubMed  Google Scholar 

  103. Yasuda S, Tanaka H, Sugiura H, Okamura K, Sakaguchi T, Tran U, et al. Activity-induced protocadherin arcadlin regulates dendritic spine number by triggering N-cadherin endocytosis via TAO2beta and p38 MAP kinases. Neuron. 2007;56:456–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Nakao S, Platek A, Hirano S, Takeichi M. Contact-dependent promotion of cell migration by the OL-protocadherin-Nap1 interaction. J Cell Biol. 2008;182:395–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Grove EA. Turning neurons into a nervous system. Development. 2008;135:2203–6.

    Article  CAS  PubMed  Google Scholar 

  106. Homayouni R, Rice DS, Curran T. Disabled-1 interacts with a novel developmentally regulated protocadherin. Biochem Biophys Res Commun. 2001;289:539–47.

    Article  CAS  PubMed  Google Scholar 

  107. Borrell V, Pujadas L, Simo S, Dura D, Sole M, Cooper JA, et al. Reelin and mDab1 regulate the development of hippocampal connections. Mol Cell Neurosci. 2007;36:158–73.

    Article  CAS  PubMed  Google Scholar 

  108. Kahr I, Vandepoele K, van Roy F. Delta-protocadherins in health and disease. Prog Mol Biol Transl Sci. 2013;116:169–92.

    Article  CAS  PubMed  Google Scholar 

  109. Kietzmann A, Wang Y, Weber D, Steinbeisser H. Xenopus paraxial protocadherin inhibits Wnt/beta-catenin signalling via casein kinase 2beta. EMBO Rep. 2012;13:129–34.

    Article  CAS  PubMed  Google Scholar 

  110. Kai M, Ueno N, Kinoshita N. Phosphorylation-dependent ubiquitination of paraxial protocadherin (PAPC) controls gastrulation cell movements. PLoS One. 2015;10:e0115111.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Schalm SS, Ballif BA, Buchanan SM, Phillips GR, Maniatis T. Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret. Proc Natl Acad Sci U S A. 2010;107:13894–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995;267:381–3.

    Article  CAS  PubMed  Google Scholar 

  113. Fernandez-Sanchez ME, Barbier S, Whitehead J, Bealle G, Michel A, Latorre-Ossa H, et al. Mechanical induction of the tumorigenic beta-catenin pathway by tumour growth pressure. Nature. 2015;523:92–5.

    Article  CAS  PubMed  Google Scholar 

  114. Faura TG, Vandepoele K, Brouwer U, Koning H, Elderman RM, Hackett TL, et al. Protocadherin-1 binds to SMAD3 and suppresses TGFbeta1-induced gene transcription. Am J Physiol Lung Cell Mol Physiol. 2015:ajplung.00346.2014.

  115. Wu C, Niu L, Yan Z, Wang C, Liu N, Dai Y, et al. Pcdh11x negatively regulates dendritic branching. J Mol Neurosci. 2015;56:822–8.

    Article  CAS  PubMed  Google Scholar 

  116. Takeichi M. Morphogenetic roles of classic cadherins. Curr Opin Cell Biol. 1995;7:619–27.

    Article  CAS  PubMed  Google Scholar 

  117. Chen X, Gumbiner BM. Paraxial protocadherin mediates cell sorting and tissue morphogenesis by regulating C-cadherin adhesion activity. J Cell Biol. 2006;174:301–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kazmierczak P, Sakaguchi H, Tokita J, Wilson-Kubalek EM, Milligan RA, Muller U, et al. Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature. 2007;449:87–91.

    Article  CAS  PubMed  Google Scholar 

  119. Chen X, Koh E, Yoder M, Gumbiner BM. A protocadherin-cadherin-FLRT3 complex controls cell adhesion and morphogenesis. PLoS One. 2009;4:e8411.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Kraft B, Berger CD, Wallkamm V, Steinbeisser H, Wedlich D. Wnt-11 and Fz7 reduce cell adhesion in convergent extension by sequestration of PAPC and C-cadherin. J Cell Biol. 2012;198:695–709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Jung B, Kohler A, Schambony A, Wedlich D. PAPC and the Wnt5a/Ror2 pathway control the invagination of the otic placode in Xenopus. BMC Dev Biol. 2011;11:36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Himmelreich N, Kaufmann, LT, Steinbeisser H, Korner C, Thiel C. Lack of phosphomannomutase 2 affects Xenopus laevis morphogenesis and the non-canonical Wnt5a/Ror2 signalling. J Inherit Metab Dis. 2015.

  123. Kozu Y, Gon Y, Maruoka S, Kazumichi K, Sekiyama A, Kishi H, et al. Protocadherin-1 is a glucocorticoid-responsive critical regulator of airway epithelial barrier function. BMC Pulm Med. 2015;15:80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Chen J, Lu Y, Meng S, Han MH, Lin C, Wang X. Alpha- and gamma-protocadherins negatively regulate PYK2. J Biol Chem. 2009;284:2880–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Suo L, Lu H, Ying G, Capecchi MR, Wu Q. Protocadherin clusters and cell adhesion kinase regulate dendrite complexity through Rho GTPase. J Mol Cell Biol. 2012;4:362–76.

    Article  CAS  PubMed  Google Scholar 

  126. Zhang X, Chattopadhyay A, Ji QS, Owen JD, Ruest PJ, Carpenter G, et al. Focal adhesion kinase promotes phospholipase C-gamma1 activity. Proc Natl Acad Sci U S A. 1999;96:9021–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Tvorogov D, Wang XJ, Zent R, Carpenter G. Integrin-dependent PLC-gamma1 phosphorylation mediates fibronectin-dependent adhesion. J Cell Sci. 2005;118:601–10.

    Article  CAS  PubMed  Google Scholar 

  128. Heemskerk FM, Chen HC, Huang FL. Protein kinase C phosphorylates Ser152, Ser156 and Ser163 but not Ser160 of MARCKS in rat brain. Biochem Biophys Res Commun. 1993;190:236–41.

    Article  CAS  PubMed  Google Scholar 

  129. Li H, Chen G, Zhou B, Duan S. Actin filament assembly by myristoylated alanine-rich C kinase substrate-phosphatidylinositol-4,5-diphosphate signaling is critical for dendrite branching. Mol Biol Cell. 2008;19:4804–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Keeler AB, Schreiner D, Weiner JA, Protein Kinase C. Phosphorylation of a gamma-protocadherin C-terminal lipid binding domain regulates focal adhesion kinase inhibition and dendrite arborization. J Biol Chem. 2015;290:20674–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Biswas S, Emond MR, Duy PQ, Hao lT, Beattie CE, Jontes JD. Protocadherin-18b interacts with Nap1 to control motor axon growth and arborization in zebrafish. Mol Biol Cell. 2014;25:633–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Takenawa T, Suetsugu S. The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol. 2007;8:37–48.

    Article  CAS  PubMed  Google Scholar 

  133. Kurisu S, Takenawa T. WASP and WAVE family proteins: friends or foes in cancer invasion. Cancer Sci. 2010;101:2093–104.

    Article  CAS  PubMed  Google Scholar 

  134. Hayashi S, Inoue Y, Kiyonari H, Abe T, Misaki K, Moriguchi H, et al. Protocadherin-17 mediates collective axon extension by recruiting actin regulator complexes to interaxonal contacts. Dev Cell. 2014;30:673–87.

    Article  CAS  PubMed  Google Scholar 

  135. Hoshina N, Tanimura A, Yamasaki M, Inoue T, Fukabori R, Kuroda T, et al. Protocadherin 17 regulates presynaptic assembly in topographic corticobasal ganglia circuits. Neuron. 2013;78:839–54.

    Article  CAS  PubMed  Google Scholar 

  136. Brigidi GS, Bamji SX. Cadherin-catenin adhesion complexes at the synapse. Curr Opin Neurobiol. 2011;21:208–14.

    Article  CAS  PubMed  Google Scholar 

  137. Biswas S, Emond MR, Jontes JD. Protocadherin-19 and N-cadherin interact to control cell movements during anterior neurulation. J Cell Biol. 2010;191:1029–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, et al. Identifying autism loci and genes by tracing recent shared ancestry. Science. 2008;321:218–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Tsai NP, Wilkerson JR, Guo W, Maksimova MA, DeMartino GN, Cowan CW, et al. Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell. 2012;151:1581–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Bassermann F, Eichner R, Pagano M. The ubiquitin proteasome system - implications for cell cycle control and the targeted treatment of cancer. Biochim Biophys Acta. 2014;1843:150–62.

    Article  CAS  PubMed  Google Scholar 

  141. Schaefer A, Nethe M, Hordijk PL. Ubiquitin links to cytoskeletal dynamics, cell adhesion and migration. Biochem J. 2012;442:13–25.

    Article  CAS  PubMed  Google Scholar 

  142. Haas IG, Frank M, Veron N, Kemler R. Presenilin-dependent processing and nuclear function of gamma-protocadherins. J Biol Chem. 2005;280:9313–9.

    Article  CAS  PubMed  Google Scholar 

  143. Trimarchi T, Bilal E, Ntziachristos P, Fabbri G, Dalla-Favera R, Tsirigos A, et al. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell. 2014;158:593–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007;129:465–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Racioppi L, Means AR. Calcium/calmodulin-dependent protein kinase kinase 2: roles in signaling and pathophysiology. J Biol Chem. 2012;287:31658–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Colomer J, Means AR. Physiological roles of the Ca2+/CaM-dependent protein kinase cascade in health and disease. Subcell Biochem. 2007;45:169–214.

    Article  CAS  PubMed  Google Scholar 

  147. Gardner HP, Ha SI, Reynolds C, Chodosh LA. The caM kinase, Pnck, is spatially and temporally regulated during murine mammary gland development and may identify an epithelial cell subtype involved in breast cancer. Cancer Res. 2000;60:5571–7.

    CAS  PubMed  Google Scholar 

  148. Takai N, Ueda T, Nasu K, Yamashita S, Toyofuku M, Narahara H. Targeting calcium/calmodulin-dependence kinase I and II as a potential anti-proliferation remedy for endometrial carcinomas. Cancer Lett. 2009;277:235–43.

    Article  CAS  PubMed  Google Scholar 

  149. Onouchi T, Kishino-Kaneko Y, Kameshita I, Ishida A, Sueyoshi N. Regulation of Ca/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F) by protocadherin-gammaC5 (Pcdh-gammaC5). Arch Biochem Biophys 2015.

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Acknowledgments

This study was supported by the funding of the Affiliated Tumor Hospital of Harbin Medical University (JJZ2010-04), the “Wu Liande” funding of Harbin Medical University (WLD-QN1118), the Special Fund of Translational Medical Research between China and Russia (CR201402), and the Hei Longjiang Province Science Fund (QC2015113).

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Authors and Affiliations

  1. Department of Breast Surgery, the Affiliated Tumor Hospital of Harbin Medical University, Harbin, China

    Ming Shan, Yonghui Su & Guoqiang Zhang

  2. Department of Oncology, General Hospital of Hei Longjiang Province Land Reclamation Headquarter, Harbin, China

    Wenli Kang

  3. Department of Breast Surgery, The First Hospital of Qiqihaer City, Qiqihaer, China

    Ruixin Gao

  4. Department of Pathology, Harbin Medical University, Harbin, China

    Xiaobo Li

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  1. Ming Shan
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  2. Yonghui Su
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  3. Wenli Kang
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  5. Xiaobo Li
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Correspondence to Xiaobo Li or Guoqiang Zhang.

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Ming Shan and Yonghui Su are co-first authors.

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Shan, M., Su, Y., Kang, W. et al. Aberrant expression and functions of protocadherins in human malignant tumors. Tumor Biol. 37, 12969–12981 (2016). https://doi.org/10.1007/s13277-016-5169-9

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