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The CCN family of proteins: a 25th anniversary picture

Journal of Cell Communication and Signaling volume 10, pages 177–190 (2016)Cite this article

Abstract

The CCN family of proteins is composed of six members, which are now well recognized as major players in fundamental biological processes. The first three CCN proteins discovered were designated CYR61, CTGF, and NOV because of the context in which they were identified. Both CYR61 and CTGF were discovered in normal cells, whereas NOV was identified in tumors. Soon after their discovery, it was established that they shared important and unique structural features and distinct biological properties. Based on these structural considerations, the three proteins were proposed to belong to a family that was designated CCN by P. Bork. Hence the CCN1, CCN2 and CCN3 acronyms. The family grew to six members a few years later with the description of three proteins WISP-1, WISP-2 and WISP-3 (CCN4, CCN5 and CCN6), that shared the same tetramodular and conserved structural features. With the functions of the CCN proteins being uncovered, this raised a nomenclature problem. A scientific committee convened in Saint Malo (France) proposed to apply the CCN nomenclature to the six members of the family. Although the unified nomenclature was proposed in order to avoid serious misconceptions and lack of precision associated with the use of the old acronyms, the acceptance of the new acronyms has taken time. In order to evaluate how the use of disparate nomenclatures have had an impact on the CCN protein field, we conducted a survey of the articles that have been published in this area since the discovery of the first CCN proteins and inception of the field. We report in this manuscript the confusion and serious deleterious scientific consequences that have stemmed from a disorganized usage of several unrelated acronyms. The conclusions that we have reached call for a unification that needs to overcome personal habits and feelings. Instead of allowing the CCN field to fully crystalize and gain the recognition that it deserves the usage of many different acronyms represents a danger that everyone must fight against in order to avoid its deliquescence. We hope that the considerations discussed in the present article will encourage all authors working in the CCN field to work jointly and succeed in building a strong and coherent CCN scientific community that will benefit all of us.

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Notes

  1. According to the Merriam-Webster dictionnary, a family may be « a group of things related by common characteristics, as a closely related series of elements or chemical compounds »

  2. The first International Workshop on the CCN Family of Genes was organized by A. Perbal and B. Perbal (co-organizer L. Lau) and held on 17–19 October 2000. For a review of the communications presented at the workshop see « Report and abstracts on the first international workshop on the CCN family of genes » by Ayer-Lelievre C, Brigstock D, Lau L, Pennica D, Perbal B, Yeger H.(2001) Mol Pathol. Apr;54(2):105–20.

  3. The second International Workshop on the CCN family of Genes held in Saint Malo (Oct 20–23, 2002) was organized by L. Lau and B. Perbal (Administration A. Perbal). For an account of the communications presented a this workshop, see « Report on the second international workshop on the CCN family of genes » by Perbal B, Brigstock DR, Lau LF. (2003) Mol Pathol. Apr;56(2):80–5.

  4. At the time this article is being written up, a PubMed search performed in « all fields » with « nov » pulled out 1,939,669 references, and a search performed on Title/Abstract pulled out 21,064 references ! This is not so surprising as articles containing nov. for « november » and nov for new genus « nov.gen » and new species « nov. spe. » are pulled out with a search using the nov filter.

  5. In spite of the fact that some numbers pulled out with « Title/abstract » were slightly lower than those obtained with the « All fields » it did not significantly alter the overall variations in the publication trends.

  6. Since the use of « nov » and « novH », filters provided sets of articles that were different, we have pulled all of them under a single category designated NOV. The numbers obtained with the « CCN3/nov », and « nov/CCN3 » filters have been pooled with the CCN3 values.

  7. As discussed later in the results section, 6 different WISP acronyms are currently used, and are found in different articles. For the sake of simplicity, we have used in our presentation a provisional WISP (1), (2), (3) denomination that encompasses both categories (with and without hyphen) for each one of the 3 proteins.

  8. The complete rtf listing (361 pages) is available in Supplementary Data ESM1

  9. Since B. Perbal, signed 40 % (67/165) of the total CCN3 publications, and 35 % (18/51) of the nov-related [novH ; ccn 3/nov ; nov/CCN3] publications, it was much easier to consolidate a wide usage of the CCN3 acronym.

  10. Of note, that situation is often encountered in scientific publishing. For example 5 articles used the original FISP-12 acronym, while 5 others used FISP12. On another ground, 1573 articles use IL-33, and 1074 use IL33. This confusion has unexpected consequences. A search with IL-33 does not pull out an article in which CCN3 was reported to physically interact with IL33, therefore suggesting that CCN3 whose expression is regulated by TNFalpha and IL1 cytokines, is a potent player in a variety of inflammatory responses, including neurodegenerative disease, and arthritis. (see Perbal (2006) New insight into CCN3 interactions--nuclear CCN3 : fact or fantasy? Cell Commun Signal. 2006 Aug 8;4:6)

  11. Full references for these articles can be found in Supplementary Data ESM2.

  12. An illustration from the CCN field, is provided by the case of M. Takigawa who switched to the CCN acronym when he realized that the « hcs24 » that he had been using until then would put him aside of the burgeoning CCN field.

  13. « HGNC is responsible for approving unique symbols and names for human loci, including protein coding genes, ncRNA genes and pseudogenes, to allow unambiguous scientific communication » http://www.genenames.org/

  14. See for example the result of a search for CCN5 conducted on the HGNC website (http://www.genenames.org/cgi-bin/search?search_type=all&search=ccn5&submit=Submit) of for CCN2 (http://www.genenames.org/cgi-bin/search?search_type=all&search=ccn5&submit=Submit)

  15. « FibroGen is a research-based biotechnology company using its expertise in connective tissue growth factor (CTGF ) …». A search for CCN2 on the website of the Company leads to a list of reference showing very scarce usage of CCN2)

  16. This type of situation is often encountered in scientific publishing. For example 5 articles used the original FISP-12 acronym, while 5 others used FISP12. On another ground, 1573 articles use IL-33, and 1074 use IL33. This confusion has unexpected consequences. A search with IL-33 does not pull out an article in which CCN3 was reported to physically interact with IL33, therefore suggesting that CCN3 whose expression is regulated by TNFalpha and IL1 cytokines, is a potent player in a variety of inflammatory responses, including neurodegenerative disease, and arthritis. (see Perbal (2006) New insight into CCN3 interactions--nuclear CCN3 : fact or fantasy? Cell Commun Signal. 2006 Aug 8;4:6)

  17. see http://ccnsociety.com

  18. see http://springer.com/12079

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Acknowledgments

We are grateful to Dr. Yeger for critical reading of the manuscript. Thanks are due to Dr.Leask (University of Western Ontario, Ontario, Canada) and Dr. Rheims (Laboratório Especial de Coleções Zoológicas, São Paulo, Brasil) for their help and suggestions.

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Affiliations

  1. International CCN Society, Paris, France

    Annick Perbal

  2. Université Côte d’Azur, CNRS, GREDEG, France and International CCN Society, Paris, France

    Bernard Perbal

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  1. Annick Perbal
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  2. Bernard Perbal
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Correspondence to Bernard Perbal.

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Perbal, A., Perbal, B. The CCN family of proteins: a 25th anniversary picture. J. Cell Commun. Signal. 10, 177–190 (2016). https://doi.org/10.1007/s12079-016-0340-z

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Keywords

  • PubMed
  • CCN proteins
  • CCN nomenclature
  • CTGF
  • CYR61
  • WISP
  • CCN1
  • CCN2
  • CCN3
  • CCN4
  • CCN5
  • CCN6