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Identification, Characterization, and Intracellular Processing of ADAM-TS12, a Novel Human Disintegrin with a Complex Structural Organization Involving Multiple Thrombospondin-1 Repeats*

  • Santiago Cal
    Footnotes
    Affiliations
    Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Medicina, Instituto Universitario de Oncologı́a, Universidad de Oviedo, 33006 Oviedo and
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  • José M. Argüelles
    Affiliations
    Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Medicina, Instituto Universitario de Oncologı́a, Universidad de Oviedo, 33006 Oviedo and
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  • Pedro L. Fernández
    Affiliations
    Servicio de Anatomı́a Patológica, Hospital Clı́nico-IDIBAPS, 08036 Barcelona, Spain
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  • Carlos López-Otı́n
    Correspondence
    To whom correspondence should be addressed:
    Affiliations
    Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Medicina, Instituto Universitario de Oncologı́a, Universidad de Oviedo, 33006 Oviedo and
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  • Author Footnotes
    * This work was supported by Comisión Interministerial de Ciencia y Tecnologı́a-Spain Grant SAF97-0258 and Plan Fondos Europeos para el Desarrollo Regional Grant 1FD97-0214. The Instituto Universitario de Oncologı́a is supported by Obra Social Cajastur-Asturias.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) AJ250725.
    § Recipient of a research contract from Ministerio de Educación y Ciencia, Spain.
Open AccessPublished:May 25, 2001DOI:https://doi.org/10.1074/jbc.M100534200
      We have identified and cloned a human fetal lung cDNA encoding a new protein of the ADAM-TS family (adisintegrin and metalloproteinase domain, with thrombospondin type-1 modules) that has been called ADAM-TS12. This protein exhibits a domain organization similar to the remaining family members including a propeptide and metalloproteinase-like, disintegrin-like, and cysteine-rich domains. However, the number and organization of the TS repeats is unique with respect to other human ADAM-TSs. A total of eight TS-1 repeats arranged in three groups are present in this novel ADAM-TS. Analysis of intracellular processing of ADAM-TS12 revealed that it is synthesized as a precursor molecule that is first activated by cleavage of the prodomain in a furin-mediated process and subsequently processed into two fragments of different size: a 120-kDa N-terminal proteolytically active fragment containing the metalloproteinase and disintegrin domains, and a 83-kDa C-terminal fragment containing most of the TS-1 repeats. Somatic cell hybrid and radiation hybrid mapping experiments showed that the human ADAM-TS12 gene maps to 5q35, a location that differs from all ADAM genes mapped to date. Northern blot analysis of RNAs from human adult and fetal tissues demonstrated that ADAM-TS12 transcripts are only detected at significant levels in fetal lung but not in any other analyzed tissues. In addition, ADAM-TS12 transcripts were detected in gastric carcinomas and in tumor cell lines from diverse sources, being induced by transforming growth factor-β in KMST human fibroblasts. These data suggest that ADAM-TS12 may play roles in pulmonary cells during fetal development or in tumor processes through its proteolytic activity or as a molecule potentially involved in regulation of cell adhesion.
      EST
      expressed sequence tag
      bp
      base pair(s)
      PCR
      polymerase chain reaction
      TS
      thrombospondin
      TGF
      transforming growth factor
      RACE
      rapid amplification of cDNA ends
      kb
      kilobase(s)
      HA
      hemagglutinin
      IL
      interleukin
      Cell-cell and cell-extracellular matrix interactions are essential for the development and maintenance of an organism. Likewise, proteolysis of the extracellular matrix is of vital importance for a series of tissue-remodeling processes occurring during both normal and pathological conditions, such as tissue morphogenesis, wound healing, inflammation, or tumor cell invasion and metastasis. These events are mediated by a variety of cell surface adhesion proteins and proteases, with different structural and functional characteristics (). Among them, a group of recently described proteins called ADAMs (adisintegrin andmetalloproteinase domain) have raised considerable interest because of their potential ability to perform both functions, adhesion and proteolysis (
      • Wolfsberg T.G.
      • Primakoff P.
      • Myles D.G.
      • White J.M.
      ,
      • Blobel C.P.
      ). ADAMs were first associated with reproductive processes like spermatogenesis and heterotypic sperm-egg binding and fusion (
      • Wolfsberg T.G.
      • White J.M.
      ). However, over the last few years, the spectrum of functional roles for ADAMs has considerably expanded to processes such as myogenesis (
      • Gilpin B.J.
      • Loeche F.
      • Mattei M.G.
      • Engvall E.
      • Albrechtsen R.
      • Wewer U.M.
      ), osteoblast differentiation (
      • Inoue D.
      • Reid M.
      • Lum L.
      • Krätzschmar J.
      • Weskamp G.
      • Myung Y.M.
      • Baron R.
      • Blobel C.P.
      ), and host defense (
      • Mueller C.G.
      • Rissoan M.C.
      • Salinas B.
      • Ait-Yahia S.
      • Ravel O.
      • Bridon J.M.
      • Briere F.
      • Lebecque S.
      • Liu Y.J.
      ). Furthermore, some ADAM family members, including TACE (tumor necrosis factor-α-converting enzyme), ADAM-12 (meltrin α), and ADAM-23, have been suggested to play important roles in the development and progression of inflammatory and tumor processes (
      • Emi M.
      • Katagiri T.
      • Harada Y.
      • Saito H.
      • Inazawa J.
      • Ito I.
      • Kasumi F.
      • Nakamura Y.
      ,
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      • Lum L.
      • Blobel C.P.
      ,
      • Yavari R.
      • Adida C.
      • Bray-Ward P.
      • Brines M.
      • Xu T.
      ,
      • Cal S.
      • Pérez-Freije J.M.
      • López J.M.
      • Takada Y.
      • López-Otı́n C.
      ,
      • Iba K
      • Albrechtsen R.
      • Gilpin B.J.
      • Loechel F.
      • Wewer U.M.
      ,
      • Wu E.N.
      • Croucher P.I.
      • McKie N.
      ,
      • Black R.A.
      • Rauch C.T.
      • Kozlosky J.J.P.
      • Slack J.L.
      • Wolfson M.F.
      • Castner B.J.
      • Stocking K.L.
      • Reddy P.
      • Srinivasan S.
      • Nelson N.
      • Bolani N.
      • Schooley K.A.
      • Gerhart M.
      • Davis R.
      • Fitzner J.N.
      • Johnson R.S.
      • Paxton R.J.
      • March C.J.
      • Cerretti D.P.
      ,
      • Izumi Y.
      • Hirata M.
      • Hasuwa H.
      • Iwamoto R.
      • Umata T.
      • Miyado K.
      • Tamai Y.
      • Kurisaki T.
      • Sehara-Fujisawa A.
      • Ohno S.
      • Mekada E.
      ).
      The structural and functional complexity of the ADAM family of cellular disintegrins has considerably grown after the finding of a series of new members characterized by the presence of thrombospondin repeats in their amino acid sequence. The first member of this subfamily, ADAM-TS1, was identified as a consequence of its association with the development of cancer cachexia as well as with various inflammatory processes (
      • Kuno K.
      • Kanada N.
      • Nakashima E.
      • Fujiki F.
      • Ichimura F.
      • Matsushima K.
      ). Subsequently, the cloning of the cDNA for procollagen I amino-proteinase, whose deficiency cause Ehlers-Danlos syndrome type VIIC in humans, revealed a significant degree of structural similarities with ADAM-TS1, and it was called ADAM-TS2 (
      • Colige A.
      • Sieron A.L.
      • Li S.W.
      • Schwarze U.
      • Petty E.
      • Wertelecki W.
      • Wilcox W.
      • Krakow D.
      • Cohn D.H.
      • Reardon W.
      • Byers P.H.
      • Lapiere C.M.
      • Prockop D.J.
      • Nusgens B.V.
      ). ADAM-TS4 and ADAM-TS5/TS11, other members of this subfamily of disintegrins containing thrombospondin motifs, have been characterized as aggrecanases responsible for the degradation of cartilage aggrecan in arthritic diseases (
      • Tortorella M.D.
      • Burn T.C.
      • Pratta M.A.
      • Abbaszade I.
      • Hollis J.M.
      • Liu R.
      • Rosenfeld S.A.
      • Copeland R.A.
      • Decicco C.P.
      • Wynn R.
      • Rockwell A.
      • Yang F.
      • Duke J.L.
      • Solomon K.
      • George H.
      • Bruckner R.
      • Nagase H.
      • Itoh Y.
      • Ellis D.M.
      • Ross H.
      • Wiswall B.H.
      • Murphy K.
      • Hillman Jr., M.C.
      • Hollis G.F.
      • Newton R.C.
      • Magolda R.L.
      • Trzaskos R.M.
      • Arner E.C.
      ,
      • Abbaszade I.
      • Liu R.Q.
      • Yang F.
      • Rosenfeld S.A.
      • Ross O.H.
      • Link J.R.
      • Ellis D.M.
      • Tortorella M.D.
      • Pratta M.A.
      • Hollis J.M.
      • Wynn R.
      • Duke J.L.
      • George H.J.
      • Hillman Jr., M.C.
      • Murphy K.
      • Wiswall B.H.
      • Copeland R.A.
      • Decicco C.P.
      • Bruckner R.
      • Nagase H.
      • Itoh Y.
      • Newton R.C.
      • Magolda R.L.
      • Trzaskos J.M.
      • Burn T.C.
      ). ADAM-TS4 has been found to be responsible for brevican cleavage in glioma cells, a proteolytic cleavage that has been proposed to be critical in mediating the invasiveness of these tumors (
      • Matthews R.T.
      • Gary S.C.
      • Zerillo C.
      • Pratta M.
      • Solomon K.
      • Arner E.C.
      • Hockfield S.
      ). On the other hand, ADAM-TS8 (also called METH-2) and ADAM-TS1 have been characterized as proteins with angio-inhibitory activity (
      • Vazquez F.
      • Hastings G.
      • Ortega M.A.
      • Lane T.F.
      • Oikemus S.
      • Lombardo M.
      • Iruela-Arispe M.L.
      ). Finally, other family members identified in human tissues such as ADAM-TS3, ADAM-TS5, ADAM-TS6, ADAM-TS7, and ADAM-TS9 have been only characterized at the structural level, and their putative functional significance is still unclear (
      • Hurskainen T.L.
      • Hirohata S.
      • Seldin M.F.
      • Apte S.S.
      ,
      • Melody E.C.
      • Gregory S.K.
      • Laurie A.T.
      • Antonia B.
      • Karen C.A.
      • Richard A.M.
      ).
      These recent findings have stimulated the search for new ADAMs potentially associated with some of the conditions involving cell-cell interactions or extracellular matrix degradation taking place during both normal or pathological conditions (,
      • Wolfsberg T.G.
      • Primakoff P.
      • Myles D.G.
      • White J.M.
      ,
      • Blobel C.P.
      ). In this work, we have examined the possibility that additional yet uncharacterized ADAMs could be produced by human tissues, with the finding of a novel family member, belonging to the ADAM-TS subfamily that we have called ADAM-TS12. We describe the molecular cloning and complete nucleotide sequence of a cDNA coding for this protein. We also report an analysis of the intracellular processing and enzymatic activity of ADAM-TS12. Finally, we describe the chromosomal location of the ADAM-TS12 gene and analyze its expression and regulation in normal and tumor tissues.

      DISCUSSION

      In this work we describe the finding of ADAM-TS12, a novel member of the ADAM-TS subfamily characterized by its complex pattern of thrombospondin domains and its restricted expression in normal human tissues. The strategy followed to identify ADAM-TS12 was first based on an extensive scanning of the EST data bases, looking for sequences with similarity to previously characterized ADAM family members. A sequence presumably encoding the disintegrin region of a new ADAM was identified, PCR amplified from human fetal lung cDNA, and used to screen a cDNA library from the same source. After screening of this library and further RACE-3′ experiments, a full-length cDNA coding for ADAM-TS12 was finally isolated and cloned. Structural analysis of the identified sequence for ADAM-TS12 shows that it exhibits a series of protein domains characteristic of ADAM-TS proteins, including a prodomain, a catalytic domain, and metalloproteinase-like, disintegrin-like, and cysteine-rich domains, as well as a series of TS repeats. However, the number and organization of these repeats are unique to ADAM-TS12. Thus, it contains a total of eight TS repeats organized in three modules, whereas all remaining human ADAM-TS proteins contain from one to four repeats, organized in one or two modules (Fig. 2 and Refs.16–23). An additional distinctive feature of the structure determined for ADAM-TS derives from the presence of an additional domain called the spacer-2 region, with an absence of overall sequence similarity to proteins present in the data bases. The pattern of ADAM-TS expression in human tissues is also somewhat unusual. Thus, in this work we have provided evidence that expression of this gene is highly restricted in normal human tissues. The observation that ADAM-TS12 is predominantly expressed in fetal lung suggests that it could be involved in extracellular matrix remodeling processes occurring within the fetal lung during development. The restricted expression of ADAM-TS12 in normal tissues also suggests that this gene is highly regulated. A survey of factors that could control ADAM-TS12 expression has shown that TGF-β is able to up-regulate ADAM-TS12 in human fibroblast cells from fetal origin, whereas other factors such as TGF-α, IL-1α, IL-1β, acidic fibroblast growth factor, and epidermal growth factor do not show any apparent up-regulatory effect on the transcription of this gene. The finding that TGF-β, widely assumed to be inhibitory for matrix metalloproteinases expression, is able to induce ADAM-TS12 is not unprecedented because recent studies have shown that this growth factor up-regulates expression of potent metalloproteases associated with tumor progression such as gelatinase A and collagenase-3 (
      • Overall C.M.
      • Wrana J.L.
      • Sodek J.
      ,
      • Urı́a J.A.
      • Jiménez M.G.
      • Balbı́n M.
      • Freije J.M.P.
      • López-Otı́n C.
      ). Nevertheless, recent works have also shown that the activity of ADAM-TS proteins can be regulated at other levels, including activation through the putative Cys switch or through furin cleavage during secretion (
      • Loechel F.
      • Overgaard M.T.
      • Oxvig C.
      • Albrechtsen R.
      • Wewer U.M.
      ,
      • Roghani M.
      • Becherer J.D.
      • Moss M.L.
      • Atherton R.E.
      • Erdjument- Bromage H.
      • Arribas J.
      • Blackburn R.K.
      • Weskamp G.
      • Tempst P.
      • Blobel C.P.
      ). Therefore, in this work we have examined the intracellular processing mechanisms of ADAM-TS12. Studies with cells transfected with the full-length ADAM-TS12 cDNA have led us to conclude that this protein is synthesized as a precursor molecule that is first activated by cleavage of the prodomain in a furin-mediated process and subsequently processed into two fragments of different size. One of these fragments corresponds to the N-terminal region of the molecule and contains the metalloproteinase and disintegrin domains of ADAM-TS12. This fragment is proteolytically active as assessed by its ability to interact with α2-macroglobulin. The second fragment generated during the intracellular processing of ADAM-TS12 corresponds to the C-terminal region of the protein and contains most of the TS-1 repeats. To date, the functional significance of this processing mechanism in the context of putative normal or pathological roles of ADAM-TS12 is unclear. In this regard, we are interested in the recent observation that ADAM-TS1 also undergoes a complex processing mechanism, leading to the formation of two distinct active forms (
      • Rodriguez-Manzaneque J.C.
      • Milchanowski A.B.
      • Dufour E.K.
      • Leduc R.
      • Iruela-Arispe M.L.
      ). Preliminary attempts to identify substrates for the proteolytically active fragment of ADAM-TS12 have not provided positive results. Nevertheless, the peculiarities of ADAM-TS12 in terms of structural organization and tissue distribution may imply the possibility that their substrates may be distinct from those hydrolyzed by other proteases of this family. Similarly, the possibility that the released C-terminal fragment containing a number of TS-1 repeats could regulate angiogenic processes will require further exploration.
      In contrast with its restricted expression in normal human tissues, ADAM-TS12 is widely expressed in gastric carcinomas and in cancer cells of diverse origin. These findings are suggestive of a role for this enzyme in the progression of these tumors as proposed for ADAM-TS4 in the case of human gliomas (
      • Matthews R.T.
      • Gary S.C.
      • Zerillo C.
      • Pratta M.
      • Solomon K.
      • Arner E.C.
      • Hockfield S.
      ). Recent studies have shown that other metalloproteases like MT1-matrix metalloproteinase are overexpressed in gastric carcinomas and that their levels correlate with the grade of vascular invasion (
      • Nomura H.
      • Sato H.
      • Seiki M.
      • Mai M.
      • Okada Y.
      ). Further studies will be required to evaluate the clinical significance of the expression of ADAM-TS12 in gastric carcinomas as well as to extend the preliminary observations indicating that this protease can be also overproduced by other malignant tumors such as colorectal, renal, and pancreatic carcinomas. Finally, we have determined the chromosomal location of the ADAM-TS12 gene in an attempt to explore further associations between this gene and tumor processes. According to our mapping studies, the ADAM-TS12 gene is located at the telomeric region of the long arm of chromosome 5. It is of interest that this region (5q35) has been found to be a recurrent site of translocations in hematological malignancies (
      • Johansson B.
      • Brondum-Nielsen K.
      • Billstrom R.
      • Schiodt I.
      • Mitelman F.
      ,
      • Jaju R.J.
      • Haas O.A.
      • Neat M.
      • Harbott J.
      • Saha V.
      • Boultwood J.
      • Brown J.M.
      • Pirc-Danoewinata H.
      • Krings B.W.
      • Muller U.
      • Morris S.W.
      • Wainscoat J.S.
      • Kearney L.
      ). In addition, a putative tumor suppressor gene involved in the development of hepatocellular carcinomas without liver cirrhosis has been mapped to 5q35-qter (
      • Ding S.F.
      • Habib N.A.
      • Dooley J.
      • Wood C.
      • Bowles L.
      • Delhanty J.D.
      ). Furthermore, it is also remarkable in the context of ADAM-TS12 overexpression in gastric carcinomas that minisatellite probes corresponding to 5q35 have detected loss of heterozygosity or new mutant alleles in gastrointestinal cancers (
      • Nagel S.
      • Borisch B.
      • Thein S.L.
      • Oestreicher M.
      • Nothinger F.
      • Birrer S.
      • Tobler A.
      • Fey M.F.
      ). The localization of ADAM-TS12 in this region will be useful for future studies aimed at exploring the possibility that this gene can be directly involved in any of these 5q35 alterations associated with tumor processes and especially with those of the gastrointestinal tract.
      In summary, our results indicated that ADAM-TS12 is a novel member of the disintegrin family of metalloproteases that contains a complex array of thrombospondin domains. Most of these repeats are released after a series of sequential proteolytic processing events that may be of relevance for the in vivo function of this protein. Further studies, now in progress, will be required to determine whether this intracellular processing of ADAM-TS12 contributes to the regulation of its activity in processes involving tissue remodeling and cell adhesion and migration, as recently demonstrated for other members of this growing family of proteases (
      • Vazquez F.
      • Hastings G.
      • Ortega M.A.
      • Lane T.F.
      • Oikemus S.
      • Lombardo M.
      • Iruela-Arispe M.L.
      ,
      • Rodriguez-Manzaneque J.C.
      • Milchanowski A.B.
      • Dufour E.K.
      • Leduc R.
      • Iruela-Arispe M.L.
      ,
      • Blelloch R.
      • Kimble J.
      ).

      Acknowledgments

      We thank Drs. J. P. Freije and E. Campo for helpful comments and support, Drs. A. Muñoz (Instituto Investigaciones Biomédicas-Madrid, Spain) and M. Namba (Okayama University, Okayama, Japan) for providing cell lines, and C. Garabaya and F. Rodrı́guez for excellent technical assistance.

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