How many cadherins do human endothelial cells express?

Abstract

The vasculature is the paradigm of a compartment generated by parallel cellular barriers that aims to transport oxygen, nutrients and immune cells in complex organisms. Vascular barrier dysfunction leads to fatal acute and chronic inflammatory diseases. The endothelial barrier lines the inner side of vessels and is the main regulator of vascular permeability. Cadherins comprise a superfamily of 114 calcium-dependent adhesion proteins that contain conserved cadherin motifs and form cell–cell junctions in metazoans. In mature human endothelial cells, only VE (vascular endothelial)-cadherin and N (neural)-cadherin have been investigated in detail. Although both cadherins are essential for regulating endothelial permeability, no comprehensive expression studies to identify which other family members could play a relevant role in endothelial cells has so far been performed. Here, we have reviewed gene and protein expression databases to analyze cadherin expression in mature human endothelium and found that at least 24 cadherin superfamily members are significantly expressed. Based on data obtained from other cell types, organisms and experimental models, we discuss their potential functions, many of them unrelated to the formation of endothelial cell–cell junctions. The expression of this new set of endothelial cadherins highlights the important but still poorly defined roles of planar cell polarity, the Hippo pathway and mitochondria metabolism in human vascular homeostasis.

This is a preview of subscription content, log in to check access.

Fig. 1

Abbreviations

APP:

Amyloid precursor protein

CCM:

Cerebral cavernous malformation

CDHR:

Cadherin-related proteins

CLSTN:

Calsyntenin

DCHS1:

Dachsous cadherin related 1

E-cadherin:

Epithelial cadherin

EMT:

Epithelial–mesenchymal transition

EndMT:

Endothelial–mesenchymal transition

GDNF:

Glial cell line-derived neurotrophic factor

GPI:

Glycosylphosphatidylinositol

HCV:

Hepatitis C virus

HUVEC:

Human umbilical vein endothelial cells

KSHV:

Kaposi ́s sarcoma-associated herpesvirus

MUCDHL:

Mucin and cadherin-like

N-cadherin:

Neural cadherin

OB-cadherin:

Osteoblast-cadherin

PCDH:

Protocadherin

PCDHG:

Protocadherin gamma (cluster)

PCP:

Planar cell polarity

phEndEC:

Primary human endoneurial endothelial cells

RET:

Rearranged during transfection

SMAD3:

Small and mothers against decapentaplegic 3

TGF- β:

Transforming growth factor-β

VE-cadherin:

Vascular endothelial cadherin

WNT:

Wingless-related integration site

YAP:

Yes-associated protein

TAZ:

Transcriptional coactivator with PDZ-binding motif

7D cadherin:

7-Domain cadherin

References

  1. 1.

    Tse D, Stan RV (2010) Morphological heterogeneity of endothelium. Semin Thromb Hemost 36:236–245

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Bryan MT, Duckles H, Feng S, Hsiao ST, Kim HR, Serbanovic-Canic J, Evans PC (2014) Mechanoresponsive networks controlling vascular inflammation. Arterioscler Thromb Vasc Biol 34:2199–2205

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Vestweber D (2002) Regulation of endothelial cell contacts during leukocyte extravasation. Curr Opin Cell Biol 14:587–593

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Reglero-Real N, Marcos-Ramiro B, Millan J (2012) Endothelial membrane reorganization during leukocyte extravasation. Cell Mol Life Sci 69:3079–3099

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Hirase T, Node K (2012) Endothelial dysfunction as a cellular mechanism for vascular failure. Am J Physiol Heart Circ Physiol 302:H499–H505

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Simionescu M (2007) Implications of early structural-functional changes in the endothelium for vascular disease. Arterioscler Thromb Vasc Biol 27:266–274

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Rohlenova K, Veys K, Miranda-Santos I, De Bock K, Carmeliet P (2017) Endothelial cell metabolism in health and disease. Trends Cell Biol 28:224–236

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Wang L et al (2016) Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 540(7634):579

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Daniel TO, Abrahamson D (2000) Endothelial signal integration in vascular assembly. Annu Rev Physiol 62:649–671

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Vestweber D (2015) How leukocytes cross the vascular endothelium. Nat Rev Immunol 15:692–704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Soon AS, Chua JW, Becker DL (2016) Connexins in endothelial barrier function—novel therapeutic targets countering vascular hyperpermeability. Thromb Haemost 116:852–867

    Article  PubMed  Google Scholar 

  12. 12.

    van Dijk CG et al (2015) The complex mural cell: pericyte function in health and disease. Int J Cardiol 190:75–89

    Article  PubMed  Google Scholar 

  13. 13.

    Gaete PS, Lillo MA, Figueroa XF (2014) Functional role of connexins and pannexins in the interaction between vascular and nervous system. J Cell Physiol 229:1336–1345

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Prinz M, Erny D, Hagemeyer N (2017) Ontogeny and homeostasis of CNS myeloid cells. Nat Immunol 18:385–392

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Zecchin A, Borgers G, Carmeliet P (2015) Endothelial cells and cancer cells: metabolic partners in crime? Curr Opin Hematol 22:234–242

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Dejana E (2004) Endothelial cell–cell junctions: happy together. Nat Rev Mol Cell Biol 5:261–270

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Gerhardt H, Wolburg H, Redies C (2000) N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken. Dev Dyn 218:472–479

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Cantelmo AR et al (2016) Inhibition of the glycolytic activator PFKFB3 in endothelium induces tumor vessel normalization, impairs metastasis, and improves chemotherapy. Cancer Cell 30:968–985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Qi J, Chen N, Wang J, Siu CH (2005) Transendothelial migration of melanoma cells involves N-cadherin-mediated adhesion and activation of the beta-catenin signaling pathway. Mol Biol Cell 16:4386–4397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Breier G, Grosser M, Rezaei M (2014) Endothelial cadherins in cancer. Cell Tissue Res 355:523–527

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Cavallaro U, Liebner S, Dejana E (2006) Endothelial cadherins and tumor angiogenesis. Exp Cell Res 312:659–667

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Sandig M, Voura EB, Kalnins VI, Siu CH (1997) Role of cadherins in the transendothelial migration of melanoma cells in culture. Cell Motil Cytoskel 38:351–364

    Article  CAS  Google Scholar 

  23. 23.

    Labernadie A et al (2017) A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat Cell Biol 19:224–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Spindler V, Waschke J (2014) Desmosomal cadherins and signaling: lessons from autoimmune disease. Cell Commun Adhes 21:77–84

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Gul IS, Hulpiau P, Saeys Y, van Roy F (2017) Evolution and diversity of cadherins and catenins. Exp Cell Res 358:3–9

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Hayashi S, Takeichi M (2015) Emerging roles of protocadherins: from self-avoidance to enhancement of motility. J Cell Sci 128:1455–1464

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Sano K, Tanihara H, Heimark RL, Obata S, Davidson M, St John T, Taketani S, Suzuki S (1993) Protocadherins: a large family of cadherin-related molecules in central nervous system. EMBO J 12:2249–2256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    van Roy F (2014) Beyond E-cadherin: roles of other cadherin superfamily members in cancer. Nat Rev Cancer 14:121–134

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Carmeliet P et al (1999) Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98:147–157

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Navarro P, Ruco L, Dejana E (1998) Differential localization of VE- and N-cadherins in human endothelial cells: VE-cadherin competes with N-cadherin for junctional localization. J Cell Biol 140:1475–1484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Uhlen M, Hallstrom BM, Lindskog C, Mardinoglu A, Ponten F, Nielsen J (2016) Transcriptomics resources of human tissues and organs. Mol Syst Biol 12:862

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Uhlen M et al (2015) Proteomics: tissue-based map of the human proteome. Science 347:1260419

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Wu C et al (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 10:R130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Wu C, Macleod I, Su AI (2013) BioGPS and MyGene.info: organizing online, gene-centric information. Nucl Acids Res 41:D561–D565

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Cao Y, Zhu J, Jia P, Zhao Z (2017) scRNASeqDB: a database for RNA-Seq based gene expression profiles in human single cells. Genes 8(12):E368

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Tirosh I et al (2016) Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352:189–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Darmanis S et al (2015) A survey of human brain transcriptome diversity at the single cell level. Proc Natl Acad Sci USA 112:7285–7290

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Forrest AR et al (2014) A promoter-level mammalian expression atlas. Nature 507:462–470

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Okazaki M, Takeshita S, Kawai S, Kikuno R, Tsujimura A, Kudo A, Amann E (1994) Molecular cloning and characterization of OB-cadherin, a new member of cadherin family expressed in osteoblasts. J Biol Chem 269:12092–12098

    CAS  PubMed  Google Scholar 

  40. 40.

    Schneider DJ, Wu M, Le TT, Cho SH, Brenner MB, Blackburn MR, Agarwal SK (2012) Cadherin-11 contributes to pulmonary fibrosis: potential role in TGF-beta production and epithelial to mesenchymal transition. FASEB J 26:503–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Gheldof A, Berx G (2013) Cadherins and epithelial-to-mesenchymal transition. Prog Mol Biol Transl Sci 116:317–336

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Dou C, Yan Y, Dong S (2013) Role of cadherin-11 in synovial joint formation and rheumatoid arthritis pathology. Mod Rheumatol 23:1037–1044

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Sfikakis PP, Vlachogiannis NI, Christopoulos PF (2017) Cadherin-11 as a therapeutic target in chronic, inflammatory rheumatic diseases. Clin Immunol 176:107–113

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Agarwal SK, Brenner MB (2006) Role of adhesion molecules in synovial inflammation. Curr Opin Rheumatol 18:268–276

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Balint B, Yin H, Chakrabarti S, Chu MW, Sims SM, Pickering JG (2015) Collectivization of vascular smooth muscle cells via TGF-beta-cadherin-11-dependent adhesive switching. Arterioscler Thromb Vasc Biol 35:1254–1264

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Ortiz A et al (2015) Angiomotin is a novel component of cadherin-11/beta-catenin/p120 complex and is critical for cadherin-11-mediated cell migration. FASEB J 29:1080–1091

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Langhe RP et al (2016) Cadherin-11 localizes to focal adhesions and promotes cell-substrate adhesion. Nat Commun 7:10909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Tomita K, van Bokhoven A, van Leenders GJ, Ruijter ET, Jansen CF, Bussemakers MJ, Schalken JA (2000) Cadherin switching in human prostate cancer progression. Cancer Res 60:3650–3654

    CAS  PubMed  Google Scholar 

  49. 49.

    Maddaluno L et al (2013) EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498:492–496

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Kim SY, Yasuda S, Tanaka H, Yamagata K, Kim H (2011) Non-clustered protocadherin. Cell Adh Migr 5:97–105

    Article  PubMed  Google Scholar 

  51. 51.

    Fukata Y, Fukata M (2010) Protein palmitoylation in neuronal development and synaptic plasticity. Nat Rev Neurosci 11:161–175

    Article  CAS  PubMed  Google Scholar 

  52. 52.

    Krishna K, Redies C (2009) Expression of cadherin superfamily genes in brain vascular development. J Cereb Blood Flow Metab 29:224–229

    Article  CAS  Google Scholar 

  53. 53.

    Redies C, Heyder J, Kohoutek T, Staes K, Van Roy F (2008) Expression of protocadherin-1 (Pcdh1) during mouse development. Dev Dyn 237:2496–2505

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    Favre CJ, Mancuso M, Maas K, McLean JW, Baluk P, McDonald DM (2003) Expression of genes involved in vascular development and angiogenesis in endothelial cells of adult lung. Am J Physiol Heart Circ Physiol 285:H1917–H1938

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Faura Tellez G et al (2015) Protocadherin-1 binds to SMAD3 and suppresses TGF-beta1-induced gene transcription. Am J Physiol Lung Cell Mol Physiol 309:L725–L735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Howell JE, McAnulty RJ (2006) TGF-beta: its role in asthma and therapeutic potential. Curr Drug Targets 7:547–565

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    Yang YC, Zhang N, Van Crombruggen K, Hu GH, Hong SL, Bachert C (2012) Transforming growth factor-beta1 in inflammatory airway disease: a key for understanding inflammation and remodeling. Allergy 67:1193–1202

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Koning H et al (2014) Mouse protocadherin-1 gene expression is regulated by cigarette smoke exposure in vivo. PLoS One 9:e98197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Goumans MJ, Ten Dijke P (2017) TGF-beta signaling in control of cardiovascular function. Cold Spring Harb Perspect Biol 10(2):a022210

    Article  CAS  Google Scholar 

  60. 60.

    Xiao H, Sun Z, Wan J, Hou S, Xiong Y (2018) Overexpression of protocadherin 7 inhibits neuronal survival by downregulating BIRC5 in vitro. Exp Cell Res 366:71–80

    Article  CAS  PubMed  Google Scholar 

  61. 61.

    Bradley RS (2018) Neural crest development in Xenopus requires Protocadherin 7 at the lateral neural crest border. Mech Dev 149:41–52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Lin YL, Wang YL, Fu XL, Li WP, Wang YH, Ma JG (2016) Low expression of protocadherin7 (PCDH7) is a potential prognostic biomarker for primary non-muscle invasive bladder cancer. Oncotarget 7:28384–28392

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Chen HF, Ma RR, He JY, Zhang H, Liu XL, Guo XY, Gao P (2017) Protocadherin 7 inhibits cell migration and invasion through E-cadherin in gastric cancer. Tumour Biol 39:1010428317697551

    PubMed  Google Scholar 

  64. 64.

    Zhou X et al (2017) PROTOCADHERIN 7 Acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis. Cancer Res 77:187–197

    Article  CAS  PubMed  Google Scholar 

  65. 65.

    Li AM, Tian AX, Zhang RX, Ge J, Sun X, Cao XC (2013) Protocadherin-7 induces bone metastasis of breast cancer. Biochem Biophys Res Commun 436:486–490

    Article  CAS  PubMed  Google Scholar 

  66. 66.

    Chen Q et al (2016) Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533:493–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Kandasamy K, Escue R, Manna J, Adebiyi A, Parthasarathi K (2015) Changes in endothelial connexin 43 expression inversely correlate with microvessel permeability and VE-cadherin expression in endotoxin-challenged lungs. Am J Physiol Lung Cell Mol Physiol 309:L584–L592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Zheng X, Zhang W, Hu X (2018) Different concentrations of lipopolysaccharide regulate barrier function through the PI3K/Akt signalling pathway in human pulmonary microvascular endothelial cells. Sci Rep 8:9963

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Yu J et al (2009) Methylation of protocadherin 10, a novel tumor suppressor, is associated with poor prognosis in patients with gastric cancer. Gastroenterology 136(640–51):e1

    Google Scholar 

  70. 70.

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

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Schnittler H, Taha M, Schnittler MO, Taha AA, Lindemann N, Seebach J (2014) Actin filament dynamics and endothelial cell junctions: the Ying and Yang between stabilization and motion. Cell Tissue Res 355:529–543

    Article  CAS  PubMed  Google Scholar 

  72. 72.

    Cao J et al (2017) Polarized actin and VE-cadherin dynamics regulate junctional remodelling and cell migration during sprouting angiogenesis. Nat Commun 8:2210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Matakatsu H, Blair SS (2004) Interactions between Fat and Dachsous and the regulation of planar cell polarity in the Drosophila wing. Development 131:3785–3794

    Article  CAS  PubMed  Google Scholar 

  74. 74.

    Mao Y, Kuta A, Crespo-Enriquez I, Whiting D, Martin T, Mulvaney J, Irvine KD, Francis-West P (2016) Dchs1-Fat4 regulation of polarized cell behaviours during skeletal morphogenesis. Nat Commun 7:11469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Mao Y et al (2011) Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development. Development 138:947–957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Mao Y, Francis-West P, Irvine KD (2015) Fat4/Dchs1 signaling between stromal and cap mesenchyme cells influences nephrogenesis and ureteric bud branching. Development 142:2574–2585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Zakaria S et al (2014) Regulation of neuronal migration by Dchs1-Fat4 planar cell polarity. Curr Biol 24:1620–1627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Durst R et al (2015) Mutations in DCHS1 cause mitral valve prolapse. Nature 525:109–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Kuta A et al (2016) Fat4-Dchs1 signalling controls cell proliferation in developing vertebrae. Development 143:2367–2375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Beste C, Ocklenburg S, von der Hagen M, Di Donato N (2016) Mammalian cadherins DCHS1-FAT4 affect functional cerebral architecture. Brain Struct Funct 221:2487–2491

    Article  CAS  PubMed  Google Scholar 

  81. 81.

    Cappello S et al (2013) Mutations in genes encoding the cadherin receptor-ligand pair DCHS1 and FAT4 disrupt cerebral cortical development. Nat Genet 45:1300–1308

    Article  CAS  PubMed  Google Scholar 

  82. 82.

    Wu YH, Hu TF, Chen YC, Tsai YN, Tsai YH, Cheng CC, Wang HW (2011) The manipulation of miRNA-gene regulatory networks by KSHV induces endothelial cell motility. Blood 118:2896–2905

    Article  CAS  PubMed  Google Scholar 

  83. 83.

    Sewduth R, Santoro MM (2016) “Decoding” Angiogenesis: new facets controlling endothelial cell behavior. Front Physiol 7:306

    Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Tatin F, Taddei A, Weston A, Fuchs E, Devenport D, Tissir F, Makinen T (2013) Planar cell polarity protein Celsr1 regulates endothelial adherens junctions and directed cell rearrangements during valve morphogenesis. Dev Cell 26:31–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Pujol F et al (2017) Dachsous1-Fat4 signaling controls endothelial cell polarization during lymphatic valve morphogenesis-brief report. Arterioscler Thromb Vasc Biol 37:1732–1735

    Article  CAS  PubMed  Google Scholar 

  86. 86.

    Ciani L, Patel A, Allen ND, ffrench-Constant RH (2003) Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype. Mol Cell Biol 23:3575–3582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Gee HY et al (2016) FAT1 mutations cause a glomerulotubular nephropathy. Nat Commun 7:10822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Yaoita E, Kurihara H, Yoshida Y, Inoue T, Matsuki A, Sakai T, Yamamoto T (2005) Role of Fat1 in cell-cell contact formation of podocytes in puromycin aminonucleoside nephrosis and neonatal kidney. Kidney Int 68:542–551

    Article  CAS  PubMed  Google Scholar 

  89. 89.

    Cohen CD et al (2006) Comparative promoter analysis allows de novo identification of specialized cell junction-associated proteins. Proc Natl Acad Sci USA 103:5682–5687

    Article  CAS  PubMed  Google Scholar 

  90. 90.

    Cao LL et al (2016) Control of mitochondrial function and cell growth by the atypical cadherin Fat1. Nature 539:575–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Jaiswal M, Agrawal N, Sinha P (2006) Fat and Wingless signaling oppositely regulate epithelial cell-cell adhesion and distal wing development in Drosophila. Development 133:925–935

    Article  CAS  PubMed  Google Scholar 

  92. 92.

    Morris LG et al (2013) Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet 45:253–261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Zang ZJ et al (2012) Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet 44:570–574

    Article  CAS  PubMed  Google Scholar 

  94. 94.

    Cai J, Feng D, Hu L, Chen H, Yang G, Cai Q, Gao C, Wei D (2015) FAT4 functions as a tumour suppressor in gastric cancer by modulating Wnt/beta-catenin signalling. Br J Cancer 113:1720–1729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Hou L, Chen M, Zhao X, Li J, Deng S, Hu J, Yang H, Jiang J (2016) FAT4 functions as a tumor suppressor in triple-negative breast cancer. Tumour Biol 37:16337–16343

    Article  CAS  Google Scholar 

  96. 96.

    Zhou Y, Nathans J (2014) Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling. Dev Cell 31:248–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Olsen JJ, Pohl SO, Deshmukh A, Visweswaran M, Ward NC, Arfuso F, Agostino M, Dharmarajan A (2017) The role of Wnt signalling in angiogenesis. Clin Biochem Rev 38:131–142

    PubMed  PubMed Central  Google Scholar 

  98. 98.

    Sadeqzadeh E, de Bock CE, Thorne RF (2014) Sleeping giants: emerging roles for the fat cadherins in health and disease. Med Res Rev 34:190–221

    Article  CAS  PubMed  Google Scholar 

  99. 99.

    Ragni CV et al (2017) Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth. Nat Commun 8:14582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    He J et al (2018) Yes-associated protein promotes angiogenesis via signal transducer and activator of transcription 3 in endothelial cells. Circ Res 122:591–605

    Article  CAS  PubMed  Google Scholar 

  101. 101.

    Wang X et al (2017) YAP/TAZ orchestrate VEGF signaling during developmental angiogenesis. Dev Cell 42(462–478):e7

    Google Scholar 

  102. 102.

    Giampietro C et al (2015) The actin-binding protein EPS8 binds VE-cadherin and modulates YAP localization and signaling. J Cell Biol 211:1177–1192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Choi HJ, Zhang H, Park H, Choi KS, Lee HW, Agrawal V, Kim YM, Kwon YG (2015) Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2. Nat Commun 6:6943

    Article  CAS  PubMed  Google Scholar 

  104. 104.

    Neto F et al (2018) YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development. eLife 7:e31037

    Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Vogt L, Schrimpf SP, Meskenaite V, Frischknecht R, Kinter J, Leone DP, Ziegler U, Sonderegger P (2001) Calsyntenin-1, a proteolytically processed postsynaptic membrane protein with a cytoplasmic calcium-binding domain. Mol Cell Neurosci 17:151–166

    Article  CAS  PubMed  Google Scholar 

  106. 106.

    Hintsch G, Zurlinden A, Meskenaite V, Steuble M, Fink-Widmer K, Kinter J, Sonderegger P (2002) The calsyntenins. A family of postsynaptic membrane proteins with distinct neuronal expression patterns. Mol Cell Neurosci 21:393–409

    Article  CAS  PubMed  Google Scholar 

  107. 107.

    Um JW et al (2014) Calsyntenins function as synaptogenic adhesion molecules in concert with neurexins. Cell Rep 6:1096–1109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Konecna A et al (2006) Calsyntenin-1 docks vesicular cargo to kinesin-1. Mol Biol Cell 17:3651–3663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Alther TA, Domanitskaya E, Stoeckli ET (2016) Calsyntenin 1-mediated trafficking of axon guidance receptors regulates the switch in axonal responsiveness at a choice point. Development 143:994–1004

    Article  CAS  PubMed  Google Scholar 

  110. 110.

    Ludwig A et al (2009) Calsyntenins mediate TGN exit of APP in a kinesin-1-dependent manner. Traffic 10:572–589

    Article  CAS  PubMed  Google Scholar 

  111. 111.

    Vagnoni A, Perkinton MS, Gray EH, Francis PT, Noble W, Miller CC (2012) Calsyntenin-1 mediates axonal transport of the amyloid precursor protein and regulates Abeta production. Hum Mol Genet 21:2845–2854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Rindler MJ, Xu CF, Gumper I, Cen C, Sonderegger P, Neubert TA (2008) Calsyntenins are secretory granule proteins in anterior pituitary gland and pancreatic islet alpha cells. J Histochem Cytochem 56:381–388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Uchida Y, Gomi F, Murayama S, Takahashi H (2013) Calsyntenin-3 C-terminal fragment accumulates in dystrophic neurites surrounding abeta plaques in tg2576 mouse and Alzheimer disease brains: its neurotoxic role in mediating dystrophic neurite formation. Am J Pathol 182:1718–1726

    Article  CAS  PubMed  Google Scholar 

  114. 114.

    Uchida Y, Gomi F (2016) The role of calsyntenin-3 in dystrophic neurite formation in Alzheimer’s disease brain. Geriatr Gerontol Int 16(Suppl 1):43–50

    Article  PubMed  Google Scholar 

  115. 115.

    Molumby MJ, Anderson RM, Newbold DJ, Koblesky NK, Garrett AM, Schreiner D, Radley JJ, Weiner JA (2017) Gamma-protocadherins interact with neuroligin-1 and negatively regulate dendritic spine morphogenesis. Cell Rep 18:2702–2714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Lin C, Meng S, Zhu T, Wang X (2010) PDCD10/CCM3 acts downstream of {gamma}-protocadherins to regulate neuronal survival. J Biol Chem 285:41675–41685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Lampugnani MG, Malinverno M, Dejana E, Rudini N (2017) Endothelial cell disease: emerging knowledge from cerebral cavernous malformations. Curr Opin Hematol 24:256–264

    Article  CAS  PubMed  Google Scholar 

  118. 118.

    Schalm SS, Ballif BA, Buchanan SM, Phillips GR, Maniatis T (2010) Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret. Proc Natl Acad Sci USA 107:13894–13899

    Article  PubMed  Google Scholar 

  119. 119.

    Romei C, Ciampi R, Elisei R (2016) A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol 12:192–202

    Article  CAS  PubMed  Google Scholar 

  120. 120.

    Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R (2017) RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res 23:1988–1997

    Article  CAS  PubMed  Google Scholar 

  121. 121.

    Yosef N, Ubogu EE (2012) GDNF restores human blood-nerve barrier function via RET tyrosine kinase-mediated cytoskeletal reorganization. Microvasc Res 83:298–310

    Article  CAS  PubMed  Google Scholar 

  122. 122.

    Quaegebeur A, Lange C, Carmeliet P (2011) The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron 71:406–424

    Article  CAS  PubMed  Google Scholar 

  123. 123.

    Mabbott NA, Baillie JK, Brown H, Freeman TC, Hume DA (2013) An expression atlas of human primary cells: inference of gene function from coexpression networks. BMC Genom 14:632

    Article  CAS  Google Scholar 

  124. 124.

    Lecuit T, Yap AS (2015) E-cadherin junctions as active mechanical integrators in tissue dynamics. Nat Cell Biol 17:533–539

    Article  CAS  PubMed  Google Scholar 

  125. 125.

    van Roy F, Berx G (2008) The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci 65:3756–3788

    Article  CAS  PubMed  Google Scholar 

  126. 126.

    Luo Y, Radice GL (2005) N-cadherin acts upstream of VE-cadherin in controlling vascular morphogenesis. J Cell Biol 169:29–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Blaschuk OW (2015) N-cadherin antagonists as oncology therapeutics. Philos Trans R Soc Lond B Biol Sci 370:20140039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Giannotta M, Trani M, Dejana E (2013) VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. Dev Cell 26:441–454

    Article  CAS  PubMed  Google Scholar 

  129. 129.

    Lampugnani MG, Resnati M, Raiteri M, Pigott R, Pisacane A, Houen G, Ruco LP, Dejana E (1992) A novel endothelial-specific membrane protein is a marker of cell-cell contacts. J Cell Biol 118:1511–1522

    Article  CAS  PubMed  Google Scholar 

  130. 130.

    Harris ES, Nelson WJ (2010) VE-cadherin: at the front, center, and sides of endothelial cell organization and function. Curr Opin Cell Biol 22:651–658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Fernandez-Martin L et al (2012) Crosstalk between reticular adherens junctions and platelet endothelial cell adhesion molecule-1 regulates endothelial barrier function. Arterioscler Thromb Vasc Biol 32:e90–e102

    Article  CAS  PubMed  Google Scholar 

  132. 132.

    Kostopoulos CG, Spiroglou SG, Varakis JN, Apostolakis E, Papadaki HH (2014) Adiponectin/T-cadherin and apelin/APJ expression in human arteries and periadventitial fat: implication of local adipokine signaling in atherosclerosis? Cardiovasc Pathol 23:131–138

    Article  CAS  PubMed  Google Scholar 

  133. 133.

    Haselton FR, Heimark RL (1997) Role of cadherins 5 and 13 in the aortic endothelial barrier. J Cell Physiol 171:243–251

    Article  CAS  PubMed  Google Scholar 

  134. 134.

    Joshi MB, Ivanov D, Philippova M, Kyriakakis E, Erne P, Resink TJ (2008) A requirement for thioredoxin in redox-sensitive modulation of T-cadherin expression in endothelial cells. Biochem J 416:271–280

    Article  CAS  PubMed  Google Scholar 

  135. 135.

    Andreeva AV, Han J, Kutuzov MA, Profirovic J, Tkachuk VA, Voyno-Yasenetskaya TA (2010) T-cadherin modulates endothelial barrier function. J Cell Physiol 223:94–102

    CAS  PubMed  Google Scholar 

  136. 136.

    Ivanov D et al (2001) Expression of cell adhesion molecule T-cadherin in the human vasculature. Histochem Cell Biol 115:231–242

    CAS  PubMed  Google Scholar 

  137. 137.

    Ludwig D, Lorenz J, Dejana E, Bohlen P, Hicklin DJ, Witte L, Pytowski B (2000) cDNA cloning, chromosomal mapping, and expression analysis of human VE-Cadherin-2. Mamm Genom 11:1030–1033

    Article  CAS  Google Scholar 

  138. 138.

    Telo P, Breviario F, Huber P, Panzeri C, Dejana E (1998) Identification of a novel cadherin (vascular endothelial cadherin-2) located at intercellular junctions in endothelial cells. J Biol Chem 273:17565–17572

    Article  CAS  PubMed  Google Scholar 

  139. 139.

    Guemez-Gamboa A et al (1998) Loss of protocadherin-12 leads to diencephalic-mesencephalic junction dysplasia syndrome. Ann Neurol. https://doi.org/10.1002/ana.25327

    Article  Google Scholar 

  140. 140.

    Huber AH, Weis WI (2001) The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin. Cell 105:391–402

    Article  CAS  PubMed  Google Scholar 

  141. 141.

    Hou R, Liu L, Anees S, Hiroyasu S, Sibinga NE (2006) The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals. J Cell Biol 173:417–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Cristina Cacho Navas and Dr. Nahuel Ramella for the critical reading of the manuscript and the Genomics Facility at the CBMSO for its helpful advice. We also thank Dr. Phil Mason, who provided English language support.

Funding

The work was supported by Grants SAF2017-88187-R from MINECO, B2017/BMD-3817 from Comunidad de Madrid and Endocornea 2, collaborative agreement with CSIC, funded by Instituto de Investigación Fundación Jiménez Díaz. N.C.A. is a recipient of an FPU fellowship from MECD.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jaime Millán.

Ethics declarations

Conflict of interest

The authors declare that no conflict of interest exists.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Colás-Algora, N., Millán, J. How many cadherins do human endothelial cells express?. Cell. Mol. Life Sci. 76, 1299–1317 (2019). https://doi.org/10.1007/s00018-018-2991-9

Download citation

Keywords

  • Cadherin
  • Gene expression
  • Endothelium
  • Vascular permeability
  • Barrier function
  • Cell adhesion molecule