Biochimica et Biophysica Acta 1550 (2001) 107^116 www.bba-direct.com
Review
Dipeptidyl peptidase IV-like molecules: homologous proteins or homologous activities? Aleksi Síedo *, Radek Mal|¨k Joint Laboratory of Cancer Cell Biology of the First Faculty of Medicine of Charles University and the Institute of Physiology of Academy of Sciences of Czech Republic, Prague, Czech Republic Received 3 May 2001; received in revised form 5 September 2001; accepted 13 September 2001
Abstract Membrane-bound proteases are widely distributed among various cell systems. Their expression in a particular cell type is finely regulated, reflecting the specific functional cell implications and engagement in defined physiological pathways. Protein turnover, ontogeny, inflammation, tissue remodeling, cell migration and tumor invasion are among the many physiological and pathological events in which membrane proteases play a crucial role, both as effector as well as regulatory molecules. The presence of proline residues gives unique structural features to peptide chains, substantially influencing the susceptibility of proximal peptide bond to protease cleavage. Among the rare group of proline-specific proteases, dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) was originally believed to be the only membrane-bound enzyme specific for proline as the penultimate residue at the amino-terminus of the polypeptide chain. However, other molecules, even structurally non-homologous with the DPP-IV but bearing corresponding enzyme activity, have been identified recently. This review summarizes the present knowledge of `DPP-IV activity- and/or structure-homologues' (DASH) and provides some insight into their multifunctional roles. ß 2001 Elsevier Science B.V. All rights reserved. Keywords: Dipeptidyl peptidase; Attractin; Quiescent cell; Proline dipeptidase; Fibroblast activation protein; N-Acetylated K-linked acidic dipeptidase
1. Introduction Membrane-bound proteases exhibit speci¢c expression patterns and characteristics unique for a particular tissue, cell type as well as cell compartment and
Abbreviations: CD, cluster of di¡erentiation; DASH, dipeptidyl peptidase IV activity- and/or structure-homologues; DPP, dipeptidyl peptidase; HIV, human immunode¢ciency virus * Corresponding author. Joint Laboratory of Cancer Cell Biology, First Department of Medical Chemistry and Biochemistry, Katerinska¨ 32, 121 08 Prague 2, Czech Republic. Fax: +420-2-2496-4280. E-mail address:
[email protected] (A. Síedo).
domain, re£ecting and determining functional cell status. Soluble counterparts of some membranebound proteases have been found intracellularly as well as in extracellular £uids, including blood plasma [1^5]. A typical cell membrane protease dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5), described on the basis of its enzymatic activity by Hopsu-Havu and Glenner [6], was for many years believed to be the unique cell membrane protease cleaving X-Pro dipeptides from the N-terminal end of peptides and proteins [7]. Many biologically active peptides contain an evolutionary conserved proline residue as a proteolytic-processing regulatory element and therefore proline-speci¢c proteases could be seen as im-
0167-4838 / 01 / $ ^ see front matter ß 2001 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 7 - 4 8 3 8 ( 0 1 ) 0 0 2 7 8 - 3
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portant `check-points' controls [8]. Thus, proteolytic activation and inactivation of such peptides was originally expected to be the main physiological function of DPP-IV. However, studies over the last three decades suggest a full array of diverse functional properties of DPP-IV in the immune, nerve and endocrine networks, in some cases probably even independent of the own DPP-IV hydrolytic activity [9]. Moreover, the existence of numerous DPP-IV-like enzyme activity-bearing molecules has been noted, both homologous as well as non-homologous with DPP-IV [2,10^ 12]. Finally, several highly homologous DPP-IV but enzymatically inactive proteins have been discovered recently [13,14]. Such molecular complexity could explain in part seeming contradictions of hypothesized DPP-IV functional roles in physiological as well as pathological processes, including cell transformation and cancer progression [15]. This review summarizes basic attributes of `DPPIV activity- and/or structure-homologues' (DASH), de¢ned foremost on the basis of their possible functional relationships. 2. DPP-IV activity- and/or structure-homologues 2.1. Dipeptidyl peptidase IV/CD26 DPP-IV is a highly glycosylated serine protease with broad tissue distribution, acting optimally under weakly basic conditions [16]. Its homodimerization seems to be essential for the enzyme activity [17,18]. DPP-IV is identical to the T-cell activation antigen CD26 [19] and to the adenosine deaminase binding protein [20]. It was shown that DPP-IV, in addition to its typical dipeptidyl aminopeptidase activity, may possess endopeptidase activity as well [21]. Three general mechanisms of DPP-IV action have been postulated [1]: 1. Limited proteolysis, i.e., highly speci¢c processing of biologically active peptides, leading to their functional activation or inactivation [22]. This mechanism has been shown to play a role in immune and endocrine system regulations [8,23], diabetes mellitus pathogenesis [24] and HIV infection [8].
2. Cell^cell, cell^extracellular matrix and cell^virus contacts; DPP-IV was described to be collagenand ¢bronectin-binding protein [25], a co-receptor for HIV-1 [9] and a homing factor for organ-speci¢c metastasizing of breast and prostate tumors [25,26]. 3. Signal transduction; DPP-IV/CD26 is considered as a co-receptor transmitting speci¢c signals through the plasma membrane [27^29].
More than one of the above-mentioned mechanisms probably participate also in the control of such complex processes like cell proliferation [30] and di¡erentiation [31], neoplastic transformation [15] and apoptosis [29]. Finally, a soluble form of DPP-IV, modulating the responsiveness of T-cells to the speci¢c antigens, has been detected in blood plasma [32]. 2.2. Fibroblast activation protein K (seprase) Fibroblast activation protein K is a serine protease bearing probably dual ^ DPP-IV-like and collagenase/gelatinase ^ enzymatic activity, the former one being less certain [33^35]. Only a single active site was found to mediate its enzymatic activity [33,35]. Fibroblast activation protein K homodimerization seems to be a condition of fully expressed enzyme activity [36,37]. Such homodimers are identical with seprase [37]. High molecular mass complexes of ¢broblast activation protein K as well as heterodimers with DPP-IV have been described [35,38,39]. Human ¢broblast activation protein K gene was localized close to DPP-IV on chromosome linkage 2q23, suggesting a common ancestry with DPP-IV probably through gene duplication [40]. Fibroblast activation protein K is expressed in tissue remodeling sites, reactive stromal ¢broblasts of over 90% of human malignant tumors, granulation tissue of healing wounds, and some fetal mesenchymal tissues [12,41], but not in normal adult human tissues [38]. Due to the localization in the invadopodia of malignant cells, seprase was hypothesized to be a possible marker of tumor invasiveness [42^44]. 2.3. Dipeptidyl peptidase IV-L Dipeptidyl peptidase IV-L is a glycosylated, mono-
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meric serine protease with DPP-IV-like enzymatic parameters. In contrast with DPP-IV, DPP IV-L does not bind adenosine deaminase [11]. To date, this enzyme has been studied only in hematopoietic and lymphoid cells, where both DPP IV-L and DPP-IV can be co-expressed and di¡erentially regulated. Dipeptidyl peptidase IV-L was suggested to either compensate the lack of DPP-IV expression or to cleave speci¢cally and/or preferentially some substrates concomitant with DPP-IV [45]. 2.4. Dipeptidyl aminopeptidase-like protein
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2.6. Quiescent cell proline dipeptidase Quiescent cell proline dipeptidase is a glycosylated serine protease with DPP-IV-like substrate preference, yet active over the broad pH range from acidic to neutral conditions [58]. Its gene sequence reveals substantial homology with lysosomal prolyl carboxypeptidase but not with DPP-IV [58]. Quiescent cell proline dipeptidase was originally identi¢ed as a component of the new caspase-independent apoptotic pathway inducible by a speci¢c inhibitor of post-proline-cleaving aminopeptidases in quiescent lymphocytes [3].
Transmembrane dipeptidyl aminopeptidase-like glycoprotein exists as a long form of 97 kDa and a short form of 91 kDa; the latter being identical with the brain-speci¢c dipeptidyl peptidase-like protein [14]. The long and short forms di¡er in having Nterminal cytoplasmic tails of 88 and 32 residues, respectively [13]. Both of them are devoid of any enzymatic activity, due to the mutation in the serine recognition site [13,46]. An additional form, di¡ering in the ¢rst 20 amino acids of the cytoplasmic tail, was identi¢ed in mouse embryonic tissues [47]. Dipeptidyl aminopeptidase-like protein was suggested to play a role in the processes of synaptic plasticity [14] and embryonic development [47].
2.7. Dipeptidyl peptidase II (DPP-II)
2.5. N-Acetylated K-linked acidic dipeptidase
2.8. Attractin (Mahogany protein)
N-Acetylated K-linked acidic dipeptidase was originally described to hydrolyze neuropeptide N-acetylL-aspartyl-L-glutamate, a type II metabotropic glutamate receptor agonist [48]. Up to now, three isoforms (I, II and L) have been characterized [49]. Isoform I is structurally similar to the prostate-speci¢c membrane antigen [50,51] and to the glutamate carboxypeptidase II [52,53]. Although N-acetylated Klinked acidic dipeptidases have no serine residue in the consensus sequence required for the serine protease activity [54] at least some of them possess DPPIV-like enzymatic activity sensitive to the serine protease inhibitors [49,53]. N-Acetylated K-linked acidic dipeptidases are speculated to play a role in the prostatic cancer progression [55^57] and in some neurodegenerative disorders [53].
Due to its enzyme activity, attractin was initially believed to be a larger molecular mass form of DPPIV present in human serum and T lymphocytes [10,60]. Notwithstanding, inhibition pro¢les of attractin and DPP-IV are fundamentally di¡erent [60]. Later studies revealed attractin identity with the mouse mahogany protein; however, sharing no signi¢cant sequence homology with DPP-IV [61]. Attractin is expressed and secreted by activated T cells. From a functional point of view, attractin seems to be a potent enhancer of recall antigen-driven T-cell proliferation [62,63] and participates in the regulations of pleiotropic phenotypic features including body weight, pigmentation, tumor susceptibility and CNS development [64^66]. At least some of attractin physiological functions could be mediated by its speci¢c interaction with an agouti protein [67].
Dipeptidyl peptidase II is serine protease acting preferentially in the acidic pH. Although DPP-II was not completely sequenced yet, its partial N-terminal sequence was found to be homologous with the lysosomal prolyl carboxypeptidase [59]. DPP-II enzymatic properties, lysosomal localization and partial homology with prolyl carboxypeptidase are resembling previously mentioned quiescent cell proline dipeptidase rather than DPP-IV. Dipeptidyl peptidase II is suggested to play a role in intracellular protein turnover. Its physiological function remains still elusive [16].
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Table 1 Characteristics of dipeptidyl peptidase IV structure- and/or activity-homologues (DASH) Molecule name and synonyms
Accession no.
Human gene Protein length Typical degree of Enzyme localization and typical Mr polymerization activity
Nucleotide Protein 2q24.3
Fibroblast activation protein K (FAPK K)
U09278
2q23
Seprase
AAC51668
Dipeptidyl aminopeptidase-like protein (DPPX) DPPX long form (DPPX-L) Dipeptidyl aminopeptidase VI (DPP6)
M96859
Dipeptidyl aminopeptidase-like protein
M96859
Dimer
Active
Gene sequence
/
/
110-120 kDa
7
P42658
760 aa
Monomer
Dimer active
95 kDa
Homodimer (FAPK/ FAPK = seprase) Heterodimer (FAPK/FAPL)
Monomer active (?)
Monomer
Inactive
859 aa
49%
43%
Hypothesized functions
Refs.
Widespread (kidney, liver, small intestine, etc.)
Transmembrane type II Soluble
Cell adhesion
[1,8,15^32]
Tumor progression Signal transduction
[91,92]
Restricted to ¢broblasts : Healing wounds Fetal mesenchymal tissues
Transmembrane type II
Cell growth regulation Tumor progression Pathogenesis of the liver cirrhosis
[12,33^44]
Transmembrane type II
Embryonic development
[13,14]
Signal transduction
[46,47]
Stroma of tumors
27%
27%
Exclusively in the brain
97 kDa
Regulation of the synaptic plasticity 7
Not available
803 aa
Monomer
Inactive
27%
27%
91 kDa
Not available not known
Monomer
Active
Sequence not known
Monomer
Active (?) 9%
82 kDa Attractin
Subcellular localization
Immune system regulations
DPPX short form P42658 (DPPX-S) Brain-speci¢c dipeptidyl peptidase-like protein (BSPL) Dipeptidyl peptidase IV-L L (DPP IV-L L)
766 aa
Amino acids sequence
Tissue distribution
AF034957 20p13
1428 aa
20%
Widespread (brain, kidney, ovary prostate, testis, etc.)
Transmembrane type II
Tested only in lymphoid cell cultures and PMBC
Widespread (brain, testis, etc.)
Embryonic development
[13,14]
Regulation of the synaptic plasticity
[46,47]
Transmembrane
Substitution of DPP-IV
[11,45]
Transmembrane type I
T-cell migration
[4,10]
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Dipeptidyl peptidase IV M74777 (DPP-IV) CD26 P27487 Adenosine deaminasebinding protein (ADA-bp) Fibroblast activating protein L (FAPL) EC 3.4.14.5
Similarity with DPP-IV
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Dipeptidyl peptidase 8 (DPP8) DPP4-related protein
NAALADase like protease (NAALADase L) Ileal I100 protein
100 kDa
AAG29766
100 kDa
746 aa
80 kDa
740 aa
882 aa
11p11.21
11q12
AF221634 15q22
CAB39968
AJ012371
CAB39967
AJ012370
80 kDa
AAD51121
N-acetylated K-linked acidic dipeptidase II (NAALADase II)
740 aa
AF176574 11q14.3^q21
N-acetylated K-linked acidic dipeptidase I (NAALADase I) Glutamate carboxypeptidase II Prostate-speci¢c membrane antigen (PSMA)EC 3.4.17.21
110 kDa
Not available
Not available not known
58 kDa
Dipeptidyl peptidase II (DPP-II) EC 3.4.14.2
AAF12747
AF154502 Not available 492 aa
Quiescent cell proline dipeptidase (QPP)
175 kDa
Monomer
Monomer
Monomer
Monomer
Monomer
Dimer
17%
Active (?) 10%
Active (?) 10%
Active
19%
Gene sequence
21%
18%
21%
19%
Sequence not known
10%
Amino acids sequence
Similarity with DPP-IV
Active (?) 11%
Active
Active
Human gene Protein length Typical degree of Enzyme localization and typical Mr polymerization activity
AAF72881
Nucleotide Protein
Accession no.
Dipeptidyl peptidase large form (DPPT-L) Mahogany protein
Molecule name and synonyms
Table 1 (Continued)
Soluble (lysosomal) Membraneassociated
Secreted
Soluble (lysosomal)
Soluble
Subcellular localization
Widespread (testis, placenta, etc.)
Widespread (small intestine, spleen, testis, etc.)
Testis, ovary, spleen, prostate, heart and placenta
Soluble (cytoplasmic)
Transmembrane type II
Transmembrane type II
Prostate, liver, kidney, Transmembrane small intestine, brain type II and spleen
Widespread
Studied only in Jurkat cell line and peripheral blood mononuclear cells (PBMC)
Tissue distribution
[16,59]
[3,58,97]
[60^68]
Refs.
T-cell activation
Prostate tumor progression
Pathogenesis of neurodegenerative disorders Modi¢cation of neurotransmission
Suppression of tumor progression
Modi¢cation of neurotransmission
Pathogenesis of neurodegenerative disorders
[2]
[48^57]
[48^57]
Suppression of tumor [48^57] progression
Protein degradation in lysosomes
Regulation of apoptosis in PBMC
Protein degradation in lysosomes
Regulation of the body weight,immune system responses, pigmentations, basal metabolism and myelinization
Hypothesized functions
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However the role of attractin hydrolytic activity remains mostly speculative, its involvement in tumor transformation is suggested [68]. 2.9. Dipeptidyl peptidase IV-related protein (DPP 8) Dipeptidyl peptidase 8 is an ubiquitous soluble non-glycosylated serine protease localized in the cytoplasmic (non-lysosomal) compartment and acting preferably at neutral pH [2]. Based on the structural similarity with DPP-IV, DPP 8 was proposed to be involved in the T-cell activation [2]. However, functional studies dealing with DPP 8 have not been published. 2.10. Other DPP-IV-related proteins There are a number of possible DASH candidates, not yet characterized in detail. Iwaki-Egawa et al. [69] described a 60 kDa DPP-IV-like enzymatically active protein in rat kidney. Recently, a new thymusspeci¢c serine protease homologous to proline carboxypeptidase was identi¢ed [70,71]. There is a broad spectrum of DPP-IV-like molecules reported in blood serum: a 450 kDa enzymatically active form in serum of pregnant women [72], a 50 kDa form cross-reacting with attractin antibodies [60] and DPP-IV-like enzymatically active form with slightly di¡erent substrate preferences [73]. Precise characterization of these multiple DPP-IV-like molecular species will be needed to decide whether they represent individual gene products, multiple splice variants or products of di¡erent posttranslational processing. 3. Is the enzyme activity essential to ful¢ll DASH functional roles? DASH were shown to participate on a broad array of physiological and pathological functions (Table 1). Indeed, some of these previous studies, namely those dealing with DPP-IV, were interpreted on the basis of the observed enzymatic activity. In light of the existence of newly identi¢ed molecules with partially overlapping, but not identical enzymatic properties, some of these deserve newer interpretations. Recently identi¢ed molecular heterogeneity could ex-
plain the previously surprising lack of correlation between DPP-IV enzyme activity and CD26 antigen expression [10,74,75]. There are still contradictory results regarding the purpose of the DASH hydrolytic activity in the reaction where the substrate cleavage is not evident, as in signal transduction, cell adhesion, apoptosis and intercellular communication. Signaling mediated by the cell surface CD26 seems to depend, at least to some extent, on the intrinsic DPP-IV hydrolytic activity. Jurkat cells transfected by enzymatically inactive CD26 construct respond much more weakly to CD26 co-stimulation than the same cells transfected with the wild-type enzyme [76]. Soluble blood plasma CD26 was shown to modulate the responsiveness of T-cells to the speci¢c antigens. To exert this e¡ect fully, DPP-IV enzyme activity was required [32]. Moreover, T-cell activation was modulated by the N-terminal part of thromboxane A2 receptor, recently described DPP-IV/CD26 inhibitor expressed on macrophages [77]. These observations strongly suggest that tight endogenous regulation of DPPIV/CD26 hydrolytic activity is an important aspect of cell^cell interactions. The most common approach to examine the physiological function of the enzyme is to use its speci¢c inhibitor. DPP-IV speci¢c inhibitors hinder DNA synthesis in keratinocytes [27] as well as in lymphocytes and lymphoid cells and block the cell cycle progression of T and NK cells, probably due to the transforming growth factor-L1 synthesis upregulation [78]. However, it should be kept on mind that some enzyme inhibitors could have additional e¡ects unrelated to the target protease activity. It is noteworthy that CD26 negative wild Jurkat cells are susceptible to the speci¢c DPP-IV inhibitors as are their CD26 transfected counterparts [9]. Similarly, DPP-IV inhibitors suppress experimental arthritis in rats, though similar e¡ect was achieved even in DPP-IV de¢cient animals [79]. Unfortunately, most inhibitors previously believed to be DPP-IV-speci¢c, were shown to inhibit enzymatic activity of DPP-IV-like activity bearing molecules [3,10,11]. Thus, some results of the functional studies could likely be misleading. Moreover, it is worthy to mention that some of the enzyme inhibitors primarily believed to be speci¢c for DPP-IV-unrelated proteases can e¤ciently inhibit some DASH enzymes as well. For example, di¡erent molecular
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Fig. 1. Structural relationships among human DPP-IV activity- and/or structure-homologues. DPP, dipeptidyl peptidase; FAPalpha, ¢broblast activation protein K; NAALADase, N-acetylated K-linked acidic dipeptidase; QPP, quiescent cell proline dipeptidase; PCP, prolyl carboxypeptidase; TSSP, thymus-speci¢c serine protease. The dendrogram was constructed using default parameters in the DNAStar program. The units at the bottom of the tree indicate the number of substitution events.
species of aminopeptidase N/CD13 were shown to play an important role in lymphoid tumor progression [80]. Bestatin, the broadly used speci¢c aminopeptidase inhibitor, acts as a potent inhibitor of cell proliferation and inducer of di¡erentiation or apoptosis in numerous cell lines [81,82] and thus it was suggested to be a promising anti-cancer compound and immunomodulator [83,84]. Surprisingly, the main aminopeptidase activity in some of the bestatin-sensitive but predominantly CD13-negative lymphoid cells was shown to be aminopeptidase N-unrelated [85]. These observations led to the hypothesis that bestatin can act via interaction with other than the aminopeptidase N/CD13 molecule [86]. Recently, bestatin was found to be a potent inhibitor of the attractin enzyme activity [60]. Together, it is possible that the bestatin antiproliferative action could be, at least in part, mediated by inhibition of attractin, which is, in contrast with DPP-IV, bestatin sensitive. Although the DPP-IV inhibitors have been shown to modulate numerous cell functions, existence of DPP-IV structurally homologous, but enzymatically inactive molecules clearly indicates that the hydrolytic activity is not a critical prerequisite for all DASH biological functions. Furthermore, even enzymatically active members of this group probably execute some of their functions independently on their proteolytic activity [87,88]. 4. More molecules ^ more functions? Although a number of DPP-IV activity- and/or structure-homologues have been identi¢ed and char-
acterized (Fig. 1 and Table 1), functional roles of individual molecules are still mostly speculative. Their broad range of tissue-speci¢c distribution, subcellular localization and substrate preferences argue for speci¢c physiological regulation and function of each particular molecule. On the other hand, co-expression of DPP-IV and DPP IV-L [11], DPP-IV and attractin [60], DPP-IV and -II [89] DPP-IV and ¢broblast activation protein K [39,90] are evident and their co-action and/or functional substitution should be considered. Such phenomenon could be the reason why Japan Fischer 344 rats are displaying only digestive system pathologies, despite being devoid of DPP-IV expression in all organ systems [91]. Moreover, the existence of possible DASH `crosstalk' is indirectly supported by the up-regulation of endogenous ¢broblast activation protein K by recombinant expression of DPP-IV in melanoma cells [90]. Interestingly, DPP-IV [21], seprase [33] and all N-acetylated K-linked acidic dipeptidase isoforms [53] bear dual enzymatic activity. This could contribute to the further divergence of their functional potential. Aberrant DASH expression and/or resulting shift of the overall DPP-IV-like enzyme activity could have a pathophysiological impact. Signi¢cant di¡erences of the `total' DPP-IV enzyme activity were observed in a number of tumors, compared to the corresponding normal tissue. The ratio of tumor to normal tissue DPP-IV-like enzyme activity is tumor type speci¢c [15]. The tissue-speci¢c DASH expression pattern could be an explanation. Besides that, individual DASH function probably depends also on the soluble proteolytic context. For example, the physiological e¡ect of attractin was supposed to be
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a¡ected by the balance of its membrane-bound and soluble forms [60]. Indeed, it is possible that the circulating DPP-IV activity, either as attractin or another DPP-IV-like enzyme, could perform and/or modify this interaction. 5. Concluding remarks and further perspectives DPP-IV activity- and/or structure-homologues comprise a growing group of molecules. Predominantly functional de¢nition of such `DASH family' is actually not strictly consistent with the enzyme nomenclature system (http://www.bi.bbsrc.ac.uk) [92] and still lacks complete coherence. As was already being hinted at in previous studies [93], molecular heterogeneity of DPP-IV-like enzymes could cause methodological artifacts arguing to re-consider with caution some former interpretations. Even though valuable attempts have been made, there is still a lack of commercially available speci¢c substrates and inhibitors of individual DPPIV-like enzyme activity-bearing molecules. Availability of these reagents would assist in understanding the separate role of particular DASH group members in the etiopathology of diseases. Speci¢c inhibitors are believed to be of signi¢cant therapeutic impact in the treatment of HIV infection, diabetes mellitus and as an immunosuppressant in the transplantation surgery and autoimmune diseases, including multiple sclerosis [94,95]. Considering its role in energy metabolism, attractin is a possible pharmacological target for body weight regulation. The knowledge of exact enzymatic parameters and localization of each individual DPP-IV-like enzyme could be the clue to the synthesis of speci¢cally targeted proteolytically activated pro-drugs [96]. A growing body of evidence suggests that the contextual repertoire of DASH, with partially overlapping, but not identical functional parameters, seems to be an important dynamically titrated feature of the cell phenotype. Eventually, from a functional point of view, an individual DASH molecule itself does not need to be highly speci¢c; the speci¢city could be provided by cells and substrates in the immediate environment [3,11,22,43,60]. Most of the molecules belonging to this group ful¢ll multiple functions relying probably on their own molecular
parameters as well as on the site and the context of their expression.1 Acknowledgements This work was supported by the Grant Agency of Charles University No. 58/1999/C and First Medical Faculty of Charles University Research Project No. 206019-2 ^ `Oncology'. We thank Dr. Piotr Zawadzki for help with dendrogram presentation and Dr. John E. Oblong for critical reading of the manuscript. References [1] A. Síedo, V. Mandys, E. Krepela, Physiol. Res. 45 (1996) 169^176. [2] C.A. Abbott, D.M. Yu, E. Woollatt, G.R. Sutherland, G.W. McCaughan, M.D. Gorrell, Eur. J. Biochem. 267 (2000) 6140^6150. [3] M. Chiravuri, T. Schmitz, K. Yardley, R. Underwood, Y. Dayal, B.T. Huber, J. Immunol. 163 (1999) 3092^3099. [4] W. Tang, T.M. Gunn, D.F. McLaughlin, G.S. Barsh, S.F. Schlossman, J.S. Duke-Cohan, Proc. Natl. Acad. Sci. USA 97 (2000) 6025^6030. [5] L.A. Goldstein, W.T. Chen, J. Biol. Chem. 275 (2000) 2554^ 2559. [6] V.K. Hopsu-Havu, G.G. Glenner, Histochemie 7 (1966) 197^201. [7] I. De Meester, S. Korom, J. Van Damme, S. Scharpe¨, Immunol. Today 20 (1999) 367^375. [8] G. Vanhoof, F. Goossens, I. De Meester, D. Hendriks, S. Scharpe¨, FASEB J. 9 (1995) 736^744. [9] B. Fleischer, Immunol. Today 15 (1994) 180^184. [10] J.S. Duke-Cohan, C. Morimoto, J.A. Rocker, S.F. Schlossman, J. Biol. Chem. 270 (1995) 14107^14114. [11] E. Jacotot, C. Callebaut, J. Blanco, B. Krust, K. Neubert, A. Barth, A.G. Hovanessian, Eur. J. Biochem. 239 (1996) 248^ 258. [12] P. Garin-Chesa, L.J. Old, W.J. Rettig, Proc. Natl. Acad. Sci. USA 87 (1990) 7235^7239. [13] K. Wada, N. Yokotani, C. Hunter, K. Doi, R.J. Wenthold, S. Shimasaki, Proc. Natl. Acad. Sci. USA 89 (1992) 197^ 201. [14] L. De Lecea, E. Soriano, J.R. Criado, S.C. Ste¡ensen, S.J.
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