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Identification of Novel Interaction between ADAM17 (a Disintegrin and Metalloprotease 17) and Thioredoxin-1*

Open AccessPublished:October 26, 2012DOI:https://doi.org/10.1074/jbc.M112.364513
      ADAM17, which is also known as TNFα-converting enzyme, is the major sheddase for the EGF receptor ligands and is considered to be one of the main proteases responsible for the ectodomain shedding of surface proteins. How a membrane-anchored proteinase with an extracellular catalytic domain can be activated by inside-out regulation is not completely understood. We characterized thioredoxin-1 (Trx-1) as a partner of the ADAM17 cytoplasmic domain that could be involved in the regulation of ADAM17 activity. We induced the overexpression of the ADAM17 cytoplasmic domain in HEK293 cells, and ligands able to bind this domain were identified by MS after protein immunoprecipitation. Trx-1 was also validated as a ligand of the ADAM17 cytoplasmic domain and full-length ADAM17 recombinant proteins by immunoblotting, immunolocalization, and solid phase binding assay. In addition, using nuclear magnetic resonance, it was shown in vitro that the titration of the ADAM17 cytoplasmic domain promotes changes in the conformation of Trx-1. The MS analysis of the cross-linked complexes showed cross-linking between the two proteins by lysine residues. To further evaluate the functional role of Trx-1, we used a heparin-binding EGF shedding cell model and observed that the overexpression of Trx-1 in HEK293 cells could decrease the activity of ADAM17, activated by either phorbol 12-myristate 13-acetate or EGF. This study identifies Trx-1 as a novel interaction partner of the ADAM17 cytoplasmic domain and suggests that Trx-1 is a potential candidate that could be involved in ADAM17 activity regulation.

      Introduction

      ADAMs (a disintegrin and metalloproteinase) comprise a family of membrane-associated metalloproteinases with a complex multidomain structure composed of the following domains: metalloproteinase, disintegrin-like, cysteine-rich, epidermal growth factor-like, transmembrane, and cytoplasmic domains. ADAM17, also known as the TNFα-converting enzyme, is responsible for cleaving of several growth factors, cytokines, and cell surface receptors (
      • Murphy G.
      The ADAMs. Signaling scissors in the tumour microenvironment.
      ).
      Progress has been made to identify the signaling molecules that participate in the induction of ADAM17 shedding. Several reports have questioned whether the cytoplasmic domain is involved (
      • Xu P.
      • Derynck R.
      Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-depent cell proliferation.
      ) or not involved (
      • Le Gall S.M.
      • Maretzky T.
      • Issuree P.D.
      • Niu X.D.
      • Reiss K.
      • Saftig P.
      • Khokha R.
      • Lundell D.
      • Blobel C.P.
      ADAM17 is regulated by a rapid and reversible mechanism that controls access to its catalytic site.
      ) in ADAM17 activation, and some mechanisms have been proposed, such as the following: 1) phosphorylation of its cytoplasmic domain at Thr735 by p38α MAP kinase (
      • Xu P.
      • Derynck R.
      Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-depent cell proliferation.
      ); 2) EGF receptor activation by G-protein-coupled receptors involving the Src-dependent phosphorylation of ADAM17 (
      • Zhang Q.
      • Thomas S.M.
      • Lui V.W.
      • Xi S.
      • Siegfried J.M.
      • Fan H.
      • Smithgall T.E.
      • Mills G.B.
      • Grandis J.R.
      Phosphorylation of TNF-α converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation.
      ); and 3) Erk MAP kinase signaling (
      • Fan H.
      • Derynck R.
      Ectodomain shedding of TGF-α and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades.
      ,
      • Díaz-Rodríguez E.
      • Montero J.C.
      • Esparís-Ogando A.
      • Yuste L.
      • Pandiella A.
      Extracellular signal-regulated kinase phosphorylates tumor necrosis factor α-converting enzyme at threonine 735. A potential role in regulated shedding.
      ). However, Le Gall et al. (
      • Le Gall S.M.
      • Maretzky T.
      • Issuree P.D.
      • Niu X.D.
      • Reiss K.
      • Saftig P.
      • Khokha R.
      • Lundell D.
      • Blobel C.P.
      ADAM17 is regulated by a rapid and reversible mechanism that controls access to its catalytic site.
      ) showed that ADAM17 activity does not depend on intracellular signaling through the ADAM17 cytoplasmic tail, suggesting that the regulation may occur through the transmembrane domain. Additionally, it has been shown that the down-regulation of thiol isomerases enhanced ADAM17 activity by inducing changes in the redox environment, and thus, a protein disulfide isomerase could be a specific regulator (
      • Willems S.H.
      • Tape C.J.
      • Stanley P.L.
      • Taylor N.A.
      • Mills I.G.
      • Neal D.E.
      • McCafferty J.
      • Murphy G.
      Thiol isomerases negatively regulate the cellular shedding activity of ADAM17.
      ). In this context, Zhang et al. (
      • Zhang Z.
      • Oliver P.
      • Lancaster Jr., J.R.
      • Schwarzenberger P.O.
      • Joshi M.S.
      • Cork J.
      • Kolls J.K.
      Reactive oxygen species mediate tumor necrosis factor α-converting, enzyme-dependent ectodomain shedding induced by phorbol myristate acetate.
      ) suggested that H2O2 can activate ADAM17 through oxidative attack of a pro-domain thiol group and therefore lead to the disruption of its inhibitory coordination with the Zn2+ in the catalytic domain. In addition, many authors have shown the involvement of reactive oxygen species (ROS) in ADAM17 activation by p38 MAP kinase (
      • Thorp E.
      • Vaisar T.
      • Subramanian M.
      • Mautner L.
      • Blobel C.
      • Tabas I.
      Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase Cδ, and p38 mitogen-activated protein kinase (MAPK).
      ,
      • Scott A.J.
      • O'Dea K.P.
      • O'Callaghan D.
      • Williams L.
      • Dokpesi J.O.
      • Tatton L.
      • Handy J.M.
      • Hogg P.J.
      • Takata
      Reactive oxygen species and p38 mitogen-activated protein kinase mediate tumor necrosis factorα-converting enzyme (TACE/ADAM-17) activation in primary human monocytes.
      ).
      Several proteins have been identified as ADAM17 cytoplasmic domain interaction partners, such as MAD2 (
      • Nelson K.K.
      • Schlöndorff J.
      • Blobel C.P.
      Evidence for an interaction of the metalloprotease-disintegrin tumour necrosis factor α-convertase (TACE) with mitotic arrest deficient 2 (MAD2), and of the metalloprotease-disintegrin MDC9 with a novel MAD2-related protein, MAD2β.
      ), PTPH1 (
      • Zheng Y.
      • Schlondorff J.
      • Blobel C.P.
      Evidence for regulation of the tumor necrosis factor α-convertase (TACE) by protein-tyrosine phosphatase PTPH1.
      ), Erk1/2 (
      • Díaz-Rodríguez E.
      • Montero J.C.
      • Esparís-Ogando A.
      • Yuste L.
      • Pandiella A.
      Extracellular signal-regulated kinase phosphorylates tumor necrosis factor α-converting enzyme at threonine 735. A potential role in regulated shedding.
      ), FHL2 (
      • Canault M.
      • Tellier E.
      • Bonardo B.
      • Mas E.
      • Aumailley M.
      • Juhan-Vague I.
      • Nalbone G.
      • Peiretti F.
      FHL2 interacts with both ADAM-17 and the cytoskeleton and regulates ADAM-17 localization and activity.
      ), and p38α MAPK (
      • Xu P.
      • Derynck R.
      Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-depent cell proliferation.
      ). The cytoplasmic domain of ADAM12 has also been described as a partner of c-Src/Yes (
      • Kang Q.
      • Cao Y.
      • Zolkiewska A.
      Metalloprotease-disintegrin ADAM 12 binds to the SH3 domain of Src and activates Src tyrosine kinase in C2C12 cells.
      ,
      • Suzuki A.
      • Kadota N.
      • Hara T.
      • Nakagami Y.
      • Izumi T.
      • Takenawa T.
      • Sabe H.
      • Endo T.
      Meltrin α cytoplasmic domain interacts with SH3 domains of Src and Grb2 and is phosphorylated by v-Src.
      ), Grb2 (
      • Suzuki A.
      • Kadota N.
      • Hara T.
      • Nakagami Y.
      • Izumi T.
      • Takenawa T.
      • Sabe H.
      • Endo T.
      Meltrin α cytoplasmic domain interacts with SH3 domains of Src and Grb2 and is phosphorylated by v-Src.
      ), PI3K (
      • Kang Q.
      • Cao Y.
      • Zolkiewska A.
      Direct interaction between the cytoplasmic tail of ADAM 12 and the Src homology 3 domain of p85α activates phosphatidylinositol 3-kinase in C2C12 cells.
      ), α-actinin-1 (
      • Cao Y.
      • Kang Q.
      • Zolkiewska A.
      Metalloprotease-disintegrin ADAM 12 interacts with α-actinin-1.
      ), Tks5/FISK (
      • Abram C.L.
      • Seals D.F.
      • Pass I.
      • Salinsky D.
      • Maurer L.
      • Roth T.M.
      • Courtneidge S.A.
      The adaptor protein fish associates with members of the ADAMs family and localizes to podosomes of Src-transformed cells.
      ), PACSIN3 (
      • Mori S.
      • Tanaka M.
      • Nanba D.
      • Nishiwaki E.
      • Ishiguro H.
      • Higashiyama S.
      • Matsuura N.
      PACSIN3 binds ADAM12/meltrin α and up-regulates ectodomain shedding of heparin-binding epidermal growth factor-like growth factor.
      ), Eve-1 (
      • Tanaka M.
      • Nanba D.
      • Mori S.
      • Shiba F.
      • Ishiguro H.
      • Yoshino K.
      • Matsuura N.
      • Higashiyama S.
      ADAM binding protein Eve-1 is required for ectodomain shedding of epidermal growth factor receptor ligands.
      ), and PKCϵ (
      • Sundberg C.
      • Thodeti C.K.
      • Kveiborg M.
      • Larsson C.
      • Parker P.
      • Albrechtsen R.
      • Wewer U.M.
      Regulation of ADAM12 cell-surface expression by protein kinase C epsilon.
      ). However, most of these partners are not necessarily related to the proteolytic activation.
      To correlate the activation of ADAM17 by inside-out regulation, we used multiple strategies to identify ADAM17 cytoplasmic domain partners and cell-based assays to analyze the functional role of the partner in ADAM17 activation. In the present study, we have demonstrated the following: 1) Trx-1
      The abbreviations used are: Trx-1
      thioredoxin-1
      ROS
      reactive oxygen species
      HB-EGF-AP
      heparin-binding epidermal growth factor in fusion with alkaline phosphatase
      XIC
      extracted ion chromatogram
      PMA
      phorbol 12-myristate 13-acetate
      IP
      immunoprecipitation
      HSQC
      heteronuclear single quantum coherence
      DSS
      disuccinimidyl suberate
      ANOVA
      analysis of variance
      RMSD
      root mean square deviation.
      is an ADAM17 cytoplasmic domain ligand in HEK293 cells; 2) Trx-1 co-localized with the ADAM17 cytoplasmic domain and full-length ADAM17 recombinant proteins; 3) Trx-1 directly interacts with the ADAM17 cytoplasmic domain; 4) the overexpression of Trx-1 recombinant protein in the presence of PMA, which generates reactive oxygen species (ROS), decreases ADAM17 activity; and 5) the physiological shedding of ADAM17 substrate, such as EGF, is modulated by interaction with Trx-1. These results suggest that Trx-1 is a direct interaction partner of the ADAM17 cytoplasmic domain and could be involved in the modulation of ADAM17 activity.

      DISCUSSION

      ADAMs are one of the main proteases responsible for the ectodomain shedding of surface membrane proteins; however, how membrane-anchored proteinases can be activated by inside-out regulation remains unclear. To identify the interaction partners of the cytoplasmic domain and to correlate them with a functional role in ADAM17 activation, we induced the expression of the ADAM17 cytoplasmic domain in HEK293 cells and identified the binding partners using mass spectrometry.
      We found thioredoxin-1 as a ligand of the ADAM17 cytoplasmic domain by MS and immunoblotting (Fig. 1, A and B). The immunoprecipitation data confirmed that full-length ADAM17 also interacts with Trx-1, which suggests that the interaction is not restricted to the soluble cytoplasmic recombinant protein (Fig. 1A, lower panel). Co-localization assays further validated the interaction, showing that endogenous Trx-1 co-localizes with the ADAM17 cytoplasmic domain and full-length ADAM17 recombinant proteins (Fig. 1C, upper and lower panels, respectively).
      ADAM cytoplasmic domains are kinase targets (
      • Xu P.
      • Derynck R.
      Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-depent cell proliferation.
      ,
      • Díaz-Rodríguez E.
      • Montero J.C.
      • Esparís-Ogando A.
      • Yuste L.
      • Pandiella A.
      Extracellular signal-regulated kinase phosphorylates tumor necrosis factor α-converting enzyme at threonine 735. A potential role in regulated shedding.
      ,
      • Fan H.
      • Turck C.W.
      • Derynck R.
      Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-α converting enzyme and of an alternatively translated polypeptide.
      ), so we evaluated whether the phosphorylation state could interfere in Trx-1 binding. We found that the Trx-1 interaction with the cytoplasmic domain is not dependent on Ser(P)791 and Ser(P)819 because changes in the phosphorylation pattern induced by PMA treatment (
      • Fan H.
      • Turck C.W.
      • Derynck R.
      Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-α converting enzyme and of an alternatively translated polypeptide.
      ), such as the decrease in Ser(P)791 and the increase in Ser(P)819, did not change the abundance of Trx-1 binding (Table 2).
      To evaluate the interaction of Trx-1 and ADAM17 cytoplasmic domain, we used three different approaches: solid phase binding assay, NMR, and chemical cross-linking coupled with MS. The solid phase binding assays demonstrated that the interaction between the proteins occurs in a concentration-dependent manner (Fig. 3). From NMR studies, we also determined that the presence of the ADAM17 cytoplasmic domain promotes perturbations in the conformational dynamics of the Trx-1 (Fig. 4). The MS analysis of the complexes showed the interaction between the two proteins to be cross-linked by the side chains of the lysine residues (Fig. 5A) in the tryptic peptides of ADAM17 cytoplasmic domain and Trx-1, 726IIKPFPAPQTPGR738 and 82KGQK85, respectively. As previously reported by Willems et al. (
      • Willems S.H.
      • Tape C.J.
      • Stanley P.L.
      • Taylor N.A.
      • Mills I.G.
      • Neal D.E.
      • McCafferty J.
      • Murphy G.
      Thiol isomerases negatively regulate the cellular shedding activity of ADAM17.
      ), the interaction of thiol isomerases is rapid and not very stable in the reduced form; therefore, this approach that stabilized the complex by chemical cross-linking in vitro made it possible to confirm this interaction through the side chain of lysine residues that showed at least a 11.4 Å of distance (based on the DSS spacer arm). In addition, based on the in silico analysis of the protein-protein interaction between ADAM17 cytoplasmic domain and Trx-1 (Fig. 5B), it can be observed that the active site residues of Trx-1 are not in contact with the interface region of ADAM17 cytoplasmic domain and are free for binding to different substrates and to thereby perform different activities. Despite the high flexibility of ADAM17 cytoplasmic domain of ADAM17, the interface region is kept along molecular dynamic simulation. Residues that contribute considerably to the binding in ADAM17 cytoplasmic domain are observed to be above zero (Fig. 5E).
      Trx-1 is known to act as a reductase via a dithiol/disulfide exchange reaction between two cysteine residues in the active site, Cys32-Gly-Pro-Cys35, on oxidized protein substrates that typically contain disulfide bonds. Trx-1 can also be found to be more oxidized when additional disulfide bonds are formed (
      • Watanabe R.
      • Nakamura H.
      • Masutani H.
      • Yodoi
      Anti-oxidative, anti-cancer and anti-inflammatory actions by thioredoxin 1 and thioredoxin-binding protein-2.
      ). ADAM17 has two CXXC motifs, but only in the disintegrin and cysteine-rich domains (
      • Collet J.F.
      • Messens J.
      Structure, function, and mechanism of thioredoxin proteins.
      ,
      • Fischer O.M.
      • Hart S.
      • Gschwind A.
      • Prenzel N.
      • Ullrich A.
      Oxidative and osmotic stress signaling in tumor cells is mediated by ADAM proteases and heparin-binding epidermal growth factor.
      ), and these motifs could be reduced by extracellular Trx-1.
      Previous studies have shown that intracellular Trx-1 plays a crucial role in the ROS scavenging (
      • Watanabe R.
      • Nakamura H.
      • Masutani H.
      • Yodoi
      Anti-oxidative, anti-cancer and anti-inflammatory actions by thioredoxin 1 and thioredoxin-binding protein-2.
      ,
      • Chen K.
      • Thomas S.R.
      • Albano A.
      • Murphy M.P.
      • Keaney Jr., J.F.
      Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling.
      ) and that ROS and thiol isomerases are involved in the regulation of ADAM proteolytic activity (
      • Willems S.H.
      • Tape C.J.
      • Stanley P.L.
      • Taylor N.A.
      • Mills I.G.
      • Neal D.E.
      • McCafferty J.
      • Murphy G.
      Thiol isomerases negatively regulate the cellular shedding activity of ADAM17.
      ,
      • Zhang Z.
      • Oliver P.
      • Lancaster Jr., J.R.
      • Schwarzenberger P.O.
      • Joshi M.S.
      • Cork J.
      • Kolls J.K.
      Reactive oxygen species mediate tumor necrosis factor α-converting, enzyme-dependent ectodomain shedding induced by phorbol myristate acetate.
      ,
      • Thorp E.
      • Vaisar T.
      • Subramanian M.
      • Mautner L.
      • Blobel C.
      • Tabas I.
      Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase Cδ, and p38 mitogen-activated protein kinase (MAPK).
      ,
      • Scott A.J.
      • O'Dea K.P.
      • O'Callaghan D.
      • Williams L.
      • Dokpesi J.O.
      • Tatton L.
      • Handy J.M.
      • Hogg P.J.
      • Takata
      Reactive oxygen species and p38 mitogen-activated protein kinase mediate tumor necrosis factorα-converting enzyme (TACE/ADAM-17) activation in primary human monocytes.
      ,
      • Myers T.J.
      • Brennaman L.H.
      • Stevenson M.
      • Higashiyama S.
      • Russell W.E.
      • Lee D.C.
      • Sunnarborg S.W.
      Mitochondrial reactive oxygen species mediate GPCR-induced TACE/ADAM17-dependent transforming growth factor-α shedding.
      ,
      • Wang Y.
      • Herrera A.H.
      • Li Y.
      • Belani K.K.
      • Walcheck B.
      Regulation of mature ADAM17 by redox agents for l-selectin shedding.
      ,
      • Bass R.
      • Edwards D.R.
      ADAMs and protein disulfide isomerase. The key to regulated cell-surface protein ectodomain shedding?.
      ,
      • Tellier E.
      • Canault M.
      • Rebsomen L.
      • Bonardo B.
      • Juhan-Vague I.
      • Nalbone G.
      • Peiretti F.
      The shedding activity of ADAM17 is sequestered in lipid rafts.
      ). Therefore, we investigated whether ADAM17 activity could be modulated by Trx-1 using a standard approach in a cell model of HB-EGF shedding coupled with an AP reporter assay (
      • Willems S.H.
      • Tape C.J.
      • Stanley P.L.
      • Taylor N.A.
      • Mills I.G.
      • Neal D.E.
      • McCafferty J.
      • Murphy G.
      Thiol isomerases negatively regulate the cellular shedding activity of ADAM17.
      ,
      • Dethlefsen S.M.
      • Raab G.
      • Moses M.A.
      • Adam R.M.
      • Klagsbrun M.
      • Freeman M.R.
      Extracellular calcium influx stimulates metalloproteinase cleavage and secretion of heparin-binding EGF-like growth factor independently of protein kinase C.
      ). We found that the transient overexpression of Trx-1-HA in HEK293 cells treated with PMA or EGF negatively modulated the activity of ADAM17 (FIGURE 6, FIGURE 7, respectively). The presence of ROS scavengers or the inhibition of cell surface oxidoreductases has previously been shown to prevent HB-EGF cleavage and LPS-induced ADAM17 activity (
      • Willems S.H.
      • Tape C.J.
      • Stanley P.L.
      • Taylor N.A.
      • Mills I.G.
      • Neal D.E.
      • McCafferty J.
      • Murphy G.
      Thiol isomerases negatively regulate the cellular shedding activity of ADAM17.
      ,
      • Scott A.J.
      • O'Dea K.P.
      • O'Callaghan D.
      • Williams L.
      • Dokpesi J.O.
      • Tatton L.
      • Handy J.M.
      • Hogg P.J.
      • Takata
      Reactive oxygen species and p38 mitogen-activated protein kinase mediate tumor necrosis factorα-converting enzyme (TACE/ADAM-17) activation in primary human monocytes.
      ). Furthermore, we may also consider that ADAM17 cytoplasmic domain can solely function as an anchor domain to recruit Trx-1, which can regulate the redox state of cysteine residues in target proteins near or in the membrane, for instance in lipid rafts (
      • Hara T.
      • Kondo N.
      • Nakamura H.
      • Okuyama H.
      • Mitsui A.
      • Hoshino Y.
      • Yodoi J.
      Cell-surface thioredoxin-1. Possible involvement in thiol-mediated leukocyte-endothelial cell interaction through lipid rafts.
      ,
      • Tellier E.
      • Canault M.
      • Rebsomen L.
      • Bonardo B.
      • Juhan-Vague I.
      • Nalbone G.
      • Peiretti F.
      The shedding activity of ADAM17 is sequestered in lipid rafts.
      ). In summary, the present study has demonstrated that Trx-1 is a novel interaction partner of the ADAM17 cytoplasmic domain and suggests that Trx-1 is a candidate that could be involved in the regulation of ADAM17 activity.

      Acknowledgments

      We thank Dr. Axel Ullrich and Dr. Michael R. Freeman for kindly donation of ADAM17-HA and HB-EGF-HA vectors, respectively; Dr. Luis E. Soares Neto for the gift of Trx-1 antibody; and Dr. Carl Blobel for mEF cell donation.

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