Department of Pediatrics Oregon Health Sciences University Portland, Oregon 97201
To the editor:
The letter by Grotendorst, Lau, and Perbal raises several important issues that relate to: 1) the biological properties of the insulin-like growth factor-binding proteins (IGFBPs) and the 9+ more recently identified proteins termed "IGFBP-related proteins" (IGFBP-rPs); 2) the concept of a protein "superfamily;" and 3) the uses and misuses of nomenclature. Certainly, the proposal of an IGFBP superfamily (1, 2) was not intended to disparage the work of these and other investigators, which has been appropriately acknowledged and referenced, but to attempt to provide some framework for structure/function analysis of this most interesting group of proteins.
A nomenclature for the IGFBPs was developed in the 1980s, when it became apparent that there were more than two proteins found in biological fluids associated with IGF peptides (3, 4). The six IGFBPs share the following characteristics: 1) the ability to bind IGF-I and -II with high affinity; and 2) a cysteine-rich structure with high conservation of the N- and C-terminal domains (5). In recent years, select IGFBPs have also been shown to regulate cell proliferation in an IGF-independent manner, associate with cell membranes and be translocated into the nucleus, and associate with a variety of proteoglycans in extracellular matrix (5, 6). The concept of an IGFBP superfamily was proposed in 1997 (7), with the recognition that four additional proteinsMac25 (8) and the three original CCN proteins (7, 9)share the cysteine-rich N-terminal domain of the IGFBPs, and bound IGF (although with low affinity; shown for Mac25, CTGF, and NOV). The fact that these proteins might have actions totally unrelated to conventional IGF physiology was felt to be consistent with the increasing evidence that some IGFBPs, as well as the conserved N-terminal domains of proteolyzed IGFBPs, might be, themselves, capable of "IGF-independent" actions, and that the conventional view of IGFBPs as simple carrier proteins for IGF ligands needed to be modified in light of an expanded involvement of IGFBPs in cell proliferation, adhesion, migration, and survival (many of the characteristics that Grotendorst et al. ascribe to the CCN proteins).
The current concept of the IGFBP superfamily has already transcended inclusion of CCN proteins, since, in addition to the CCN proteins listed by Grotendorst et al., the superfamily also includes Mac25, L56, and ESM-1, all of which also share the N-terminal domain of the IGFBPs but are otherwise dissimilar to the CCN proteins (2). It is of note that in all six high-affinity IGFBPs and all nine to-date identified IGFBP-rPs, the conserved N-terminal domain is encoded by a single exon. Indeed, all of these proteins are modular proteins, in which the N-terminal domain was almost certainly introduced through exon shuffling. Furthermore, an N-terminal domain-like sequence has been identified in the twisted gastrulation protein (Tsg) from Drosophila. A phylogenetic tree of the N-terminal domain of the IGFBP superfamily demonstrates evolutionary conservation of this motif (2).
The term "superfamily" was introduced by Dayhoff (10) in 1978, with the relatedness of proteins based determined exclusively on the basis of primary protein structures, and set at less than 50% amino acid similarity for superfamilies (and >50% for "families"). The similarities between the N-terminal domains from human IGFBPs and human IGFBP-rPs ranges from 40 to 57%, consistent with the definition of a superfamily. This view of a superfamily can be expanded to include functional relationships, tissue specificity, and hormonal regulation (much of which is shared by the various members of the IGFBP superfamily). It is certainly reasonable to consider the CCN proteins to be a family within the domain of the IGFBP superfamily; the same is true for the family of six high-affinity IGFBPs.
We do agree with Grotendorst et al. that the selection of the terminology "IGFBP" superfamily was arbitrary and certainly reflects our bias as IGF investigators. On the other hand, it is necessary to point out that this nomenclature was selected to specifically underscore the structural relationship among these proteins, the evolutionary conservation of the exon-defined N-terminal domain, and the significant functional relationships among the proteins. Ultimately, nomenclature is always arbitrary. It is not clear, for example, what particular biological insight is obtained from the names "CYR61" or "NOV," and the biological actions of CTGF are certainly not limited to connective tissue cells. Mac25 had already had a half dozen names assigned to it, before its inclusion as a member of the IGFBP superfamily (11). If, on the other hand, such names provide value to research, they should, by all means, be preserved; doing so will not undermine or challenge the structural and functional relationships among the various proteins. In the case of the IGFBP superfamily, the proposal was made in an effort to focus attention on the potential biological significance of the remarkably conserved N-terminal IGFBP motif and to encourage investigators from the IGF field, CCN field, and Mac25, L56, and ESM-1 areas to search for insights from each others work. We are hopeful that this is a goal that we can share with Grotendorst, Lau, and Perbal. Ultimately, it is far more important to explore what the physiological and evolutionary significance may be for preserved modular domains, rather than quibbling over nomenclature.
With great insight into the arbitrariness of nomenclature, Gould (12) wrote: "But classifications are not passive ordering devices in a world objectively divided into obvious categories. Taxonomies are human decisions imposed upon naturetheories about the causes of natures order. The chronicle of historical changes in classification provided our finest insight into conceptual revolutions in human thought. Objective nature does exist, but we can converse with her only through the structure of our taxonomic systems. ... Categories are human impositions upon nature (though natures factuality offers hints and suggestions in return)."
Received January 4, 2000.
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