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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON
1Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, Maryland; 2MedImmune, Gaithersburg, Maryland; 3Graduated Institute of Biochemistry and Molecular Biology, College of Medicine National Taiwan University, Taipei, Taiwan; 4Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, Republic of China; 5Brigham and Women's Hospital, Division of Rheumatology, Immunology, and Allergy, Boston, Massachusetts; 6Lombardi Cancer Center, Department of Oncology, Georgetown University, Washington, DC
Submitted 20 March 2008 ; accepted in final form 5 June 2008
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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1-antitrypsin, and 2-antiplasmin. Identification of matriptase-serpin inhibitor complexes provides evidence for the first time that the proteolytic activity of matriptase, from those cells that express no or low levels of HAI-1, may be controlled by secreted serpins. protease; type 2 transmembrane serine protease; protease inhibitor; ST-14; hepatocyte growth factor activator inhibitor 1
In addition to this expression correlation and the formation of complexes in vivo and in vitro, an intimate functional linkage between matriptase and HAI-1 was clearly demonstrated during embryonic development and the tumorigenesis of epithelial cells (29). Matriptase and HAI-1 are coexpressed in chorionic trophoblasts during early development of the mouse placenta. Genetic ablation of HAI-1 causes placenta defects leading to embryonic death due to the loss of undifferentiated chorionic trophoblasts and impaired formation of the labyrinth layers (7, 29, 31). Genetic ablation of matriptase in HAI-1-deficient mouse embryos corrects the impaired processes of placentation caused by HAI-1 ablation (29). Therefore, coexpression of HAI-1 and matriptase is not required for placental development. However, HAI-1 must be expressed if matriptase is expressed, but placentation proceeds normally in embryos lacking both HAI-1 and matriptase. The close functional relationship between matriptase and HAI-1 is also observed in the skin of zebrafish (5). The loss of epithelial integrity in the HAI-1-deficient zebrafish epidermis can be rescued by simultaneous inactivation of matriptase. The functional linkage between matriptase and HAI-1 also has important implications for the development of cancer. Matriptase activity that is only partially opposed by endogenous HAI-1 causes increased carcinogen sensitivity and produces spontaneous tumorigenesis in the skin of keratin-5-matriptase transgenic mice (21). Matriptase-induced malignant transformation and its strong prooncogenic potential can, however, be counteracted by increasing epidermal HAI-1 expression (21). The close functional relationship of this cognate pair of protease and protease inhibitor has also been observed at the cellular and subcellular levels. Enforced expression of matriptase in breast cancer cell lines that do not naturally express the enzyme only results in the production of significant amounts of protein when HAI-1 is coexpressed (24, 27). In the absence of functional HAI-1, matriptase is only produced at very low levels and fails to traffic out of the endoplasmic reticulum/Golgi apparatus (24). In breast cancer cells that express both proteins, reducing expression of HAI-1 by small interfering RNA (siRNA)-mediated HAI-1 knockdown resulted in spontaneous zymogen activation of matriptase and significantly enhanced the zymogen activation of matriptase induced by sphingosine 1-phosphate (24). Unexpectedly, HAI-1 is required for matriptase activation (27), and, as a consequence, zymogen activation of matriptase is immediately followed by HAI-1-mediated inhibition of the active matriptase. Consistent with the dual roles of HAI-1 as a conventional protease inhibitor and as a cofactor for matriptase zymogen activation, activated matriptase has been consistently detected in HAI-1 complexes (3, 14).
In light of the pivotal role of HAI-1 in the expression, zymogen activation, and inhibition of matriptase and in light of the data from the animal models, it is perhaps not surprising that a growing body of evidence shows that the tight expression correlation and close functional linkage of matriptase and HAI-1 may be altered or lost during the progression of human ovarian cancer. Both matriptase and HAI-1 are expressed by ovarian surface epithelial cells (25). However, expression of matriptase in the absence of HAI-1 or with very low levels of HAI-1 was observed in primary human ovarian carcinomas, particularly in advanced disease (25). Similar imbalances between matriptase and HAI-1 expression have been noted in other cancers of epithelial origin, particularly in the context of more advanced or aggressive disease, suggesting that this imbalance may play a significant role in carcinogenesis and tumor progression (28).
It is, therefore, surprising that there are some normal cell types that have been reported to express matriptase in the absence of HAI-1. Matriptase messenger RNA (mRNA) has been detected in peripheral blood leukocytes (30). The THP-1 human monocytic cell line has been reported to express matriptase but no HAI-1 (11). Matriptase mRNA is present in mouse peritoneal macrophages but not in bone marrow macrophages; however, HAI-1 is not detectable in macrophages of either type (4). These data and the finding that some tumors of epithelial origin apparently express matriptase in the absence of HAI-1 suggest that there must be a HAI-1-independent mechanism at work that can facilitate the expression, trafficking, activation, and inhibition of matriptase in these cells. HAI-1-independent matriptase expression by cells may lead to the release of active, non-HAI-1-complexed matriptase.
In the present study, we identified novel matriptase-containing complexes in human milk that contain no HAI-1. Further purification of these complexes followed by analysis with mass spectrometry-based protein identification and confirmation by immunoblotting studies demonstrated that they contain secreted serpin-type serine protease inhibitors, including antithrombin III (ATIII), 1-antitrypsin (1AT), and 2-antiplasmin (2AP). The existence of these matriptase-serpin complexes in human milk suggests that serpins may play an important role in regulating the activity of matriptase, particularly in the context of cell types that express matriptase in the absence of measurable HAI-1.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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1AT was purchased from Sigma (St. Louis, MO). Human plasma 2AP was purchased from Haematologic Technologies (Essex Junction, VT). CM-Sepharose and activated Sepharose beads were obtained from GE Healthcare (Piscataway, NJ). All other chemical reagents were obtained from Sigma unless otherwise specified.
Monoclonal antibodies.
Human matriptase protein was detected with either the M32 monoclonal antibody (mAb), which recognizes the third LDL receptor class A domain of matriptase in both the latent (one chain) and activated (two-chain) forms of the protease, or with the M69 mAb, which recognizes an epitope present only in the activated (two-chain) form of the enzyme (1, 2). Human HAI-1 was detected with the use of the HAI-1-specific mAb M19 (17). ATIII and 2AP polyclone antibodies were purchased from R&D Systems (Minneapolis, MN). 1AT polyclone antibody was purchased from Bethyl Laboratories (Montgomery, TX).
Immobilization of mAbs. mAbs M19, M69, and 21-9 were covalently coupled to Sepharose 4B at 5 mg/ml gel following the manufacturer's instructions (GE Healthcare). Briefly, the mAbs were purified and dialyzed against the coupling buffer (0.1 M sodium bicarbonate containing 0.5 M sodium chloride) and incubated overnight at 4°C with cyanogen bromide-activated Sepharose 4B. The uncoupled mAbs were removed by washing the beads with the coupling buffer, and the residual coupling sites on beads were blocked by 1 M Tris buffer. The mAb-Sepharose beads were stored in PBS.
Purification of the 110-kDa matriptase complexes from human milk. Frozen human milk from Georgetown University Medical Center Milk Bank was thawed and centrifuged to remove the milk fat and insoluble debris. The defatted milk was dialyzed against 10 mM phosphate buffer, pH 6.0, and loaded onto a CM-Sepharose FF column (2.5 x 20 cm; GE Health Science) equilibrated with 10 mM phosphate buffer, pH 6.0. The column was washed with 10 column volumes of equilibrium buffer. Proteins were eluted with a linear gradient of 0–0.5 M NaCl in 10 mM phosphate buffer, pH, 6.0, with a total volume of 500 ml. The column fractions containing 110-kDa complexes were collected and pooled. To remove the 95-kDa matriptase-HAI-1 complexes from the 110-kDa matriptase complex-enriched fractions, the samples were loaded onto a HAI-1 immunoaffinity column containing 1 ml mAb M19-Sepharose at a flow rate of 7 ml/h. The flow through, which contained the 110-kDa complexes, was then loaded onto a matriptase mAb 21-9 immunoaffinity column and the column washed with 1% Triton X-100 in PBS. Bound proteins then were eluted with 0.1 M glycine HCl, pH 2.4. Fractions were immediately neutralized by addition of 2 M Trizma base.
Western blotting. Protein samples for Western blotting were diluted in 5x sample buffer. The sample buffer did not contain a reducing agent, and samples were not boiled before SDS-PAGE unless otherwise specified since reducing agents destroy the epitopes recognized by the mAbs and boiling disrupts matriptase-HAI-1 complexes. Proteins were resolved by 7.5% SDS-PAGE, transferred to Protran nitrocellulose membranes (Schleicher & Schuell, Keene, NH), and probed with the mAbs M32, M69, and M19 or the polyclonal antibodies directed against serpins. The binding of the primary antibody was detected with the use of horseradish peroxidase-conjugated secondary antibodies (Jackson ImmunoResearch Laboratories, West Grove, PA) and visualized using the Western Lightening Chemiluminescence Reagent Plus (Perkin-Elmer, Boston, MA).
Diagonal SDS-PAGE. The 110-kDa complex was first boiled with SDS sample buffer in the absence of reducing agents and then resolved by electrophoresis. A gel strip was then sliced out from the gel used in the previous step and boiled with SDS sample buffer containing reducing agent. The reducing agent-treated strip was placed on the top of a new gel and subjected to electrophoresis in the second dimension, at 90 degrees to that in the first gel. Protein and protein fragments were assayed by colloidal Coomassie blue staining of the second gel.
Liquid chromatography/mass spectrometry analysis and identification of proteins. The selected bands from the gels were initially excised, washed, destained, and trypsinized overnight at 37°C using standard protocol after DTT reduction and iodoacetamide alkylation. Liquid chromatography/mass spectrometry (LC/MS) analysis of tryptic peptides derived from protein samples were performed on Thermo Finnigan LCQ DECA XP mass spectrometer (ThermoFinnigan, San Jose, CA), which was connected to a nanoelectrospray ionizer. The Surveyor LC system with auto sampler (ThermoFinnigan) was used for peptide separation. The LC system was connected to a 10.5-cm fused silica reverse-phase C18 column (PicoFrit column; New Objective, Woburn, MA). The peptides were separated during 90 min of linear gradient of 5–90% acetonitrile/water mixture, containing 0.1% formic acid at a flow rate of 300 nl/min. MS scan events and HPLC solvent gradients were controlled by the Xcalibur software (ThermoFinnigan). The spectrums were accumulated in data-dependant acquisition mode, and the acquired MS/MS scans were searched against the human database (IPI) using SORCERER/SEQUEST search algorithm. Database search parameters were set to allow carboxyamidomethylation (+57.021464 Da) of cysteine residues and oxidation (15.99492 Da) of methionine as fixed modification. The best hit was selected on the basis of probability/percent of coverage and number of peptides or on the basis of Xcore.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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1AT, and 2AP.
Both the 80-kDa and 45-kDa protein bands were subjected to MS-based protein identification studies as described in the MATERIALS AND METHODS (Fig. 3). The 80-kDa protein bands contained multiple proteins. Tryptic fragments derived from this protein band contain five peptides matched to matriptase, 30 peptides matched to ATIII, three peptides matched to 1AT, and two matched to 2AP. Eleven tryptic peptides derived from the 45-kDa protein bands were matched to matriptase (Fig. 3). Interestingly, the five tryptic peptides derived from the 80-kDa bands, which matched to matriptase, were all located within the serine protease domain of matriptase, whereas, the matriptase-matching tryptic peptides from the 45-kDa bands were all localized in the noncatalytic domains of matriptase. These data suggest that the 110-kDa complexes contain disulfide-linked, two-chain, activated matriptase. Considering the molecular mass of the three serpins identified (
55 kDa for ATIII, 60 kDa for 1AT, and 70 kDa for 2AP) and of the serine protease domain of matriptase (25 kDa), it seems very likely that the 80-kDa bands are composed of three different complexes of the matriptase serine protease domain with one or other of these three serpins. Therefore, the 110-kDa complexes are likely to be a mixture of matriptase-ATIII, matriptase-1AT, and matriptase-2AP complexes.
We further confirmed that the 110-kDa matriptase complexes are a mixture of matriptase associated with each of the three secreted serpins by immunoblot with ATIII, 1AT, and 2AP polyclonal antibodies and the matriptase mAb M32 (Fig. 4). The 110-kDa complexes and the various serpins were subjected to SDS-PAGE and then blotted with each of the four antibodies, respectively. The 110-kDa complexes were recognized by the matriptase mAb M32 and all three serpin polyclonal antibodies (Fig. 4, A–D, lane 1). The matriptase mAb M32 did not interact with these three serpin proteins (Fig. 4A, lanes 2, 3, and 4); the serpin polyclonal antibodies only interacted with their corresponding proteins and not the other serpins (Fig. 4, B–D, lanes 2, 3, and 4).
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1AT, and 2AP, inhibit proteases by forming covalent-linked complexes in a suicide mode (9, 34). This unique feature of serpin-type inhibitors is consistent with the resistance to dissociation by boiling SDS in the absence of reducing agents exhibited by the 110-kDa matriptase-serpin complexes (Fig. 2). Interestingly, chemical reduction of the 110-kDa matriptase-serpin complexes cleaved the disulfide-linkage between the serine protease domain and noncatalytic domain of matriptase in the complexes and resulted in the release of the noncatalytic domains of matriptase, seen as the 45-kDa protein band in the diagonal gel electrophoresis study (Fig. 3). After releasing the 45-kDa matriptase noncatalytic domain, the 110-kDa complexes were converted into 80-kDa complexes consisting of the matriptase serine protease domain covalently linked with either ATIII, 1AT, or 2AP. In Fig. 4E, we summarize the structure of 110-kDa complexes and the conversion into their subunits by chemical reduction.
Matriptase and its inhibitors in human milk.
We further analyzed the expression status of matriptase and its endogenous inhibitors, including HAI-1, ATIII, 1AT, and 2AP in defatted human milk (Fig. 5). Matriptase was detected predominantly in its 95-kDa HAI-1 complexes and also as a minor species at 110-kDa, which may represent a mixture of matriptase complexes with the individual secreted serpins (Fig. 5, lane 1). There was no free (noncomplexed) matriptase, either in its latent or activated form, detected in human milk. The activated matriptase-specific mAb M69, only detected the 95-kDa matriptase-HAI-1 complexes (Fig. 5, lane 2), further confirmed that there was no free, active matriptase in human milk. HAI-1 was detected only in 95-kDa matriptase complex, demonstrating that there was also no free (noncomplexed) HAI-1 (Fig. 5, lane 3). In contrast, free (noncomplexed) ATIII and 1AT were detected in human milk in addition to the complexed forms (Fig. 5, lanes 4 and 5).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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1AT, in human milk provides evidence that free, active matriptase indeed exists extracellularly either on the cell surface or in the interstitial space of lactating mammary glands, where free, active matriptase encounters these secreted serpins. As a membrane-bound serine protease with a single-pass transmembrane domain, the bulk of the matriptase molecule, including its serine protease domain, has been believed to orient itself toward the extracellular side and to function as a protease activator on the cell surface to activate substrates extracellularly (17). However, the dual roles of HAI-1 as a conventional protease inhibitor for matriptase (1) and as a factor required for zymogen activation of the protease (27) would seem to dictate that free, active matriptase is only likely to exist for a very short time. Activated matriptase has been consistently detected in complexes with HAI-1 regardless of the cell source, such as breast cancer cells vs. immortal mammary epithelial cells (2), regardless of the mode of zymogen activation, such as the constitutive activation exhibited by breast cancer cells (2) compared with the induced zymogen activation in immortal mammary epithelial cells by sphingosine 1-phosphate (2), or in prostate cancer cells by androgen (13), or more broadly in other cell types by suramin (16). Although it has been challenging to determine the exact cellular locations where the activation of matriptase occurs, it seems likely that it takes place either at the plasma membrane or in the secretory pathway during its trafficking toward the plasma membrane because activated matriptase was previously detected at cell-cell junctions (2, 8) and in vesicle-like structures within cells (16). In either case, given that HAI-1 participates in the activation process and is therefore present and able to immediately bind to the newly activated enzyme, the accessibility of free, active matriptase to its potential extracellular substrates, or to protease inhibitors other than HAI-1, may be very limited. Therefore, in matriptase-expressing cells that also express a comparable amount of HAI-1, free, active matriptase may never reach the extracellular environment at meaningful levels. It is, therefore, paradoxical that, in the present study, we purified matriptase complexed with secreted serpins from human milk. The ATIII and 1AT are probably derived from blood or locally produced during lactation and deposited in the extracellular matrix (33). Furthermore, serpins are activated after secretion, and, therefore, it is unlikely that inhibition and formation of matriptase-serpin complexes occur in the secretory pathway. Therefore, free, active matriptase has to reach the extracellular environment, at least on the extracellular surface of the plasma membrane, for exposure to these secreted serpin-type serine protease inhibitors.
Mammary epithelial cells produce most milk proteins, and, since milk-derived, immortal mammary epithelial cells express both matriptase and HAI-1, the milk-derived matriptase-HAI-1 complexes are very likely produced by mammary epithelial cells (17). Robust zymogen activation of matriptase apparently takes places in these mammary epithelial cells during lactation since a large amount of matriptase-HAI-1 complexes are present in milk (Fig. 8). Since the activated matriptase produced by mammary epithelial cells is sequestered in HAI-1 complexes and in light of the stability of HAI-1/matriptase complexes, it seems very unlikely that the activated matriptase in serpin complexes is derived from matriptase liberated from HAI-1 complexes, being inhibited by and forming complexes with these three serpins. This possibility is made more unlikely by the facts that 1) the pH of milk does not favor the dissociation of matriptase-HAI-1 complexes, 2) no free HAI-1 was detected in milk as would be expected if the serpin-bound matriptase was derived from HAI-1 complexes (Figs. 1 and 8), and 3) free 2AP was undetectable in milk and is however found in complexes with matriptase (Fig. 5). Furthermore, there is probably much more free 1AT than free ATIII in human milk (20), yet the levels of matriptase-ATIII complexes are apparently higher than those of 1AT complexes in human milk. Had matriptase been dissociated from HAI-1 complexes in milk, one would expect 1AT to have a quantitative advantage in forming complexes with matriptase compared with ATIII due to the large amount of free 1AT. These observations suggest that there are complicated biological processes behind the formation of these matriptase-serpin complexes regarding the cell types that express matriptase and where the active matriptase encounters these serpins.
The activated matriptase found in these serpin-complexes could be produced by cell types other than mammary epithelial cells. There are multiple cell types other than epithelial cells present in the stroma of a lactating mammary tissues, including fibroblasts, adipocytes, endothelial cells in the blood vessels, and migrating leukocytes, such as macrophages, plasma cells, and eosinophils to name a few. Among all these cell types, migrating leukocytes are a potential source of free active matriptase for what could subsequently be inhibited by ATIII and 1AT. Peritoneal macrophages have been reported to express matriptase but not HAI-1 (4). THP-1 human monocytic cells express matriptase and very low levels of HAI-1 (Fig. 6). In the absence of HAI-1, migrating macrophages may secret free active matriptase. ATIII and 1AT are produced by the liver, are found at high levels in the blood, and may be transported and deposited in the interstitial spaces of the lactating mammary tissues, thus finding their way into milk, with their free forms detected in milk. ATIII has been detected in the basement membrane bound to heparin sulfate proteosaminoglycan underneath endothelial cells in blood vessels from a variety of tissues (33). The mRNA of 1AT has also been detected in the lactating mammary tissues, suggesting that local expression of the serpin may also contribute to its presence in milk (6). Therefore, an appealing hypothesis for the presence of both free and matriptase-complexed ATIII and 1AT in human milk is that matriptase is activated in migrating leukocytes and/or plasma cells when these cells are extravasating and migrating through the basement membrane of capillaries in the lactating mammary gland, where both serpins are deposited.
The biology of the inhibition of matriptase by 2AP may be different from the other two secreted serpins since free 2AP was not detected in human milk by immunoblot analysis (Fig. 8). Transcytosis of 2AP into milk apparently does not occur to any significant extent compared with the levels of ATIII and 1AT (Fig. 5). The presence of matriptase-2AP complexes in the absence of free 2AP in human milk suggests that 2AP may be expressed by the same cells that are expressing and activating matriptase, resulting in the formation of 2AP complexes before shedding into the extracellular milieu, in a fashion similar to HAI-1. In contrast to ATIII for which expression is restricted to hepatocytes, 2AP has been detected in several other tissues, including kidney, intestine, striated muscle, testis, hippocampus, and placenta (22). It is of interest to determine whether and what cell types might produce 2AP in mammary tissues in future studies.
Unlike Kunitz-type protease inhibitors, such as HAI-1, which inhibit proteases by forming very tight but reversible complexes, the mode of protease inhibition by serpin-type serine protease inhibitors has been considered to be a "suicide" or "single-use" approach due to its distinctive conformational alteration for inhibiting serine proteases. Serpin-type serine protease inhibitors inactivate their target proteases by binding to them covalently in a 1:1 stoichiometry. Protease inactivation by serpin inhibitors involves the attack of the target protease on the P1-P1' bond in the reactive center loop of the serpins that results in the trapping of the protease in complexes with serpin inhibitors and deforms the protease catalytic triad (9, 34). In the case of the 110-kDa matriptase-serpin complexes, the covalent linkage between the reactive centers of the serpins and active site triad serine of matriptase held both proteins together under boiled and nonreduced conditions (Fig. 2). The binding, inhibition, and trapping of serine proteases by serpins likely significantly disrupts the active site triad and substrate binding pocket of proteases since the activation-associated epitope recognized by the mAb M69 is no longer present on the 110-kDa complexes (Figs. 2 and 5).
In summary, in this study, we have purified three novel matriptase complexes containing secreted serpins. These secreted serpins may provide the long-sought answer for the question as to how the proteolytic activity of matriptase is controlled in those cells that express no or very low levels of HAI-1. In addition, the presence of free, active matriptase in the extracellular milieu and the formation of matriptase-serpin complexes suggest that these serpins could be useful tools to detect active matriptase in those cells that express very low levels of or no HAI-1. Despite their common ability to inhibit matriptase, secreted serpins, at least for ATIII and 1AT, are likely to be responsible to the control of active matriptase possibly produced by migrating leukocytes in contrast to HAI-1, which regulates matriptase in mammary epithelial cells. Therefore, in the lactating mammary tissues, there appears to be two sources of matriptases: epithelial matriptase and stromal matriptase. The major difference between these two matriptase forms is their inhibitions by different inhibitor systems.
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FOOTNOTES |
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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.
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