Discovery and Characterization of a Novel, Widely Expressed Metalloprotease, ADAMTS10, and Its Proteolytic Activation

Abstract

We describe the discovery and characterization of ADAMTS10, a novel metalloprotease encoded by a locus on human chromosome 19 and mouse chromosome 17. ADAMTS10 has the typical modular organization of the ADAMTS family, with five thrombospondin type 1 repeats and a cysteine-rich PLAC (protease and lacunin) domain at the carboxyl terminus. Its domain organization and primary structure is similar to a novel long form of ADAMTS6. In contrast to many ADAMTS proteases, ADAMTS10 is widely expressed in adult tissues and throughout mouse embryo development. In situ hybridization analysis showed widespread expression of Adamts10 in the mouse embryo until 12.5 days of gestation, after which it is then expressed in a more restricted fashion, with especially strong expression in developing lung, bone, and craniofacial region. Mesenchymal, not epithelial, expression in the developing lung, kidney, gonad, salivary gland, and gastrointestinal tract is a consistent feature of Adamts10 regulation. N-terminal sequencing and treatment with decanoyl-Arg-Val-Lys-Arg-chloromethylketone indicate that the ADAMTS10 zymogen is processed by a subtilisin-like proprotein convertase at two sites (Arg64↓Gly and Arg233↓Ser). The widespread expression of ADAMTS10 suggests that furin, a ubiquitously expressed proprotein convertase, is the likely processing enzyme. ADAMTS10 expressed in HEK293F and COS-1 cells is N-glycosylated and is secreted into the medium, as well as sequestered at the cell surface and extracellular matrix, as demonstrated by cell surface biotinylation and immunolocalization in nonpermeabilized cells. ADAMTS10 is a functional metalloprotease as demonstrated by cleavage of α2-macroglobulin, although physiological substrates are presently unknown. We describe the discovery and characterization of ADAMTS10, a novel metalloprotease encoded by a locus on human chromosome 19 and mouse chromosome 17. ADAMTS10 has the typical modular organization of the ADAMTS family, with five thrombospondin type 1 repeats and a cysteine-rich PLAC (protease and lacunin) domain at the carboxyl terminus. Its domain organization and primary structure is similar to a novel long form of ADAMTS6. In contrast to many ADAMTS proteases, ADAMTS10 is widely expressed in adult tissues and throughout mouse embryo development. In situ hybridization analysis showed widespread expression of Adamts10 in the mouse embryo until 12.5 days of gestation, after which it is then expressed in a more restricted fashion, with especially strong expression in developing lung, bone, and craniofacial region. Mesenchymal, not epithelial, expression in the developing lung, kidney, gonad, salivary gland, and gastrointestinal tract is a consistent feature of Adamts10 regulation. N-terminal sequencing and treatment with decanoyl-Arg-Val-Lys-Arg-chloromethylketone indicate that the ADAMTS10 zymogen is processed by a subtilisin-like proprotein convertase at two sites (Arg64↓Gly and Arg233↓Ser). The widespread expression of ADAMTS10 suggests that furin, a ubiquitously expressed proprotein convertase, is the likely processing enzyme. ADAMTS10 expressed in HEK293F and COS-1 cells is N-glycosylated and is secreted into the medium, as well as sequestered at the cell surface and extracellular matrix, as demonstrated by cell surface biotinylation and immunolocalization in nonpermeabilized cells. ADAMTS10 is a functional metalloprotease as demonstrated by cleavage of α2-macroglobulin, although physiological substrates are presently unknown. Proteolytic processing of structural components of the extracellular matrix (ECM) 1The abbreviations used are: ECM, extracellular matrix; α2-M, α2-macroglobulin; ORF, open reading frame; IMAGE, Integrated Mapping of Genomes and their Expression; BLAST, Basic Local Alignment Search Tool; aa, amino acid(s); TSR, thrombospondin type 1 repeat; EST, expressed sequence tag; dec, decanoyl; cmk, chloromethylketone; PNGase F, peptide:N-glycanase F. and cell signaling-related molecules such as cytokines, growth factors, their binding proteins, receptors, and adhesion molecules has important biological consequences (1Somerville R.P. Oblander S.A. Apte S.S. Genome Biol. 2003; 4: 216Crossref PubMed Scopus (248) Google Scholar, 2Sternlicht M.D. Werb Z. Annu. Rev. Cell Dev. Biol. 2001; 17: 463-516Crossref PubMed Scopus (3256) Google Scholar). Proteases that cleave such molecules thus play important roles in tissue remodeling, morphogenesis, inflammatory and degenerative diseases, and cancer. Zinc-metalloendopeptidases (metalloproteases) comprise an important superfamily of such enzymes. Specific roles for distinct metalloprotease families and their individual members have emerged over the past decade through genetic studies in humans and mice. Matrix metalloproteases are the major ECM-degrading enzymes, but they also have a role in proteolysis of other secreted molecules and cell surface proteins (1Somerville R.P. Oblander S.A. Apte S.S. Genome Biol. 2003; 4: 216Crossref PubMed Scopus (248) Google Scholar, 2Sternlicht M.D. Werb Z. Annu. Rev. Cell Dev. Biol. 2001; 17: 463-516Crossref PubMed Scopus (3256) Google Scholar). ADAMs are primarily “sheddases,” proteases that process cell surface molecules and are thought to have little, if any, direct role in ECM catabolism (3Kheradmand F. Werb Z. BioEssays. 2002; 24: 8-12Crossref PubMed Scopus (111) Google Scholar, 4Blobel C.P. Cell. 1997; 90: 589-592Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar). The ADAMTS (adisintegrin-like and metalloprotease domain with thrombospondin type 1 motifs) family was unknown until 1997 (5Kuno K. Kanada N. Nakashima E. Fujiki F. Ichimura F. Matsushima K. J. Biol. Chem. 1997; 272: 556-562Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar), but functions for some of these enzymes are beginning to emerge (5Kuno K. Kanada N. Nakashima E. Fujiki F. Ichimura F. Matsushima K. J. Biol. Chem. 1997; 272: 556-562Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar, 6Colige A. Li S.W. Sieron A.L. Nusgens B.V. Prockop D.J. Lapiere C.M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2374-2379Crossref PubMed Scopus (158) Google Scholar, 7Fernandes R.J. Hirohata S. Engle J.M. Colige A. Cohn D.H. Eyre D.R. Apte S.S. J. Biol. Chem. 2001; 276: 31502-31509Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, 8Iruela-Arispe M.L. Carpizo D. Luque A. Ann. N. Y. Acad. 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A. 1997; 94: 2374-2379Crossref PubMed Scopus (158) Google Scholar, 7Fernandes R.J. Hirohata S. Engle J.M. Colige A. Cohn D.H. Eyre D.R. Apte S.S. J. Biol. Chem. 2001; 276: 31502-31509Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, 9Levy D.R. D. 2001; PubMed Scopus Google Scholar, A. Sieron A.L. Li S.W. U. E. D. Cohn D.H. Lapiere C.M. Prockop D.J. Nusgens B.V. J. Full Text Full Text PDF PubMed Scopus Google Scholar, S. M.L. K. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). two processing to and the enzymes for have distinct sequence and structural not by the other ADAMTS proteases D. K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. Li S.W. Prockop D.J. Lapiere C.M. Nusgens B.V. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). the other a of ADAMTS with domain and sequence as and are to process such as and M.D. J.M. S.A. C.P. A. F. K. Y. K. PubMed Scopus Google Scholar, F. S.A. M.D. J.M. K. C.P. Y. J.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Luque A. M.L. 2002; PubMed Scopus Google Scholar). is not a of ADAMTS proteases, have that process at sites by the other ADAMTS R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ADAMTS proteases are of a domain and an domain S.S. J. Cell Biol. PubMed Scopus Google Scholar). The domain of these enzymes, that of but not is of the The of the ADAMTS proteases is the of at thrombospondin type 1 are in a and are the carboxyl in members of the ADAMTS family with the of S.S. J. Cell Biol. PubMed Scopus Google Scholar). ADAMTS proteases are as that are to the and by proprotein processing to of a in the at the cell 19 ADAMTS proteases are and ADAMTS10, the of have in the the ADAMTS family, of proteases have domain primary sequence and of a and functional R.J. Hirohata S. Engle J.M. Colige A. Cohn D.H. Eyre D.R. Apte S.S. J. Biol. Chem. 2001; 276: 31502-31509Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S.S. J. Cell Biol. PubMed Scopus Google Scholar). In of the primary structure of ADAMTS10 to of a long form of domain organization and primary structure the that it a with other ADAMTS proteases, Hirohata S. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), ADAMTS10 is widely We the of the Adamts10 in and the and of the in cells. ADAMTS10 is to a functional although physiological substrates are presently unknown. of and ADAMTS10 the Local Alignment Search at the for the of expressed sequence the of a of ADAMTS proteases, and in a human the human The was and the was in on the at the of used with human as a to of by at and as Hirohata S. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Hirohata S. Apte S.S. PubMed Scopus Google Scholar). sequencing was at the of of the and sequence of the the and primary sequence of human that the human a the human sequence and the of the ADAMTS10 in in was human human cell as and the for 1 and then of for for and for The was into and The mouse was in as a Adamts10 has in with the ADAMTS10 and Adamts10 are human and mouse The of are as is used for other ADAMTS and their and was in mouse sequence was mouse with and the at the of on the at to the in these The mouse ADAMTS10 was by of mouse embryo in similar to that for the human embryo and tissue adult human and mouse tissues and human cell and to the of human and mouse ADAMTS10 as the by for In was with and to of the The the was with of and to an Adamts10 of the cysteine-rich and two was used to and with of mouse of and days to the Adamts10 as R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar), by in for Adamts10 was with cell with which ADAMTS10 of human ADAMTS10 was by the and is and The and to the The of a was then into the and of for expression of with a and The ADAMTS10 was in with a and and of Cell cells at in with of ADAMTS10 expression as the it was with 1 and with was used to the of expression in the of these and of ADAMTS10 and cells ADAMTS10 and in in with the was with by at in the of for was to and with to a of was by with 1 of binding The and at in a in binding binding the was by at and then five with of binding proteins by with binding and The and for the and of proteins by and by with was on in of major of and after to a N-terminal sequence was by at the of of the of the cells with of the decanoyl-Arg-Val-Lys-Arg-chloromethylketone for and secreted was by analysis of as R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was with PNGase and by with as R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of ADAMTS10 was HEK293F cells cells was with was as R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of was by with as R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the and cells was as R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of cells with of and the of a by the M.D. J. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google was by of the as R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). ADAMTS10 in studies the of ADAMTS10 in in to the cells COS-1 cells with 1 of ADAMTS10 to of secreted in nonpermeabilized as S. D.R. Apte S.S. J. Biol. Chem. 2002; Full Text Full Text PDF Scopus Google Scholar). ADAMTS10 was and in an that not for ADAMTS10, cells and with as S. D.R. Apte S.S. J. Biol. Chem. 2002; Full Text Full Text PDF Scopus Google Scholar), by cell and extracellular matrix these and HEK293F cells as and to with S. D.R. Apte S.S. J. Biol. Chem. 2002; Full Text Full Text PDF Scopus Google Scholar). HEK293F cells ADAMTS10 in as R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of proteins the cell surface and their analysis by was as R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a cells with to cell surface proteins to as R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of and ADAMTS10 the to for novel that to ADAMTS proteins, the was the was with the sequence of but not with other ADAMTS of the by of in an of human and the cell The encoded an open reading of amino with the typical ADAMTS modular structure and was as of mouse an the cysteine-rich domain through to the of mouse chromosome sequence in was used to the likely amino of that then by of the mouse embryo and The human and mouse and amino have an of and although mouse ADAMTS10 is amino The of human ADAMTS10 is the in the and is an sequence is not a at to of is a at an J. Cell Biol. PubMed Scopus Google Scholar). The mouse ADAMTS10 is also a of the of ADAMTS10 sequence in mouse and human ADAMTS10 are and the that to human ADAMTS10, mouse ADAMTS10 it the of ADAMTS10 are similar to of other and of is in and of with of the other ADAMTS proteases Hirohata S. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The is by a a of that ADAMTS10 is a secreted to for a of proteins J. Biol. PubMed Scopus Google Scholar), it that cleavage and the secreted zymogen has the The to by with other ADAMTS proteases is in the ADAMTS family in sequence in with the convertase sequence K. J. 1997; PubMed Scopus Google Scholar, S. A. Biol. 2003; PubMed Scopus Google Scholar, F. J. 24: PubMed Scopus Google Scholar). ADAMTS proteases have proprotein convertase with the of these the processing that the processed form S. M.L. K. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the to the processing the sequence not the is a the and but the is and is not a at the F. J. 24: PubMed Scopus Google Scholar). is a at the which is in over of processed F. J. 24: PubMed Scopus Google Scholar). The two sites amino The ADAMTS10 domain a typical sequence that is to other ADAMTS The and cysteine-rich domain have the typical sequence and of and in other ADAMTS and are to The of ADAMTS10 a binding at and also a that binding The not have these and not other although has the N-terminal and the typical of the carboxyl of ADAMTS10, a of has the of a PLAC (protease and lacunin) domain domain was in an ECM D.J. Biol. PubMed Scopus Google Scholar), and is also the carboxyl of some proprotein and ADAMTS In to the other sites are and mouse and human ADAMTS10, that ADAMTS10 is likely to a such sites are in the and in the domain of human ADAMTS10 is in the The of the human and mouse ADAMTS10 zymogen and processed are and to ADAMTS10 a of sequence of ADAMTS10 to to a form of with the modular organization as of sequence of unknown that to a of the Hirohata S. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The that the and a PLAC domain to the the structure of of is and is by in ADAMTS10 and have an domain organization and amino and amino of and The to the of two proprotein convertase processing sites and a similar binding sequence the in amino and two sites in the is in of the discovery of in R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The two to the K. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). sequence is in ADAMTS10 and S. 2002; PubMed Scopus Google also have five and a PLAC but they have to ADAMTS10 has amino sequence and and are thus to ADAMTS10 is ADAMTS6. and ADAMTS10 have with ADAMTS10 to human chromosome 19 and mouse chromosome 17. has by analysis in the mouse and in F. K. and S. S. to human chromosome and mouse chromosome Hirohata S. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ADAMTS10 was expressed at mouse expression was in and and the in of was in the similar of was in some adult mouse tissues such as the and in kidney, and and Adamts10 was in adult The ADAMTS10 in that two of and on human and cell expression was also in human and as in the the of expression the human cell the expression was in the cell a with of a type Adamts10 situ hybridization of mouse at a of expression with widespread expression in and and expression in and was in tissues of the mouse embryo has not at the tissue was days and the expression was and the was and cell In the craniofacial strong expression was in the craniofacial and and the developing and in the and expression was in and but not in was and was not in developing surface and and the the expression restricted to the cells the developing and expressed Adamts10 but the was In the cells in the of the and and the The not have of in and is In the was strong expression in the and primary of cells in and and the developing and expression was in the tissue the of the and in the not In tissue such as and the not that the was expression of Adamts10 in mouse development. In these are on the and the is on the and to In the the is to and the cell are by of hybridization to the is in are and is a The an developing and developing is in to of in and the of in the developing and strong in and and expression of Adamts10 in but not in F, expression in the of hybridization to with and and expression in gonad, likely a the and in the of an expression in developing gonad, likely to a that expression is in expression in is in the of in the lung, expression is are by the through the strong expression in and strong expression in and but not in with the of expression in and In the the expression was similar to that at days and with some The expression in the craniofacial and the developing of at The expression was in the developing and for the expression was in in the developing of the at with strong expression in and and the expression on In strong expression was in the of and in the which are of the and the of ADAMTS10 in HEK293F of HEK293F cells with human ADAMTS10 a at two of the The the of the ADAMTS10 zymogen cells in medium, a of by the that ADAMTS10 proteolysis in the of the of ADAMTS10 was a of it PNGase F. in on and the ADAMTS10 an of which is to the of the of also emerged after which the ADAMTS10 and by of The secreted of cells was also PNGase F, but as by the primary was restricted to the of the processed domain was by PNGase treatment major in the of a of and the zymogen and an of and the of The of PNGase to the the and that they have ADAMTS10 was to cleave the of in the of the in an with M.D. A. J. K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). an of ADAMTS10 is cleavage of the and of the of the with in the of the the of ADAMTS10 as a metalloprotease ADAMTS10 was to the used an that a by cleavage of the of the M.D. J. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ADAMTS10 of to the on In the as has R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, M.D. J. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of ADAMTS10 of which for of processed the was used for studies of zymogen was HEK293F cells by on on to on of the although the of in of the and N-terminal sequencing the of the as secreted zymogen sequence thus the cleavage processed zymogen and processed domain of cells with the showed that of the form was cells in the of but the of the of the at ADAMTS10 to Cell and COS-1 cells by with not that some ADAMTS10 is in the by with cell surface matrix nonpermeabilized COS-1 cells with cells showed cells showed of that was to their surface and their matrix and not to the of secreted ADAMTS10, more was in these cells cells not well to the to of ADAMTS10 was by surface of HEK293F cells with cell surface with to proteins cell by and by The cells a of that was to the with the that HEK293F cells of matrix, suggests that the secreted ADAMTS10 is in to the cell ADAMTS10 is the ADAMTS that the of ADAMTS proteases to over of the human and mouse have it is that ADAMTS proteases in ADAMTS10 has a domain organization the it with in sequence and analysis S.S. J. Cell Biol. PubMed Scopus Google Scholar). ADAMTS enzymes a have domain S.S. J. Cell Biol. PubMed Scopus Google Scholar), the that an form of the domain structure of to the has not as a the of the to ADAMTS10 was to of to describe it The of the and expression are the of the and A. Oblander and S. S. also a domain structure similar to ADAMTS10, and are to other but not to ADAMTS10 and a S.S. J. Cell Biol. PubMed Scopus Google Scholar). The primary structure of ADAMTS10 many of the typical of ADAMTS the of it is a secreted The indicate that it is as a zymogen that is processed by proprotein in the the process to zymogen is also In ADAMTS10 other ADAMTS In HEK293F the ADAMTS10 zymogen and processed form are secreted the cells the processed form R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). In zymogen some of the processing to at the cell surface and was by with by R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the other the processing in ADAMTS10 for suggests that to into to the ADAMTS10 processing the processing for of the ADAMTS10 the typical proprotein convertase sequence K. J. 1997; PubMed Scopus Google Scholar, S. A. Biol. 2003; PubMed Scopus Google Scholar). of a of substrates suggests an for the and that at two of the at and for cleavage K. J. 1997; PubMed Scopus Google Scholar, S. A. Biol. 2003; PubMed Scopus Google Scholar). The in ADAMTS10 not the although is a at the in ADAMTS10 that was in of substrates F. J. 24: PubMed Scopus Google Scholar). these N-terminal sequencing and that the processed form is by a proprotein convertase, ADAMTS10 is widely expressed and is the proprotein convertase K. J. 1997; PubMed Scopus Google Scholar, F. J. 24: PubMed Scopus Google Scholar), it is likely to the physiological processing of The of the in has not to by that it processing at cleavage that is in mouse and human the and for but it has a The of and processed zymogen that the cleavage is of the at two of processing an important physiological by which expressed is studies have demonstrated of and to the cell surface R.P. J.M. Engle J.M. S. Apte S.S. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. S. F. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The in ADAMTS10 such and as for and the cell surface a for R.P. J.M. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. S. F. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ADAMTS10 in to the processing to for and The of in these proteases has to have a on and J. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus (158) Google Scholar, M.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). ADAMTS10 substrates are the role of proteolysis in The of proteolysis in the of by such as suggests that the enzymes in the cells and that processing of ADAMTS10 ADAMTS proteases other have to have such a expression proteases such as the ADAMTS are likely to at the and in the ADAMTS family is that enzymes of a to have expression and and that biological roles for by sites of a in is widely but is to expressed primarily in the Hirohata S. Apte S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), but ADAMTS10 is widely the expression of ADAMTS10 is in the developing and human cell in a cell to ADAMTS10 are not presently it is not of the expressed ADAMTS10 is into ADAMTS10 have a in and in a of not that it has an role at expression some widely expressed proteases have roles development. The of roles in genetic as well as for substrates more to on characterization of in ADAMTS10 in J. the We and of for ADAMTS10 sequence