Transmembrane proteases in focus: diversity and redundancy? Brigitte Bauvois Unite´ 365 INSERM, Institut Curie, Paris, France
Abstract: Recent advances have led to the identification and characterization of an array of transmembrane proteases that mediate the proteolysis of various substrates (including bioactive peptides, components of the extracellular matrix, and integral proteins) and cell-cell or cell-matrix adhesion. The membrane proteases known to participate in these processes currently include the ectopeptidases, the membrane-type matrix metalloproteases (MT-MMPs), the ADAM (a disintegrin and metalloprotease) family, the meprins, and the secretases, and this list may be expected to grow. The roles that these molecules play within neoplastic and inflammatory sites are being investigated actively. The capacity of these ectoenzymes to transmit intracellular-transduction signals through the plasma membrane has to be considered. An appreciation of their functional redundancy is emerging. J. Leukoc. Biol. 70: 11–17; 2001. Key Words: ADAM 䡠 ectopeptidase 䡠 meprin 䡠 MMP 䡠 proteinase 䡠 secretase
INTRODUCTION Various cell types including leukocytes synthesize proteolytic enzymes. Apart from well-known, secreted proteases, it has become evident that transmembrane proteases also have a prominent role in processing soluble factors (including growth factors, hormones, chemokines, and other bioactive peptides), in degrading the components of the extracellular matrix, and in shedding a large variety of cell-surface proteins. Several families of membrane proteases are distinguishable on the basis of their different chromosomal and/or structural organizations, and/or functions (Table 1). There are the ectopeptidases [1–3], the membrane-type matrix metalloproteinases (MT-MMPs) [4 –7], the ADAM (a disintegrin and metalloprotease) family [8 –10], the meprins [11–13], and the secretases (also termed sheddases or convertases) [14]. To date, secretases were grouped according to their capacity to release proteins specifically from the cell surface [14]. However, recent cloning of the secretase tumor necrosis factor ␣ (TNF-␣) convertase (TACE) led to its identification as an ADAM protein, raising the idea that some secretases may belong to the ADAM family [15, 16]. Future cloning of secretases should settle this question. In this review, we will distinguish secretases from
ADAMs, but the reader should be aware of their possible relation. Analyses of the extracellular regions of these ectoenzymes indicate marked differences (Fig. 1). However, some aspects of these membrane enzymes have inspired a growing conviction that they may exhibit functional redundancy. The structure and enzymatic action of most ectoenzymes have been the subject of recent reviews [1, 2, 6 – 8, 10, 12–14, 17] and are summarized here. We review current information on the functional similarities of different families of membrane proteases in view of their possible overlapping, biological activities.
STRUCTURAL DIVERSITY Table 2 summarizes the characteristics of membrane proteases, for which cDNA clones have been obtained, expressed, and/or characterized in functional terms. Most of these ectoenzymes are distributed widely outside and inside the hematopoietic system [1, 6, 9, 18 –21]. Moreover, one given cell type can express different protease families, such as monocytic-lineage cells, which possess several ADAMs (ADAM-8, -9, -10, and -15) [8]; the TACE secretase [15]; the ectopeptidases aminopeptidase N (APN), carboxypeptidase M, ␥-glutamyl transpeptidase, and angiotensin-converting enzyme [1–3, 22]; and two MT-MMPs (MT1-MMP and MT4-MMP) [20, 21, 23]. The patterns of expression of these proteases have been reviewed previously [2, 6, 8, 13, 14, 24]. They are regulated tightly during fetal/postnatal development, tissue repair, inflammation, and disease [2, 6, 8, 13, 14, 24]. Various growth factors and cytokines can control their expression by inducing or repressing their levels of gene transcription and/or protein synthesis [3, 6, 8, 9, 13, 14]. Finally, soluble isoforms of ectopeptidases, meprins, and ADAMs with undefined functions are found in biological fluids [3, 8, 9, 25, 26].
The ectopeptidases So far, about 20 ectopeptidases have been identified [1–3]. They are anchored in the plasma membrane with the Nterminus (type I) or the C-terminus (type II), facing extracellularly or through the glycosylphosphatidylinositol (GPI) moi-
Correspondence: B. Bauvois, Unite´ 365 INSERM, Institut Curie, Pavillon Pasteur, 26 rue d’Ulm, 75231 Paris cedex 05, France. E-mail:
[email protected] Received November 20, 2000; revised January 25, 2001; accepted January 29, 2001.
Journal of Leukocyte Biology Volume 70, July 2001 11
TABLE 1.
Classification of Membrane Proteases Described in This Review
SERINE
[
ECTOPEPTIDASES (DPPIV. . .) ECTOPEPTIDASES (APN, CPM, ECE. . .) MMPs MMPs MT-MMPs
METALLO
a group containing enzymes for which the mechanism remains undefined, such as ␥-glutamyltranspeptidase [3]. Their recognized role concerns their capacity to modulate bioactive-peptide responses [1–3]. A cysteine-rich domain is present in the ectopeptidase dipeptidylpeptidase IV (DPPIV), which interacts with collagen and fibronectin of the extracellular matrix (ECM; Fig. 1) [2, 3, 27]. To date, no endogenous inhibitors of ectopeptidases have been characterized.
ADAMs
The MT-MMPs
ADAMs ADAM-TSs MEPRINS SECRETASES UNCLASSIFIED
[
ECTOPEPTIDASES (␥-GT. . .)
Proteolytic enzymes are commonly termed proteases, proteinases, or peptidases. The table does not include all families of proteases but only that studied in the field of related membrane enzymes. ADAM, a disintegrin and metallo protease; ADAM-TS, soluble ADAMs with thrombospondin-type 1 motifs; APN, aminopeptidase N; CPM, carboxypeptidase M; DPPIV, dipeptidyl peptidase IV; ECE, endothelin-converting enzyme; MMP, soluble matrix-degrading metalloproteinase; MT-MMP, membrane-type MMP; NEP, neutral endopeptide. Membrane-bound proteases are underlined.
ety. Based on their amino acid sequences, ectopeptidases have been classified according to their catalytic mechanism: the serine peptidases characterized by the catalytic amino acid triad His, Asp, and Ser; the metallodependent peptidases; and
The secreted MMPs are multidomain, zinc-dependent endopeptidases that share a basic structural organization comprising a prometallo domain, a metallo domain, and a hemopexin-like domain [4, 28 –31]. The prometallo domain maintains the metalloprotease domain in an inactive state until it is cleaved off. Their natural inhibitors are ␣-macroglobulins and TIMPs (tissue inhibitors of metalloproteases) [28 –31]. The contribution of MMPs is the destruction of a variety of molecules constituting the ECM, including collagens, fibronectin, laminin, proteoglycans, and others [29, 31]. Over recent years, the MMP family has been expanded to include a new subfamily of membrane-tethered MMPs known as MT-MMPs [5, 6, 18 – 20, 32–34]. MT(1, 2, 3, 5)-MMPs contain a membrane-spanning sequence in the fourth and last pexin-like repeat of the carboxy-terminal domain [4 –7] (Fig. 1), and MT4-MMP and MT6-MMP are anchored into the plasma membrane through
Fig. 1. Diagram of the structures of the different families of membrane proteases. TM, transmembrane domain; cyt-tail, cytoplasmic tail; GPI, glycosylphosphatidylinositol. The protease domain has protease activity. The cys-rich domain, the EGF-like domain, and the disintegrin domain may have adhesion abilities. The cytoplasmic tail may be involved in the transduction of signals.
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TABLE 2.
Protease
Number
Main Features of Different Families of Membrane Proteases
Anchor
Soluble form
Adhesion Catalytic type
Proteolysis
to ECM
to cell
Natural inhibitors
⫹
⫹
TIMP-1,-3
⫹ ? ?
? ? ?
? TIMP-2 ?
?
?
?
ADAMs
29
Type I
Yes
Metallo
ECTOPEPTIDASES MT-MMPs MEPRINS
20 6 3
Type I or II or GPI Type I or GPI Type I
Yes ? Yes ␣ forms ?
Metallo or serine Metallo Metallo
Peptides, ECM membrane proteins Peptides Pro-MMP2, ECM Peptides, ECM
Metallo or serine
Membrane proteins
SECRETASES
⬎15
?
ECM, extracellular matrix; GPI, glycosylphosphatidylinositol; TIMP, tissue inhibitor of metalloproteases. ?, not known.
the GPI moiety [34, 35]. MT1-MMP is implicated in the activation of the latent form of secreted progelatinase A (proMMP-2) [4, 7, 36]. Some MT(1, 2, 3)-MMPs can also be involved in the proteolysis of ECM [6, 10, 17]. New functions for TIMPs are emerging based on the interaction of TIMP-2 with MT1-MMP (in its catalytic domain) and soluble proMMP-2 (in its hemopexin-like domain) [37]. This interaction could lead to the formation of a ternary complex thought to cluster pro-MMP-2 at the cell surface near a TIMP-free, active MT1-MMP, which initiates activation of pro-MMP-2 [36 –38].
The ADAMs Like the MT-MMPs, the ADAMs belong to the metzincin superfamily of Zn-dependent metalloproteinases [8 –10]. They have also been referred to as MDCs (metalloproteinase disintegrin with cysteine-rich domains). The name of disintegrin refers to the disruption of integrin binding, because the disintegrin domain of ADAM-15 containing a RGD (Arg-Gly-Asp) motif was shown initially to inhibit platelet aggregation by competing with the integrin ␣IIb3 [8 –10]. The basic structure of an ADAM protein is well-conserved phylogenically, containing a disintegrin and a metalloprotease domain as well as a prodomain [8 –10] (Fig. 1). A subset of the ADAMs (ADAMs-9, -10, -12, -17) contains the distinctive, zinc-binding consensus HEXXH (His-Glu-XaaXaa-His) sequence in the metalloprotease domain, and they are active enzymes following the cleavage of the prodomain by a furin-type protease [8 –10, 39]. The disintegrin domain contains the RGD motif recognized by integrins or a nonRGD motif [8 –10]. For example, ADAM-15, expressed in a wide variety of cells including human leukocytes, exhibits RGD [8], and ADAM-2 and ADAM-9 contain an electron capture detection (Glu-Cys-Asp) motif [40 – 42]. A limited number of ADAMs, like ADAM-12, possess a cysteine-rich domain involved in cell-cell fusion and/or an epidermal growth factor (EGF)-like domain [43] (Fig. 1). Usually, ADAMs are inhibited by ethylenediaminetetraacetate (EDTA) and o-phenanthroline, which chelate Zn2⫹ ions [8 –10, 17]. Several studies in vitro and in vivo have shown that ADAMs are involved in the proteolysis of integral membrane proteins and ECM as well as in adhesive interactions [8 –10]. Unexpectedly, the endogenous inhibitors of MMPs (TIMP-1 and TIMP-3) can inhibit ADAM-10 and ADAM-17 at least [8, 44].
The meprins The meprins belong to the astacin family of metalloendopeptidases. They are multidomain, oligomeric proteases, composed of ␣ and/or  subunits that are related evolutionarily [11–13]. The two subunits have similar, multidomain structures (Fig. 1), containing a terminal, signal-peptide sequence, a propeptide sequence, and the protease domain [11–13]. The catalytic domain is followed by a cysteine-rich domain and an EGF-like domain [11–13]. It is interesting that the cytosolic domain of the  subunit contains a consensus sequence for phosphorylation by protein kinase C (PKC) [12, 13]. Different amino acid hydroxamates have been found to inhibit meprins, with aromatic hydroxamates being the most effective [13]. Meprins are able to degrade ECM proteins such as collagen and gelatin, hormones, and several biologically active peptides [11, 45].
The secretases The term “secretase” for the membrane proteases that release soluble isoforms of membrane proteins was used first a few years ago by Hooper et al. [14] following their characterization of an integral protease able to shed the cell-surface, angiotensin-converting enzyme (ACE; Fig. 1). Secretases are involved in the shedding of the ectodomain of various membrane proteins with a type I and type II structure at a cleavage site located close to the membrane [14, 17]. Many secretase activities can be inhibited by metal-chelating agents and by certain hydroxamic, acid-based compounds, suggesting that secretases are zinc metalloproteases [14]. Because TIMPs fail to inhibit secretase-mediated events, it has been assumed that secretases are distinct from the MMP family [14]. Recently, the secretase involved in the release of TNF-␣ from the cell surface, i.e., TACE, was isolated and cloned, and it was found to belong to the ADAM family [15].
FUNCTIONAL REDUNDANCY Membrane-protease interaction with functional, blocking antibodies or (synthetic or natural) inhibitors has revealed that these ectoenzymes are involved in proteolysis (peptide processing, cell-surface protein-shedding, extracellular-matrix degradation), adhesion, and signal transduction (Table 2) [3, 7, 10, 12, 14]. Despite their different structural characteristics, memBauvois Cell-suface proteases
13
brane proteases have convergent properties, supporting the contention that there could be functional redundancy amongst them. The following examples illustrate the functional interplays found among membrane protease families (Table 3).
Release of pro-TNF-␣
Although the physiological targets of membrane proteases are still not established, several peptides in vitro are found to be substrates of these ectoenzymes. Ectopeptidases and meprins have the capacity to process similar bioactive peptides implicated in vascular permeability, such as bradykinin, angiotensin, substance P [1, 2, 13, 27], and the growth-stimulating hormone gastrin [1, 2, 27, 46] (Table 3).
The inflammatory cytokine TNF-␣ is produced as a 26-kDa transmembrane protein and released as a 17-kDa, soluble TNF-␣. Initial observations indicated that TNF-␣ was released through the action of a metallosecretase, known as TACE [14, 17]. Other groups have identified ADAM-10 and ADAM-17 as candidates for the release of soluble TNF-␣ [8, 48]. TACE was cloned subsequently and found to be ADAM-17 [15]. More recently, the recombinant form of MT4-MMP has also been shown to shed pro-TNF-␣ when cotransfected in COS-7 cells [21]. Together, these observations underline the fact that a given substrate may be acted on by various membrane proteases.
Shedding membrane proteins
Release of -amyloid precursor protein (APP)
Many integral membrane proteins lead a dual existence as membrane-bound and soluble counterparts in vivo, as indicated by their detection in blood, seminal plasma, urine, milk, cerebrospinal, and amniotic fluids [25]. At least two different mechanisms may generate soluble and membrane-bound isoforms of the same protein: 1) by alternative splicing and 2) by posttranslational release of the extracellular domain of membrane proteins by hydrolytic cleavage of the membrane anchor [25]. Hydrolysis involves cleavage of the glycolipid of GPIanchored proteins by phospholipases or limited proteolysis of membrane proteins at a site adjacent to the membrane-spanning sequence by proteases [25]. Various proteolytic activities, including metallopeptidase and serine-protease activities, have been implicated in this process [14, 17, 25]. Various cell-surface proteins are released, such as interleukin-6 (IL-6) receptors, TNF receptors, Fas ligand, transforming growth factor-␣ (TGF-␣), CD23, and CD30 [14, 25, 47]. Examples of protein shedding involving the interplay of different metalloprotease families are presented below (Table 3).
Cleavage of the transmembrane APP by three different proteolytic enzymes, ␣-, -, and ␥-secretases, gives rise to three peptides, two of them (resulting from the action of - and ␥-secretases) being the major components of amyloid plaques, which are involved in the pathogenesis of Alzheimer’s disease [14, 17, 49]. In contrast, processing APP at the ␣-secretase site precludes cleavage by the - and ␥-secretases and thus formation of the respective peptides [14, 17, 49]. ADAM-10 and ADAM-17/TACE can also function as ␣-secretases (14, 17) [Table 3].
Processing bioactive peptides
TABLE 3.
Cell adhesion to Collagen Other cells Cell signalization
Many cell-surface molecules such as integrins, selectins, members of the immunoglobulin superfamily (CD43/sialoadhesin), and CD44 are implicated in cell-cell and cell-matrix contacts [50 –52]. Adhesion may be altered in different conditions such as inflammation, wound healing, or the host response to infections [53, 54]. Soluble forms of L-selectin, CD43, CD44, and integrin ␣4 have been identified [25]. Initial studies indicated that release of L-selectin from the leukocyte surface was me-
Examples of Functional Redundancy among Membrane Proteases
Ectopeptidases Processing of bioactive peptides Bradykinin Substance P Angiotensin I Angiotensin II Neuropeptide Y Gastrin Shedding of integral proteins Pro-TNF-␣ APP L-selectin ECM degradation Collagen IV
Release of cell-adhesion molecules
ADAMs
NEP, ACE NEP, ACE, DPPIV NEP, ACE NEP DPPIV ACE
Meprins Meprin Meprin Meprin Meprin Meprin Meprin
Secretases
MT-MMPs
A A A A A A
ADAMs-10, -17 ADAM-10, -17 ADAM-17
␣-Secretase L-selectin secretase
MT4-MMP
FAP-␣ APN*
ADAMs-10, -12, -17
Meprin A
MT(1, 2, 3)-MMPs MT1-MMP*
DPPIV, FAP-␣ ? DPPIV DPPIV, APN
ADAMs ? ADAMs-2, -9, -15 ADAMs-8, -9, -15 ?
Meprins ?
MT-MMPs ?
 Subunit ?
ACE, angiotensin-converting enzyme; APN, aminopeptidase N; APP, amyloid precursor protein; DPPIV, dipeptidyl peptidase IV; ECM, extracellular matrix; FAP-␣, fibroblast activation protein; meprin A, endopeptidase-24.18 (␣- and -chain association); TACE, TNF-␣ convertase enzyme. * Indirect effect.
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diated by able from L-selectin L-selectin
a membrane-bound metalloproteinase distinguishknown MMPs and termed L-selectin sheddase or secretase [55]. ADAM-17 could also contribute to shedding from human leukocytes [56].
Release of membrane proteases themselves
Instead of soluble meprins, which are generated by an alternative splicing pathway [26], many ectopeptidases [3, 25] and ADAMs [8] are released from the cell surface by specific, post-translational shedding mechanisms. Whether a given membrane protease can shed itself or is shed by another membrane protease and hence influences cell behavior has to be considered. The ectopeptidase ACE is released by an ACE secretase, which is distinct from ADAM-17/TACE and ␣ secretase [14, 17].
Cell migration Cell migration is essential for development, inflammation, and tissue repair, but it also allows malignant cells to exert their lethal ability to invade tissues and metastasize. Cell migration is linked intrinsically to concomitant cell adhesiveness and localized degradation of the ECM. Examples of the involvement of membrane proteases in cell adhesion and in ECM degradation are described below. Extracellular matrix degradation
Like secreted MMPs and the serine proteinases cathepsin G, elastase, and plasminogen activators [57– 60], membrane proteases may also contribute to ECM degradation by virtue of their localization in membrane structures that contact the ECM. Several ADAMs (-10, -12, -17) and MT-MMPs (-1, -2-, 3), meprin A, and the ectopeptidase fibroblast activation protein ␣ (FAP-␣) are involved directly in the degradation of collagen type IV, which is abundant in inflamed tissues [3, 6, 8, 10, 13] (Table 3). The rat DPPIV, which cleaves peptide bonds normally after penultimate proline, has been suggested to exhibit endopeptidase activity toward denatured collagen [61]. The ectopeptidase APN and the MT1-MMP are implicated indirectly in collagen breakdown by inducing the secretion of type IV epithelial collagenase [62] and the activation of soluble proMMP-2 [5], respectively. Cell adhesion
Consistent with their proteolytic activity toward collagen, it is conceivable that membrane proteases such as ADAMs, meprins, MT-MMPs, and FAP-␣ may use their proteolytic domain to form transient, adhesive bonds with collagen of the ECM (Table 3). Independently of its catalytic domain, the ectopeptidase DPPIV of epithelial-, fibroblast-, and T-cell types binds to fibronectin and collagen in domains distinct from each other [27] (Fig. 1 and Table 3). In a rat-lung, capillary endothelia cell model, DPPIV serves as an adhesion molecule for breast cancer cells via tumor cell-surface-associated fibronectin [63]. As a consequence of their capacities to shed some celladhesion molecules, it is obvious that membrane proteases affect the adhesive properties of cells. Apart from their proteolytic domains, ADAMs function in cell-cell adhesion through their disintegrin domains [8 –10]. ADAMs can interact with integrins on adjacent cells through their RGD sequence as an
integrin ligand, as observed for ADAM-15, which interacts with ␣v3 and ␣51 integrins on hematopoietic cells [8, 40] (Table 3). ADAM-2 and ADAM-9 bind to ␣61 through their disintegrin sequence ECD [8, 41, 42] (Table 3). However, in two recent studies, the integrins ␣v3 and ␣91 have been shown to interact, respectively, with ADAM-23 or ADAM-12 and ADAM-15 through an RGD-independent mechanism [64, 65].
Signal transduction Recent studies suggest that ADAMs, meprins, and ectopeptidases may be involved in signaling. Although no homologies with sequences found at phosphorylation acceptor sites for protein tyrosine kinases or PKC are observed in the intracellular tails of the ectopeptidases DPPIV and APN, there is evidence that ectopeptidase-mediated signal transduction involves tyrosine phosphorylation [3]. Molecular associations between DPPIV and other molecules such as CD45 (a tyrosine phosphatase exclusively expressed in the hematopoietic compartment) or the insulin-like growth-factor II receptor may contribute to cell activation [3, 27]. The  cytoplasmic subunit of meprins contains a consensus sequence for phosphorylation by PKC [12, 13], and the cytoplasmic tail of ADAMs (ADAMs -9, -10, -12, -15, -17, -19) contains SH3 consensus sequences, suggesting a role in signal transduction [8, 9]. However, there are no data available presently on the specific second messengers, which could be involved in the signals transduced by meprins and ADAMs. Recent insights into the nervous system link ADAM and secretase activities indirectly in Notch-mediated signaling [10, 17, 49]. Notch is a transmembrane receptor involved in the regulation of neural potential [49]. To be activated, Notch undergoes proteolytic cleavages, two of which depend, respectively, on ADAM-10 (also termed KUZ) and ␥-secretase activities releasing the cytoplasmic fragment of Notch, which can then translocate to the nucleus and activate target genes [10, 17, 49].
CONCLUDING REMARKS The importance of different groups of transmembrane proteases (including ADAMs, MT-MMPs, ectopeptidases, meprins, and secretases) as critical regulators of cellular processes is already appreciable. The main functions of these ectoenzymes reside in their proteolytic and adhesive capacities, thus influencing cell growth and invasion. In a general way, a functional receptor is assumed to be a transmembrane protein with cell-signaling capacities. Based on our current understanding of their functions by delivering regulatory signals in cells, it is becoming evident that membrane proteases may also act as receptors. The idea that emerges from the studies summarized in this review is that a given membrane protease may have several functions (diversity) and that more than one membrane-protease family may mediate the same function (redundancy). Thus, the existence of different families of membrane proteases with several and overlapping actions may be necessary to compensate an important control system in regulating cellular Bauvois Cell-suface proteases
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responses. During the past years, mice deficient in some membrane proteases have been generated [3, 10, 66 – 68]. These include mice deficient in the ectopeptidases NEP, ACE, DPPIV, ␥-glutamyltranspeptidase (reviewed in [3]), ADAM-2 and -17 [10, 66, 67], and MMP-9 [68]. Although these mice have provided critical insights into in vivo functions, there is a lack of evaluation for determining whether these different ectoenzymes have overlapping functions in vivo. Overexpression and inappropriate regulation of proteolytic activity occur often in diseases. For example, MT1-MMP of human macrophages is over-expressed in atherosclerotic plaques [20]. There are many studies of the dysregulated expression of ectopeptidases in leukocyte malignancies (leukemias, lymphomas, autoimmune diseases, HIV) as well as in solid tumor malignancies [3]. - and ␥-Secretases responsible for the production of APP peptides are involved in amyloid deposition in Alzheimer’s disease [14, 17, 49] and are therefore potential targets for the development of therapeutic inhibitors to treat this disease [14, 17, 49]. Mapping the proteolytic profile of human cancers and other diseases might be valuable as an index of prognosis and as a guide in the design of anti-proteolytic strategies aimed at controlling progression of the disease [69]. With regard to ectopeptidases, ACE inhibitors have proven effective already in the treatment of hypertension, diabetic nephropathy, and posttransplantation erythrocytosis [3]. As monotherapy, NEP inhibitors have beneficial, hemodynamic effects in patients with heart failure [3]. A difficult issue, however, relates to the possible overlapping activities of different proteases effective simultaneously in some pathological situations. Finally, soluble forms of these membrane proteases are found in biological fluids. Although their roles are still poorly understood, it may be expected that the released proteases retain their proteolytic activities and therefore add to the battery of secreted enzymes such as MMPs [70], elastase and cathepsin G [57], the plasminogen activators [58], and the related ADAM-TSs (ADAMs with thrombospondin-type 1 motifs) [71], all proteolytic enzymes involved in ECM degradation. By addressing these issues in future studies, we should gain insight into the relationships between membrane proteases and the roles they play in physiological and pathophysiological processes.
ACKNOWLEDGMENTS This work was supported by grants from the Institut National de la Sante´ et de la Recherche Me´dicale (I.N.S.E.R.M.). The author is grateful to Dr. Ingrid De Meester (University of Antwerp, Belgium), Dr. Jelena Gavrilovic (University of East Anglia, Norwich, UK), and Dr. Jacqueline Jouanneau and Miss Catherine Kern (Institut Curie, Paris, France) for critical review of the manuscript.
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