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AC133 Antigen, CD133, Prominin-1, Prominin-2, Etc.: Prominin Family Gene Products in Need of a Rational Nomenclature

^a Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108;
^b Medical Clinic and Polyclinic I, Technical University Dresden, Dresden, Germany

Key Words. CD133 • Prominin • AC133 antigen • Stem cell marker

Denis Corbeil, Ph.D., Medical Clinic and Polyclinic I, Technical University Dresden, Fetscherstrasse 74, D-01307 Dresden, Germany. Telephone: 49-351-210-1488; Fax: 49-351-210-1489; e-mail: corbeil{at}mpi-cbg.de

The pentaspan membrane glycoprotein prominin was first characterized in 1997 in two independent studies [1, 2]. The interest in this molecule has grown exponentially, since it appears to be an important cell surface marker [3, 4] widely used to identify and isolate stem cells from various sources, including the hematopoietic and central nervous systems [5, 6]. Lately, several sequences related to prominin, including splice variants, have been reported, with sometimes confusing, if not whimsical, designations (Table 1). We therefore wish to contribute to the clarification of this issue by proposing a revised and simplified nomenclature for the members of the growing prominin family, including splice variants.

Prominin was originally identified in mouse neuroepithelial stem cells [1]. Its exact function being unknown, this glycoprotein was named prominin because of its notable subcellular localization in plasma membrane protrusions (from the Latin word prominere, to be prominent). In humans, this protein was originally identified as an antigenic marker expressed on hematopoietic stem and progenitor cells and referred to as AC133 antigen [2, 5]. Although this antigen displayed an identical membrane topology to mouse prominin (Fig. 1) [1, 2], there was uncertainty as to their relationship [7, 8] because of, among other reasons, the low level of amino acid identity and the unfaithful detection in certain tissues of the human gene products by the AC133 antibody (Miltenyi Biotech; Gladbach, Germany; http//www.miltenyibiotech.com), which binds to a glycosylation-dependent epitope [2]. Once it was demonstrated that both mouse prominin and the human AC133 antigen show similar cellular distribution and subcellular localization [9], it was proposed that the AC133 antigen be referred to as "prominin (mouse)-like 1" (PROML1) [9] until the completion of the sequencing of the human genome. It is now clear that the human genome does not contain any open reading frame more closely related to mouse prominin than PROML1. Hence in the meantime, human prominin was also assigned the designation "CD133" [10].

View larger version (27K): [in this window] [in a new window]   Figure 1. Membrane topology of mouse prominin-1. After the cleavage of the signal peptide, prominin-1 is predicted to consist of an extracellular N-terminal domain, five transmembrane segments (1–5) separating two small cytoplasmic loops and two large glycosylated extracellular loops containing more than 250 amino acid residues, and a cytoplasmic C-terminal domain. Potential N-glycosylation sites are indicated by forks.

Recently, a second membrane protein structurally related to prominin and encoded by a distinct gene has been characterized in humans and rodents [4, 11, 12]. In the absence of information regarding its cellular localization, this prominin paralogue had been originally referred to as "prominin-related protein" (prom-rp) based on its structural similarity to the prominin [4] (Table 1). Immunocytochemical studies have shown since that prom-rp does associate with plasma membrane protusions and therefore constitutes a second prominin molecule [11]. Moreover, phylogenetic analyses have clearly established that human and rodent prominins constitute a first orthologous group of genes (prominin-1), while the recently characterized paralogues constitute a second orthologous group (prominin-2) [11]. The exon-intron organization is very similar between prominin-1 and prominin-2, and is identical across species within each orthologous group [11].

AUNIFYING NOMENCLATURE

In view of the above developments in the field, and given the existence of yet other designations for certain prominins (Table 1), we wish to suggest a nomenclature for prominin family gene products, including splice variants, that is simple and consistent.

First, we propose to refer to these molecules according to the orthologous group of genes from which they are produced, i.e., prominin-1 or prominin-2 (Table 1). It is conceivable that additional prominin genes will be found, as defined by the presence of features characteristic of the prominins such as A) five transmembrane domains; B) two large loops (>200 residues), and C) a specific localization in high-curvature membrane subdomains. In this case, these gene products should be referred to as prominin-3, prominin-4, and so on. CD133 is an alternative name for prominin-1, whereas the term AC133 antigen should only be used to refer to the human prominin-1/CD133 form bearing the glycosylation-dependent AC133 epitope [2, 4] (see below). All other names (Table 1) should be abandoned.

Second, the principal name prominin-1 or prominin-2 should be followed, whenever relevant, by a suffix (s) indicating the splice variant, numbered according to the chronology of publication (including database submissions in which the sequence is designated as a distinct splice variant) and irrespective of the species, e.g., prominin-1.s1 (Table 1).

Third, with regard to glycosylation, in the case of human prominin-1 evidence exists that cells in certain states of differentiation [9] and certain tissues such as kidney (Mareike Florek and Denis Corbeil, unpublished observations) express a polypeptide that does not bear the glycosylation-dependent [2] AC133 epitope. In anticipation that this will not only reflect alternative splicing but also differential glycosylation of a given splice variant, we propose to use the suffix (g) followed by a number that defines the glycosylation in the chronology of characterization, e.g., prominin-1.g1 for the forms bearing the AC133 epitope and prominin-1.g2 for those lacking it.

Fourth, whenever the orthologous versus paralogous relationship of a given prominin-related sequence cannot (yet) be established, as is presently the case for the nonmammalian vertebrates and invertebrates [11], for the time being, it should be referred to as prominin-like and numbered chronologically.

REFERENCES

1. Weigmann A, Corbeil D, Hellwig A et al. Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. Proc Natl Acad Sci USA 1997;94:12425–12430.[Abstract/Free Full Text]

2. Miraglia S, Godfrey W, Yin AH et al. A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 1997;90:5013–5021.[Abstract/Free Full Text]

3. Bhatia M. AC133 expression in human stem cells. Leukemia 2001;15:1685–1688.[Medline]

4. Corbeil D, Röper K, Fargeas CA et al. Prominin: a story of cholesterol, plasma membrane protrusions, and human pathology. Traffic 2001;2:82–91.[CrossRef][Medline]

5. Yin AH, Miraglia S, Zanjani ED et al. AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 1997;90:5002–5012.[Abstract/Free Full Text]

6. Uchida N, Buck DW, He D et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 2000;97:14720–14725.[Abstract/Free Full Text]

7. Corbeil D, Röper K, Weigmann A et al. AC133 hematopoietic stem cell antigen: human homologue of mouse kidney prominin or distinct member of a novel protein family? Blood 1998;91:2625–2626.[Free Full Text]

8. Miraglia S, Godfrey W, Buck S. A response to AC133 hematopoietic stem cell antigen: human homologue of mouse kidney prominin or distinct member of a novel protein family? Blood 1998;91:4390–4391.[Free Full Text]

9. Corbeil D, Röper K, Hellwig A et al. The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem 2000;275:5512–5520.[Abstract/Free Full Text]

10. Bühring HJ, Marxer A, Lammers R et al. CD133 cluster report. In: Mason DY, ed. Leukocyte Typing VII. London: Oxford University Press, 2002:622–623.

11. Fargeas CA, Florek M, Huttner WB et al. Characterization of prominin-2, a new member of the prominin family of pentaspan membrane glycoproteins. J Biol Chem 2003;278:8586–8596.[Abstract/Free Full Text]

12. Zhang Q, Haleem R, Cai X et al. Identification and characterization of a novel testosterone-regulated prominin-like gene in the rat ventral prostate. Endocrinology 2002;143:4788–4796.[Abstract/Free Full Text]

13. Yu Y, Flint A, Dvorin EL et al. AC133-2, a novel isoform of human AC133 stem cell antigen. J Biol Chem 2002;277:20711–20716.[Abstract/Free Full Text]

14. Zhu G, Chang Y, Zuo J et al. Fudenine, a C-terminal truncated rat homologue of mouse prominin, is blood glucose-regulated and can up-regulate the expression of GAPDH. Biochem Biophys Res Commun 2001;281:951–956.[CrossRef][Medline]

15. Corbeil D, Fargeas CA, Huttner WB. Rat prominin, like its mouse and human orthologues, is a pentaspan membrane glycoprotein. Biochem Biophys Res Commun 2001;285:939–944.[CrossRef][Medline]

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