Home LiteratureArticle Details
PMID: 23097623 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Opposite roles of furin and PC5A in N-cadherin processing.

Neoplasia (New York, N.Y.) ·Vol. 14 ·No. 10 ·2012-10-00 ·Pages 880-92

Maret D, Sadr MS, Sadr ES, Colman DR, Del Maestro RF, Seidah NG

Abstract

We recently demonstrated that lack of Furin-processing of the N-cadherin precursor (proNCAD) in highly invasive melanoma and brain tumor cells results in the cell-surface expression of a nonadhesive protein favoring cell migration and invasion in vitro. Quantitative polymerase chain reaction analysis of malignant human brain tumor cells revealed that of all proprotein convertases (PCs) only the levels of Furin and PC5A are modulated, being inversely (Furin) or directly (PC5A) correlated with brain tumor invasive capacity. Intriguingly, the N-terminal sequence following the Furin-activated NCAD site (RQKR↓DW(161), mouse nomenclature) reveals a second putative PC-processing site (RIRSDR↓DK(189)) located in the first extracellular domain. Cleavage at this site would abolish the adhesive functions of NCAD because of the loss of the critical Trp(161). This was confirmed upon analysis of the fate of the endogenous prosegment of proNCAD in human malignant glioma cells expressing high levels of Furin and low levels of PC5A (U343) or high levels of PC5A and negligible Furin levels (U251). Cellular analyses revealed that Furin is the best activating convertase releasing an ~17-kDa prosegment, whereas PC5A is the major inactivating enzyme resulting in the secretion of an ~20-kDa product. Like expression of proNCAD at the cell surface, cleavage of the NCAD molecule at RIRSDR↓DK(189) renders the U251 cancer cells less adhesive to one another and more migratory. Our work modifies the present view on posttranslational processing and surface expression of classic cadherins and clarifies how NCAD possesses a range of adhesive potentials and plays a critical role in tumor progression.

MeSH Terms
Antigens, CD/genetics,metabolism Blotting, Western Brain Neoplasms/genetics,metabolism,pathology Cadherins/genetics,metabolism Cell Movement Furin/antagonists & inhibitors,genetics,metabolism Glioma/genetics,metabolism,pathology HeLa Cells Humans Immunoenzyme Techniques Proprotein Convertase 5/antagonists & inhibitors,genetics,metabolism RNA, Messenger/genetics RNA, Small Interfering/genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured Wound Healing
Chemicals
Antigens, CD CDH2 protein, human Cadherins RNA, Messenger RNA, Small Interfering Proprotein Convertase 5 FURIN protein, human Furin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Maret Deborah
Brain Tumor Research Centre, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada.
Sadr Mohamad Seyed
Sadr Emad Seyed
Colman David R
Del Maestro Rolando F
Seidah Nabil G
References (81)
81 references, click to expand
  1. Lateral dimerization of the E-cadherin extracellular domain is necessary but not sufficient for adhesive activity.
    J Biol Chem. 2002 May 31;277(22):19600-8 PMID: 11916976
  2. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role.
    Cell. 1991 Jul 12;66(1):107-19 PMID: 2070412
  3. Furin at the cutting edge: from protein traffic to embryogenesis and disease.
    Nat Rev Mol Cell Biol. 2002 Oct;3(10):753-66 PMID: 12360192
  4. Molecular aspects of the loss of cell adhesion and gain of invasiveness in carcinomas.
    Princess Takamatsu Symp. 1994;24:214-32 PMID: 8983077
  5. Correlation of N-cadherin expression in high grade gliomas with tissue invasion.
    J Neurooncol. 2004 Oct;70(1):3-15 PMID: 15527101
  6. Cadherin switching in human prostate cancer progression.
    Cancer Res. 2000 Jul 1;60(13):3650-4 PMID: 10910081
  7. Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin.
    Cancer Res. 2005 May 15;65(10):4162-71 PMID: 15899807
  8. The proprotein convertase PC7: unique zymogen activation and trafficking pathways.
    J Biol Chem. 2011 Jan 28;286(4):2728-38 PMID: 21075846
  9. Proprotein cleavage of E-cadherin by furin in baculovirus over-expression system: potential role of other convertases in mammalian cells.
    FEBS Lett. 1998 Nov 6;438(3):306-10 PMID: 9827567
  10. Two-step adhesive binding by classical cadherins.
    Nat Struct Mol Biol. 2010 Mar;17(3):348-57 PMID: 20190754
  11. A causal role for E-cadherin in the transition from adenoma to carcinoma.
    Nature. 1998 Mar 12;392(6672):190-3 PMID: 9515965
  12. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?
    Nat Rev Cancer. 2007 Jun;7(6):415-28 PMID: 17508028
  13. E-cadherin expression in melanoma cells restores keratinocyte-mediated growth control and down-regulates expression of invasion-related adhesion receptors.
    Am J Pathol. 2000 May;156(5):1515-25 PMID: 10793063
  14. Molecular modification of N-cadherin in response to synaptic activity.
    Neuron. 2000 Jan;25(1):93-107 PMID: 10707975
  15. Guidance of optic nerve fibres by N-cadherin adhesion molecules.
    Nature. 1988 Jul 7;334(6177):62-4 PMID: 3386742
  16. The cadherins: cell-cell adhesion molecules controlling animal morphogenesis.
    Development. 1988 Apr;102(4):639-55 PMID: 3048970
  17. Inactivation of the E-cadherin-mediated cell adhesion system in human cancers.
    Am J Pathol. 1998 Aug;153(2):333-9 PMID: 9708792
  18. Cadherins in cancer: implications for invasion and metastasis.
    Curr Opin Cell Biol. 1993 Oct;5(5):806-11 PMID: 8240824
  19. Transendothelial migration of melanoma cells involves N-cadherin-mediated adhesion and activation of the beta-catenin signaling pathway.
    Mol Biol Cell. 2005 Sep;16(9):4386-97 PMID: 15987741
  20. N-cadherin-catenin complexes form prior to cleavage of the proregion and transport to the plasma membrane.
    J Biol Chem. 2003 May 9;278(19):17269-76 PMID: 12604612
  21. E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells.
    J Cell Biol. 1991 Apr;113(1):173-85 PMID: 2007622
  22. Exogenous expression of N-cadherin in breast cancer cells induces cell migration, invasion, and metastasis.
    J Cell Biol. 2000 Feb 21;148(4):779-90 PMID: 10684258
  23. The proprotein convertase PC5/6 is protective against intestinal tumorigenesis: in vivo mouse model.
    Mol Cancer. 2009 Sep 08;8:73 PMID: 19737405
  24. Regulators of neurite outgrowth: role of cell adhesion molecules.
    Ann N Y Acad Sci. 2004 Apr;1014:140-54 PMID: 15153429
  25. The minimal essential unit for cadherin-mediated intercellular adhesion comprises extracellular domains 1 and 2.
    J Biol Chem. 2004 Dec 31;279(53):55914-23 PMID: 15485826
  26. Biosynthesis of the cell adhesion molecule uvomorulin (E-cadherin) in Madin-Darby canine kidney epithelial cells.
    J Biol Chem. 1991 Oct 15;266(29):19672-80 PMID: 1918074
  27. Dynamics of intercellular communication during melanoma development.
    Mol Med Today. 2000 Apr;6(4):163-9 PMID: 10740255
  28. Regulation of cadherin-mediated adhesion in morphogenesis.
    Nat Rev Mol Cell Biol. 2005 Aug;6(8):622-34 PMID: 16025097
  29. New signals from the invasive front.
    Nature. 2006 May 25;441(7092):444-50 PMID: 16724056
  30. Structure of the neural (N-) cadherin prodomain reveals a cadherin extracellular domain-like fold without adhesive characteristics.
    Structure. 2004 May;12(5):793-805 PMID: 15130472
  31. The biology and therapeutic targeting of the proprotein convertases.
    Nat Rev Drug Discov. 2012 May;11(5):367-83 PMID: 22679642
  32. Expression of N-cadherin adhesion molecules associated with early morphogenetic events in chick development.
    Nature. 1986 Apr 3-9;320(6061):447-9 PMID: 3515198
  33. Optimization of protease-inhibitor interactions by randomizing adventitious contacts.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8205-10 PMID: 12832612
  34. Cadherin switch in tumor progression.
    Ann N Y Acad Sci. 2004 Apr;1014:155-63 PMID: 15153430
  35. N-cadherin-mediated intercellular interactions promote survival and migration of melanoma cells.
    Cancer Res. 2001 May 1;61(9):3819-25 PMID: 11325858
  36. The proteolytic processing of pro-platelet-derived growth factor-A at RRKR(86) by members of the proprotein convertase family is functionally correlated to platelet-derived growth factor-A-induced functions and tumorigenicity.
    Cancer Res. 2003 Apr 1;63(7):1458-63 PMID: 12670890
  37. A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor.
    Cancer Cell. 2002 Oct;2(4):301-14 PMID: 12398894
  38. The cysteine-rich domain of the secreted proprotein convertases PC5A and PACE4 functions as a cell surface anchor and interacts with tissue inhibitors of metalloproteinases.
    Mol Biol Cell. 2005 Nov;16(11):5215-26 PMID: 16135528
  39. Immunohistochemical distribution of the prohormone convertase PC5-A in rat brain.
    Neuroscience. 1999;92(2):641-54 PMID: 10408612
  40. Proprotein convertases [corrected] are responsible for proteolysis and inactivation of endothelial lipase.
    J Biol Chem. 2005 Nov 4;280(44):36551-9 PMID: 16109723
  41. Inhibition of furin-mediated processing results in suppression of astrocytoma cell growth and invasiveness.
    Clin Cancer Res. 2002 Jun;8(6):1740-6 PMID: 12060611
  42. Regulation of homotypic cell-cell adhesion by branched N-glycosylation of N-cadherin extracellular EC2 and EC3 domains.
    J Biol Chem. 2009 Dec 11;284(50):34986-97 PMID: 19846557
  43. N-cadherin promotes adhesion between invasive breast cancer cells and the stroma.
    Cell Adhes Commun. 1997 Mar;4(6):399-411 PMID: 9177902
  44. Proprotein convertase PC7 enhances the activation of the EGF receptor pathway through processing of the EGF precursor.
    J Biol Chem. 2011 Mar 18;286(11):9185-95 PMID: 21209099
  45. Neural crest cells: a model for invasive behavior.
    Int J Biochem Cell Biol. 2004 Feb;36(2):173-7 PMID: 14643882
  46. The regulated cell surface zymogen activation of the proprotein convertase PC5A directs the processing of its secretory substrates.
    J Biol Chem. 2008 Jan 25;283(4):2373-84 PMID: 18039650
  47. Complex cadherin expression in human prostate cancer cells.
    Int J Cancer. 2000 Feb 1;85(3):446-50 PMID: 10652439
  48. N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression.
    J Cell Biol. 1999 Nov 1;147(3):631-44 PMID: 10545506
  49. N-cadherin prodomain processing regulates synaptogenesis.
    J Neurosci. 2012 May 2;32(18):6323-34 PMID: 22553038
  50. C-cadherin ectodomain structure and implications for cell adhesion mechanisms.
    Science. 2002 May 17;296(5571):1308-13 PMID: 11964443
  51. The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene.
    Trends Biochem Sci. 1999 Feb;24(2):73-6 PMID: 10098402
  52. CDH11 expression is associated with survival in patients with osteosarcoma.
    Cancer Genomics Proteomics. 2008 Jan-Feb;5(1):37-42 PMID: 18359978
  53. Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion.
    J Cell Biol. 1996 Dec;135(6 Pt 1):1643-54 PMID: 8978829
  54. Neuronal growth-promoting and inhibitory cues in neuroprotection and neuroregeneration.
    Ann N Y Acad Sci. 2005 Aug;1053:376-85 PMID: 16179543
  55. Molecular Validation of PACE4 as a Target in Prostate Cancer.
    Transl Oncol. 2011 Jun;4(3):157-72 PMID: 21633671
  56. Inhibition of furin by polyarginine-containing peptides: nanomolar inhibition by nona-D-arginine.
    J Biol Chem. 2004 Aug 27;279(35):36788-94 PMID: 15197180
  57. Morphologic correlates in gliomas: where do we stand?
    Monogr Pathol. 1990;(32):16-29 PMID: 2192277
  58. N-cadherin in the spotlight of cell-cell adhesion, differentiation, embryogenesis, invasion and signalling.
    Int J Dev Biol. 2004;48(5-6):463-76 PMID: 15349821
  59. Epithelial-mesenchymal transitions in development and disease.
    Cell. 2009 Nov 25;139(5):871-90 PMID: 19945376
  60. Inhibition of proprotein convertases is associated with loss of growth and tumorigenicity of HT-29 human colon carcinoma cells: importance of insulin-like growth factor-1 (IGF-1) receptor processing in IGF-1-mediated functions.
    J Biol Chem. 2001 Aug 17;276(33):30686-93 PMID: 11402025
  61. Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity.
    J Mol Biol. 2005 Jan 14;345(2):211-27 PMID: 15571716
  62. Proprotein convertase inhibition results in decreased skin cell proliferation, tumorigenesis, and metastasis.
    Neoplasia. 2010 Jul;12(7):516-26 PMID: 20651981
  63. Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides.
    Brain Res. 1999 Nov 27;848(1-2):45-62 PMID: 10701998
  64. Opposing function of the proprotein convertases furin and PACE4 on breast cancer cells' malignant phenotypes: role of tissue inhibitors of metalloproteinase-1.
    Cancer Res. 2007 Oct 1;67(19):9030-4 PMID: 17909005
  65. Inhibition of proprotein convertases enhances cell migration and metastases development of human colon carcinoma cells in a rat model.
    Am J Pathol. 2004 Jun;164(6):1925-33 PMID: 15161629
  66. Proprotein convertases: "master switches" in the regulation of tumor growth and progression.
    Mol Carcinog. 2005 Nov;44(3):151-61 PMID: 16167351
  67. Proprotein convertases in tumor progression and malignancy: novel targets in cancer therapy.
    Am J Pathol. 2002 Jun;160(6):1921-35 PMID: 12057895
  68. A small-molecule furin inhibitor inhibits cancer cell motility and invasiveness.
    Neoplasia. 2008 Apr;10(4):363-70 PMID: 18392131
  69. Correct proteolytic cleavage is required for the cell adhesive function of uvomorulin.
    J Cell Biol. 1990 Oct;111(4):1645-50 PMID: 2211831
  70. Furin is the major processing enzyme of the cardiac-specific growth factor bone morphogenetic protein 10.
    J Biol Chem. 2011 Jul 1;286(26):22785-94 PMID: 21550985
  71. Surface expression of precursor N-cadherin promotes tumor cell invasion.
    Neoplasia. 2010 Dec;12(12):1066-80 PMID: 21170270
  72. Deletion of the gene encoding proprotein convertase 5/6 causes early embryonic lethality in the mouse.
    Mol Cell Biol. 2006 Jan;26(1):354-61 PMID: 16354705
  73. Dominant and recessive genes involved in tumor cell invasion.
    Curr Opin Cell Biol. 1991 Oct;3(5):832-40 PMID: 1931083
  74. The activity and signaling range of mature BMP-4 is regulated by sequential cleavage at two sites within the prodomain of the precursor.
    Genes Dev. 2001 Nov 1;15(21):2797-802 PMID: 11691831
  75. Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells.
    Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10326-31 PMID: 11517338
  76. The crystal structure of the proprotein processing proteinase furin explains its stringent specificity.
    Nat Struct Biol. 2003 Jul;10(7):520-6 PMID: 12794637
  77. Furin overexpression suppresses tumor growth and predicts a better postoperative disease-free survival in hepatocellular carcinoma.
    PLoS One. 2012;7(7):e40738 PMID: 22808247
  78. Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells.
    J Clin Invest. 2008 Jan;118(1):352-63 PMID: 18064302
  79. Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results.
    J Clin Oncol. 1998 Jun;16(6):2202-12 PMID: 9626222
  80. Mechanism and dynamics of cadherin adhesion.
    Annu Rev Biomed Eng. 2006;8:259-87 PMID: 16834557
  81. A systematic study of site-specific GalNAc-type O-glycosylation modulating proprotein convertase processing.
    J Biol Chem. 2011 Nov 18;286(46):40122-32 PMID: 21937429
Article Info
Journal
Neoplasia (New York, N.Y.)
Abbr.
Neoplasia
ISSN
1476-5586
DOI
10.1593/neo.121250
Published
2012-10-00
Pages
880-92
Language
English
Region
United States
NLM ID
100886622
PMCID
PMC3479834
Subset
IM
Grants
Canadian Institutes of Health Research · 44363 · Canada
External Links
PubMed source DOI: 10.1593/neo.121250 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2