Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The ADAMs family of metalloproteases: multidomain proteins with multiple functions Darren F. Seals and Sara A. Courtneidge1 Van Andel Research Institute, Grand Rapids, Michigan 49503, USA The ADAMs family of transmembrane proteins belongs diseases such as arthritis and cancer (Chang and Werb to the zinc protease superfamily. Members of the family 2001). Adamalysins are similar to the matrixins in their have a modular design, characterized by the presence of metalloprotease domains, but contain a unique integrin metalloprotease and integrin receptor-binding activities, receptor-binding disintegrin domain (Fig. 1). It is the and a cytoplasmic domain that in many family members presence of these two domains that give the ADAMs specifies binding sites for various signal transducing pro- their name (a disintegrin and metalloprotease). The do- teins. The ADAMs family has been implicated in the main structure of the ADAMs consists of a prodomain, a control of membrane fusion, cytokine and growth factor metalloprotease domain, a disintegrin domain, a cyste- shedding, and cell migration, as well as processes such as ine-rich domain, an EGF-like domain, a transmembrane muscle development, fertilization, and cell fate determi- domain, and a cytoplasmic tail. The adamalysins sub- nation. Pathologies such as inflammation and cancer family also contains the class III snake venom metallo- also involve ADAMs family members. Excellent reviews proteases and the ADAM-TS family, which although covering various facets of the ADAMs literature-base similar to the ADAMs, can be distinguished structurally have been published over the years and we recommend (Fig. 1). their examination (Black and White 1998; Schlondorff and Blobel 1999; Primakoff and Myles 2000; Evans 2001; Kheradmand and Werb 2002). In this review, we will first Expression, subcellular location, and domain discuss the properties of each of the domains of the activity of the ADAMs family ADAMs. We will then go on to describe the involvement of ADAMs in selected biological processes. Then, we In humans, there are 19 adam genes, as shown in Table 1. In will highlight recent interesting findings suggesting the literature, this family is often also referred to as the MDC roles for ADAMs in human disease. Finally, we look to family, indicating the presence of metalloprotease, disinte- the future and discuss some of the open issues in grin, and cysteine-rich domains. Furthermore, individual ADAMs function and regulation. family members often have two or more names. For clarity, in this review, we will use the ADAM nomenclature for each mammalian family member. However, the alternative ADAMs are members of the zinc protease superfamily names of the individual ADAMs are also provided in Table 1. In total, there have been at least 34 adam genes described in Zinc proteases are subdivided according to the primary a variety of species. Up-to-date registries of all ADAMs fam- structure of their catalytic sites and include gluzincin, ily members in different species can be found at: http://www. metzincin, inuzincin, carboxypeptidase, and DD car- uta.fi/∼loiika/ADAMs/HADAMs.htm, http://www.uta.fi/ boxypeptidase subgroups (Hooper 1994). The metzincin %7Eloiika/ADAMs/MMADAMs.htm, and http://www. subgroup (to which the ADAMs belong) is further di- people.virginia.edu/%7Ejw7g/Table_of_the_ADAMs.html. vided into serralysins, astacins, matrixins, and adamaly- sins (Stocker et al. 1995). The matrixins comprise the matrix metalloproteases, or MMPs. These enzymes are the principle agents responsible for extracellular matrix Expression degradation and remodeling, and play important roles in ADAMs are found in vertebrates, as well as in Cae- development, wound healing, and in the pathology of norhabditis elegans, Drosophila, and Xenopus. They are not present in Escherichia coli, Saccharomyces cerevi- siae, or plants. The fission yeast Schizosaccharomyces 1Corresponding author. pombe has what may be an early progenitor of the E-MAIL [email protected]; FAX (616) 234-5705. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ ADAMs family, although its properties have not been gad.1039703. studied. Expression profiles of the ADAMs can vary con- GENES & DEVELOPMENT 17:7–30 © 2003 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/03 $5.00; www.genesdev.org 7 Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Seals and Courtneidge Figure 1. The topography of the ADAMs and related metalloproteases. Generalized domain structures of the ADAMs, SVMPs, ADAM-TS, and MMP families are shown. Note that ADAM-TS family members have a variable number of thrombospondin-like (TS) motifs. The MMP shown is of the gelatinase class. Other subclasses of MMPs lack hemopexin-like sequences and/or fibronectin type II-like sequences. The subclass of MT-MMPs have transmembrane domains and cytoplasmic tails in addition to the domains shown. siderably. In mammals, many of them (including ADAMs node specific (Roberts et al. 1999). ADAM9 and 2, 7, 18, 20, 21, 29, and 30) are exclusively or predomi- ADAM10 are also alternatively spliced and have both nantly expressed in the testis and/or associated struc- secreted and membrane-associated forms (Yavari et al. tures. Other members (ADAMs 8, 9, 10, 11, 12, 15, 17, 1998; Hotoda et al. 2002). Finally, there is evidence 19, 22, 23, 28, and 33) show a more broad somatic dis- that adam11 and adam33 genes produce alternative tribution. Yet, there are clear differences in the pattern of spliced products (Katagiri et al. 1995; Van Eerdewegh expression of these enzymes (Table 1). ADAMs 9, 12, and et al. 2002). 19 were originally cloned from myoblasts (Yagami-Hiro- To date, there have been few studies reporting the phe- masa et al. 1995), but have been shown subsequently to notypes of mice lacking individual ADAMs family mem- be more broadly expressed. bers. However, ADAM2, ADAM3, ADAM9, ADAM10, Several ADAMs are expressed in multiple splice forms ADAM17, and ADAM23-deficient mice have been de- (Table 1). For example, ADAM22 (Sagane et al. 1998), scribed. Mice lacking either ADAM2 or ADAM3 are vi- ADAM29 and ADAM30 (Cerretti et al. 1999) have two to able and healthy with normal development, although three forms that vary in the lengths of their cytoplasmic male mice are infertile (Cho et al. 1998; Nishimura et al. tails, although no functional differences in these iso- 2001). The molecular basis for the infertility will be dis- forms have been reported. In other cases, alternative cussed later. Despite the ubiquitous, and in certain tis- splicing produces proteins with markedly different activ- sues high expression of ADAM9, null mice develop nor- ity. For example, ADAM12 has two splice forms: One, mally, are viable and fertile, and do not show any major called L, produces a membrane-bound protein, the other, pathologies (Weskamp et al. 2002). This perhaps suggests called S, diverges just upstream of the transmembrane redundancy with other members of the ADAMs family. domain, which results in a shorter form that is secreted Mice harboring a germ-line mutation in the metallopro- fromthe cell (Gilpin et al. 1998). Recent studies indicate tease domain of ADAM17 exhibit perinatal lethality that ADAM12-S has functional IGFBP-3 and IGFBP-5 pro- (Black et al. 1997; Peschon et al. 1998). Those born alive tein cleavage activity (Shi et al. 2000). Because ADAM12 usually die within several hours. The more obvious de- is overexpressed during pregnancy, it is possible that fects in newborns include open eyelids, stunted vibris- ADAM12-S is responsible for increasing the pool of IGF sae, and wavy hair. Histological studies of mutant fe- in the bloodstreamduring pregnancy through IGFBP pro- tuses reveal defects in epithelial maturation and organi- teolysis. Alternative splicing of adam28 yields isoforms zation that impairs the development of the digestive, with different subcellular localization patterns and tis- respiratory, and hormonal systems (Peschon et al. 1998). sue expression. Murine ADAM28 may have three forms, A gene-trapping analysis of murine genes involved in two larger ones predicted to encode membrane-anchored brain-wiring patterns revealed that homozygous deletion proteins and expressed in the epididymis and lung, as of ADAM23 results in tremor and ataxia (Leighton et al. well as a smaller one predicted to encode a secreted pro- 2001). There is a recent report describing the targeted dis- tein with testis-specific expression (Howard et al. 2000). ruption of the adam10 gene (Hartmann et al. 2002). Meanwhile, human ADAM28 has two forms. In this ADAM10--deficient mice die by day 9.5 of embryogenesis case, the secreted formis preferentially expressed in the with pronounced defects in the neural and cardiovascular spleen, whereas the membrane-bound form is lymph systems. ADAM12, ADAM15, and ADAM19 null em- 8 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press ADAMs family metalloproteases Table 1. Human ADAMs Domain function Common Alternative MP Integrin ADAM name(s) Potential functions Expression splicing active binding PxxP 2 fertilin-␤, PH-30␤ sperm/egg binding/fusion testis1 ߛ 7 EAP1 epididymis2 ߛ 8 MS2, CD156 granulocytes/ ߛ(d) ߛ monocytes3 9 meltrin-␥, MDC9 sheddase, cell migration somatic4,5 ߛ(FL,s)5 ߛ(d) ߛߛ 10 Kuz, MADM, SUP-17 sheddase; cell fate somatic6 ߛ(L,S)7 ߛ(d) ߛ determination 11 MDC putative tumor repressor brain8 ߛ9,10 12 meltrin-␣ sheddase, myoblast fusion somatic11,12,13 ߛ(L,S)13 ߛ(d) ߛa ߛ 15 metargidin, MDC15 cell/cell binding somatic14 ߛ(p) ߛߛ 17 TACE sheddase somatic15 ߛ(d) ߛ 18 tMDCIII testis16 19 meltrin-␤, MADDAM sheddase, dendritic cell dev. somatic11,17 ߛ(d) ߛ 20 testis18 ߛ(p) 21 testis18 ߛ(p) 22 MDC2 brain8,19 ߛ(␥,␦,␧)19 ߛ 23 MDC3 cell adhesion/neural dev.