Article |
Address correspondence to Shigeki Higashiyama, Dept. of Medical Biochemistry, Ehime University School of Medicine, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan. Tel.: 81-89-960-5253. Fax: 81-89-960-5256. email: shigeki{at}m.ehime-u.ac.jp
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Abstract |
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Key Words: HB-EGF; ADAM12; shedding; PLZF; transcriptional repression
Abbreviations used in this paper: ADAM, a disintegrin and metalloprotease; EGFR, epidermal growth factor receptor; GPCR, G proteincoupled receptor; HB-EGF, heparin-binding EGF-like growth factor; PLZF, promyelocytic leukemia zinc finger; proHB-EGF, membrane-anchored heparin-binding EGF-like growth factor; TPA, 12-O-tetradecanoylphorbol-13-acetate.
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Introduction |
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The proHB-EGF molecule is proteolytically cleaved by "a disintegrin and metalloprotease" (ADAM) 9, 12, 10, or 17 (Izumi et al., 1998; Asakura et al., 2002; Lemjabbar and Basbaum, 2002; Sunnarborg et al., 2002; Yan et al., 2002) to release a soluble form of HB-EGF. This cleavage can be stimulated by treating cells with various agents, including the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of PKC (Goishi, et al., 1995). Recent analyses have shown that the processing of proHB-EGF by metalloproteases plays important roles in cutaneous wound healing (Tokumaru et al., 2000) and branching morphogenesis of the submandibular gland (Umeda et al., 2001). Furthermore, the cleavage of proHB-EGF is required for EGFR transactivation by GPCR signaling (Prenzel et al., 1999), which is involved in various biological processes such as cardiac hypertrophy (Asakura et al., 2002), cystic fibrosis (Lemjabbar and Basbaum, 2002), and the mitogenic effects of arachidonic acid metabolites (Chen et al., 2002; Cussac et al., 2002).
Although much has been learned about the functions of extracellular domains produced by ectodomain shedding, very little attention has been paid to the remnant cell-associated domains also created by the processing event. Here, we focus on a biological role played by the carboxy-terminal remnant (HB-EGF-C) produced in parallel with HB-EGF, and characterize it as a novel intracellular signaling molecule acquired posttranslationally. Using fluorescent proteintagged proHB-EGF and an antibody recognizing the cytoplasmic region of proHB-EGF, we visualized the translocation of HB-EGF-C from the plasma membrane into the nucleus after ectodomain shedding of proHB-EGF. Yeast two-hybrid screening resulted in the cloning of an HB-EGF-C binding protein, promyelocytic leukemia zinc finger (PLZF), previously identified as a transcriptional repressor and a negative regulator of the cell cycle. The proteolytic release of HB-EGF-C via metalloprotease activation caused nuclear export of PLZF and reversal of cyclin A suppression and delayed entry of S-phase by PLZF in human fibrosarcoma HT1080 cells. Intracellular trafficking of endogenous HB-EGF-C into the nucleus and the subsequent nuclear export of PLZF after metalloprotease processing of proHB-EGF were also observed in human primary cultured keratinocytes. Thus, our present data provide new insights into the inter- and intracellular communication generated by proHB-EGF processing.
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Results |
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To test whether -secretase activity is involved with the proteolytic release of HB-EGF-C, we investigated the effect of a dominant-negative mutant of presenilin-1 (PS1 D385A), which reduces
-secretase activity (Wolfe et al., 1999), on HB-EGF-C translocation after TPA treatment. Transient expression of amino-terminally FLAG-tagged dominant-negative PS1 in HT1080 cells was not altered the HB-EGFYFP translocation induced by TPA treatment (Fig. 1 F).
Identification of PLZF as a proHB-EGF cytoplasmic domainbinding protein
The translocation of HB-EGF-C after proHB-EGF processing suggested that after proHB-EGF processing, HB-EGF-C could interact with cytoplasmic or nuclear proteins. To identify potential binding proteins of HB-EGF-C, we used yeast two-hybrid cloning and screened a human heart cDNA library using the cytoplasmic region of proHB-EGF (residues 185208) as bait. Screening of 106 transformants yielded 16 positive clones. One of the clones (referred to as clone 3) encoded a carboxy-terminal sequence of PLZF protein (Fig. 2 A), a transcriptional repressor that is localized in the nucleus (Chen et al., 1993; Reid et al., 1995). Immunoprecipitation from COS cells expressing proHB-EGF and CFP-tagged PLZF (CFP-PLZF) revealed that CFP-PLZF was coimmunoprecipitated with the #H1 antibody once the cells were treated with TPA (Fig. 2 B).
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Nuclear export of PLZF triggered by TPA-inducible ectodomain shedding of proHB-EGF
Next, we examined the subcellular localization of PLZF by using the expression vector encoding CFP-PLZF. This expression vector was transfected into four types of cell lines as follows: HT1080 cells; a stable transfectant of HT1080 expressing proHB-EGF (HT1080/HB-EGF); a stable double transfectant of HT1080 cells expressing proHB-EGF and a metalloprotease domaindeleted mutant of ADAM12 (HT1080/MP-ADAM12/HB-EGF); and a stable transfectant of HT1080 expressing an uncleavable mutant (L148G; Hirata et al., 2001) of proHB-EGF (HT1080/HB-EGF-UC). Endogenous HB-EGF expression was very low in parental HT1080 cells (unpublished data).
CFP-PLZF was predominantly localized in the nucleus in HT1080 cells and in the three transfectants. TPA treatment did not alter the subcellular localization of CFP-PLZF in HT1080 cells. In contrast, TPA treatment for 60 min distributed CFP-PLZF in the entire cytoplasm of HT1080/HB-EGF cells (Fig. 3 A). A previous experiment had revealed that ADAM12 can mediate HB-EGF shedding, and that expression of a dominant-negative (metalloprotease domaindeleted mutant) form of ADAM12 inhibited proHB-EGF processing in HT1080 cells (Asakura et al., 2002). In HT1080/MP-ADAM12/HB-EGF cells, the export of CFP-PLZF from the nucleus to the cytoplasm was not observed after TPA stimulation. Similarly, HT1080/HB-EGF-UC cells did not show the nuclear export of CFP-PLZF despite TPA treatment (Fig. 3 A). Quantitative analyses (see Materials and methods) verified that the number of cells with nuclear-localized CFP-PLZF was reduced by the TPA treatment in HT1080/HB-EGF cells, but not in parental HT1080 cells, HT1080/
MP-ADAM12/HB-EGF cells, or HT1080/HB-EGF-UC cells (Fig. 3 C).
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The GST pull-down analysis indicated that deletion of Zn67 of PLZF abrogated the binding to HB-EGF-C. Therefore, we investigated the nuclear export of CFP-PLZF with deletion of Zn6
7 (CFPPLZF
Zn6
7) in HT1080/HB-EGF cells. The frequency of the CFP-PLZF
Zn6
7 export much decreased as compared with CFP-PLZF after TPA stimulation (Fig. 3, E and F). This result indicates that binding of PLZF to HB-EGF-C is essential for the nuclear export of PLZF.
Translocation and interaction of HB-EGF-C with PLZF precedes nuclear export of PLZF
Next, we performed the simultaneous visualization of proHB-EGF processing and PLZF transport. Processing of HB-EGFYFP did not promote nuclear export of PLZF (unpublished data), possibly due to the fused YFP interfering with the interaction between HB-EGF-C and PLZF. Therefore, HB-EGFYFP and CFP-PLZF expression vectors were cotransfected into HT1080/HB-EGF or HT1080/MP-ADAM12/HB-EGF cells that stably expressed wild-type proHB-EGF. Images were collected every 15 min up to 90 min after TPA treatment. In HT1080/HB-EGF cells, internalization of HB-EGFYFP was observed 30 min after the treatment, but nuclear export of CFP-PLZF did not occur until 45 min after TPA stimulation (Fig. 4 A). In HT1080/
MP-ADAM12/HB-EGF cells, subcellular localization of HB-EGFYFP and CFP-PLZF were not changed despite TPA treatment (Fig. 4 B).
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The proHB-EGF cytoplasmic region is required for PLZF transport
The data presented in Fig. 3 indicated that proteolytic release of HB-EGF-C by proHB-EGF processing could trigger the nuclear export of PLZF. Therefore, we designed three types of cytoplasmic deletion mutants of proHB-EGF (HBC10, HB
C19, and HB
C22; Fig. 5 A), constructed their expression vectors, and established stable transfectants of HT1080 cells with each of the vectors. All YFP-tagged deletion mutants of proHB-EGF were also localized at the plasma membrane and internalized into the cytoplasm by TPA treatment (unpublished data). HT1080/HB
C10 cells (as well as HT1080/HB-EGF cells) showed TPA-responsible nuclear export of PLZF. However, in HT1080/HB
C19 and HT1080/HB
C22 cells, nuclear export of PLZF did not occur despite TPA stimulation (Fig. 5, B and C).
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Intracellular localization of HB-EGF-C in human keratinocyte cell line HaCaT and primary cultured cells
We examined human keratinocyte cell line HaCaT and primary cultured cells to determine the localization of endogenous HB-EGF-C. TPA treatment of HaCaT cells (Fig. 7 A) as well as primary cultured cells (unpublished data) resulted in the production of an 6.7-kD band, the expected size of an HB-EGF-C retaining both the transmembrane and cytoplasmic domains of proHB-EGF. HB-EGF-C was in the Golgi apparatus after 30 min of TPA treatment, as determined by its colocalization with the Golgi protein p115 (Nelson et al., 1998; Fig. 7 B). HB-EGF-C accumulated and partially colocalized with FLAG-tagged PLZF at the nucleus of HaCaT cells after 60 min of TPA treatment (Fig. 7 C).
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PLZF-HB-EGF-C interaction in vivo
We also examined the interaction of PLZF and HB-EGF-C in vivo using a TPA-treated mouse skin model of keratinocyte hyperplasia. TPA treatment of mouse skin tissue for 24 and 48 h produced keratinocyte hyperplasia as reported previously (Hawighorst et al., 2001; Fig. 9 A). Immunoprecipitation of PLZF in the homogenates of TPA-treated and control mouse skin tissues resulted in the coprecipitation of a 6.7-kD band recognized by anti-HB-EGF-C antibody #H1 in TPA-treated tissue homogenates alone (Fig. 9 B), suggesting that the PLZF-HB-EGF-C interaction occurs in vivo.
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Discussion |
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Using the technology of fluorescent proteins, we first demonstrated that HB-EGF-C was internalized into the cytoplasm after ectodomain shedding. Immunoblotting of the nuclear fraction and immunostaining using the antibody recognizing the cytoplasmic region of proHB-EGF (#H1) revealed the accumulation of endogenous HB-EGF-C in the nucleus after the processing. The 6.7-kD band of HB-EGF-C and no effect of dominant-negative presenilin-1 on HB-EGF-C translocation indicate that HB-EGF-C has the proHB-EGF transmembrane domain and is not further processed by -secretase. The colocalization of HB-EGF-C with p115, a marker protein of the Golgi apparatus, indicates that it is internalized by vesicular trafficking. Although the detailed transport mechanism of HB-EGF-C containing transmembrane domain remains unclear, recent analyses of nuclear localization of receptor tyrosine kinases raise the possibility that the GolgiER pathway is a route to the nucleus of type I transmembrane molecules (Carpenter, 2003). As shown in Fig. 1, TPA treatment localized HB-EGFYFP around the nucleus, but not in the nucleus. HB-EGFYFP did not promote the nuclear export of PLZF after TPA treatment (unpublished data). Therefore, we speculate that the YFP moiety fused to the carboxy terminus of HB-EGF-C might aggregate and fail to enter the nucleus, which abrogates the HB-EGF-CPLZF interaction.
Recently, it has been reported that neuregulin-1 is cleaved at the transmembrane domain and the released intracellular domain (Nrg-1-ICD) enters the nucleus to repress expression of several regulators of apoptosis (Bao et al., 2003). Bao et al. (2003) also mentioned that Nrg-1-ICD forms the complex with a second zinc fingercontaining protein related to PLZF. Although the machinery of carboxy-terminal signaling of proHB-EGF and neuregulin-1 seems to be different, these results, together with our present data, suggest that the carboxy-terminal fragments of the EGF family precursors are functional molecules that control gene expression by regulating transcription factors in the nucleus.
It is apparent that nuclear accumulation of HB-EGF-C, nuclear export of PLZF, and interaction between HB-EGF-C and PLZF are mutually exclusive. Although the machinery of this signaling is still unclear, one possible mechanism suggested by time coursedependent changes in the interaction and localization of HB-EGF-C and PLZF is as follows: (1) HB-EGF-C is translocated into the nucleus after proHB-EGF processing; (2) HB-EGF-C associates with nuclear PLZF; and (3) PLZF is exported from the nucleus in a CRM1-dependent manner (Fig. 10 A).
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It has been reported that PLZF is a transcriptional repressor of cyclin A and suppresses cell growth by inhibiting entry or progression of S-phase in the cell cycle (Shaknovich et al., 1998; Yeyati et al., 1999). Gene expression control by transcriptional regulators occurs in the nucleus, and nuclear export of these factors results in loss of the regulation. The present data show that HB-EGF-C generated by ectodomain shedding of proHB-EGF causes nuclear export of PLZF, increases the expression of cyclin A, and promotes S-phase entry. Furthermore, the interaction of HB-EGF-C and PLZF occurs in the TPA-treated mouse skin model of keratinocyte hyperplasia. On the other hand, proHB-EGF processing also generates HB-EGF, a soluble ligand of EGFR. It is well known that HB-EGF activates EGFR signaling and promotes G1-phase progression in the cell cycle by regulating the expression of cyclin D via the Ras-MAPK signaling cascade (Hackel et al., 1999; Prober and Edgar, 2001). Therefore, our current paper suggests that proHB-EGF has two functional domains affecting mitogenic signaling. Posttranslational processing of proHB-EGF by metalloprotease activation produces intercellular and intracellular signaling molecules simultaneously (Fig. 10 A). The coordination of the resulting dual mitogenic signals may be important for cell cycle progression in various signaling cascades (Fig. 10 B).
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Materials and methods |
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Yeast two-hybrid assay
The cytoplasmic domain of proHB-EGF (residues 185208; Higashiyama et al., 1991) was used to screen a human heart cDNA library in the yeast two-hybrid assay, following the manufacturer's instructions for the MatchmakerTM two-hybrid assay system (CLONTECH Laboratories, Inc.). About 106 transformants were screened, and library plasmids from 16 positive clones were analyzed by transformation tests and DNA sequencing (Gietz et al., 1992). ß-Galactosidase activity was measured by liquid and filter assays.
Cellular fractionation, immunoprecipitation, and immunoblotting
Cytoplasmic and nuclear fractions were prepared using the CellLytic NuClear extraction kit (Sigma-Aldrich). Immunoprecipitation and immunoblotting of cell lysates was performed as described previously (Goishi et al., 1995). Primary antibodies were used as follows: mouse monoclonal IgG antibodies to FLAG (Sigma-Aldrich), PLZF (Oncogene Research Products), and cyclin A (Neomarkers); rabbit pAbs to GFP (MBL International Corporation), and HB-EGF-C (#H1) and HB-EGF (#H6) (Miyagawa et al., 1995). Secondary antibodies were HRP-conjugated goat antimouse and antirat IgG (Promega).
GST pull-down assay
GST and GSTHB-EGF-C were expressed in and purified from the Escherichia coli BL21 strain according to standard protocol. After binding of GST and GSTHB-EGF-C to the glutathione Sepharose beads, cell lysates containing various FLAG-tagged PLZF derivatives were incubated with 20 µl of the beads for 2 h at 4°C. After being washed, bound proteins were analyzed by immunoblotting using anti-FLAG antibody (Sigma-Aldrich).
Cell lines and transfection
HT1080/HB-EGF and HT1080/MP-ADAM12/HB-EGF cells were described previously (Asakura et al., 2002). For the establishment of HT1080/HB-EGF-UC or HT1080/HB
C cells, the plasmids encoding uncleavable-type proHB-EGF, HB
C mutants were introduced into HT1080 cells using LipofectAMINETM 2000 (Life Technologies), and stably transfected clones were isolated. HT1080 cells and its transfectants were grown in MEM supplemented with nonessential amino acids (Life Technologies), 10% FBS, and antibiotics. COS and HaCaT cells were maintained in DME containing 10% FBS. The culture of primary human keratinocytes was as described previously (Hashimoto et al., 1994). All cells were cultured in a humidified 37°C/5% CO2 incubator.
For transient transfections, 4.0 x 105 cells were seeded per 35-mm cell culture dish (Corning), grown for 12 h in the respective medium, and then transfected with expression vectors using LipofectAMINETM 2000 (Life Technologies).
Imaging of YFP or CFP fusion proteins
Transiently transfected cells were cultured for 24 h and then used for experiments. For treatment with the EGFR-neutralizing antibody (Upstate Biotechnology), KB-R7785 (Asakura et al., 2002), or leptomycin B (Sigma-Aldrich), the cells were incubated in serum-free medium with 10 µg/ml antibody for 2 h, 10 µM KB-R7785 for 30 min, or 10 ng/ml leptomycin B for 2 h, and then cultured in the same medium containing 100 nM TPA for 1 h. Subcellular localization of YFP or CFP fusion proteins was examined under an epifluorescence microscope (Eclipse TE300; Nikon) (Fig. 1, A and F, Fig. 3, and Fig. 5). Time-lapse observations were made with the same epifluorescence microscope with a stage incubator (Fig. 1 C and Fig. 4).
Quantitation of the fraction of cells with nuclear-localized CFP-PLZF
To quantitate the fraction of cells in a population that displayed predominantly nuclear localization of CFP-PLZF, fields of cells were scored using a completely blind manner. The cells expressing CFP-PLZF were categorized into two classes: those in which CFP-PLZF was predominantly localized in the nucleus (N), and those in which CFP-PLZF was distributed throughout the entire cytoplasm (C). The ratio of the number of cells with nuclear CFP-PLZF among total transfected cells (N/[N + C] x 100) was then calculated to generate the percentage of cells with nuclear-localized CFP-PLZF. This ratio was found to be in good agreement with the qualitative impression of microscopic observations. The values (means ± SD) were determined based on the results obtained in at least two independent transfections, and at least 200 independent cells expressing CFP-PLZF were examined in each experiment.
Immunofluorescence microscopy
Cells were fixed in 4% PFA in PBS at 4°C for 10 min and permeabilized for 10 min in 0.2% Triton X-100 in PBS. Cells were blocked with 1% BSA, and subsequently incubated at RT with primary and secondary antibodies. Primary antibodies were used as follows: mouse monoclonal IgG antibodies to FLAG (Sigma-Aldrich), PLZF (Oncogene Research Products), and cyclin A (Neomarkers); a rabbit pAb to HB-EGF-C (#H1), and a goat pAb to p115 (Santa Cruz Biotechnology, Inc.). Secondary antibodies were used as follows: FITC- and rhodamine-conjugated goat antimouse IgG, rhodamine-conjugated goat antirat IgG, FITC-conjugated goat antirabbit IgG (CHEMICON International), and Alexa® Fluor 568conjugated donkey antigoat IgG (Molecular Probes, Inc.). Some cells were also stained with Hoechst 33258 (Molecular Probes, Inc.). Stained cells were viewed with an epifluorescence microscope (Eclipse TE300; Nikon) (Fig. 1 E, Fig. 6, and Fig. 7) or a confocal microscope (model LSM 510; Carl Zeiss MicroImaging, Inc.) (Fig. 1 B and Fig. 8). The thickness of optical sections was 0.8 µm.
Adenovirus vector construction and infection
Adenovirus vectors carrying genes encoding PLZF and LacZ were prepared using the adenovirus expression vector kit (Takara Biomedicals). Purified, concentrated, and titer-checked viruses were infected to the cells at a multiplicity of infection of 50.
Cell cycle analysis
For DNA staining, cells were fixed in 70% ethanol for 2 h at 4°C and incubated with 0.25 mg/ml RNase for 1 h at 37°C. After being washed, cells were stained with 0.05 mg/ml propidium iodide. Data acquisition was performed with a FACScanTM (Becton Dickinson) flow cytometer. Cell cycle distribution was analyzed with ModFit software (Nippon Becton Dickinson).
TPA treatment of mouse skin
200 µl of 0.1 mM TPA, dissolved in acetone, was applied topically to the shaved back skin of 20-wk-old female C57/BL6 mice every 24 h. After 24 or 48 h, skin samples were harvested as an 8-mm punch biopsy and stored at -80°C until use. For immunoprecipitation, protein was extracted in 1,000 µl lysis buffer with protease inhibitors using a polytron homogenizer.
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Acknowledgments |
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This work is supported by Grants-in-aid for Scientific Research (no. 13670139, 13216057, and 15390097) to S. Higashiyama from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Submitted: 4 March 2003
Accepted: 19 September 2003
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