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1 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, and 2 First Department of Internal Medicine, Graduate School of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
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Abstract |
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Introduction |
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In contrast to the activation mechanisms for the Raf1-ERK cascade, the regulatory mechanisms of this pathway remain to be investigated. Recently, a family of novel membrane-bound molecules, mammalian Sproutys (mSproutys) and Spreds (Sprouty-related EVH1 domain containing protein), were identified (Hacohen et al. 1998; Minowada et al. 1999; Tefft et al. 1999; Wakioka et al. 2001) as negative regulators for growth factor-induced ERK activation (Casci et al. 1999; Gross et al. 2001; Impagnatiello et al. 2001; Lee et al. 2001; Ozaki et al. 2001; Sasaki et al. 2001; Egan et al. 2002). Sproutys and Spreds share a well-conserved cysteine-rich domain (CR-domain) at the C-terminus. The CR-domain of Sprouty is palmitoylated; therefore, Sprouty localizes in the membrane fraction (Casci et al. 1999; Impagnatiello et al. 2001). The Drosophila Sprouty (dSprouty) gene was identified as an inhibitor of FGF-signaling using genetic screens (Hacohen et al. 1998), and then dSprouty was characterized as a general inhibitor of RTK signaling (Casci et al. 1999; Kramer et al. 1999; Reich et al. 1999). A conserved function between dSprouty and vertebrate Sprouty implicated that they act as negative-feedback regulators of FGF-signaling in embryogenesis (Minowada et al. 1999; Tefft et al. 1999) and angiogenesis (Lee et al. 2001). However, unlike dSprouty, mSproutys can inhibit FGF-induced ERK activation, but they cannot affect EGF-induced ERK activation (Impagnatiello et al. 2001; Egan et al. 2002). On the other hand, Spreds are now considered to be more general inhibitors of receptor tyrosine kinases (RTKs)- and cytokine-induced ERK signaling (Nonami et al. 2004). In addition, unlike Sproutys, expression of Spred-1 seems to be a developmentally regulated inhibitor rather than a negative-feedback suppressor (Nonami et al. 2004).
The CR-domain of Sprouty, and probably Spred, is palmitoylated; thereby, Sprouty and Spred localize in the membrane fraction. Palmitoylated proteins have been shown to be localized in a specific membrane compartment, the so-called lipid raft, or caveola. Caveola are invaginations, 50-100 nm in diameter, of lipid raft that are rich in cholesterol, glycosphingolipids, and glycosylphosphatidylinositol (GPI)-linked molecules (Harris et al. 2002). They are involved in clathrin-independent endocytosis, cholesterol transport, and signal transduction. Impagnatiello et al. (2001) reported that Sprouty-1 and Sprouty-2 are anchored to membranes by palmitoylation and associate with caveolin-1 in perinuclear and vesicular intracellular structures. Cav-1 and Cav-3 are both independently necessary and sufficient to drive caveola formation in heterologous expression systems, whereas Cav-2 requires the presence of Cav-1 for proper membrane targeting and stabilization. It has been proposed that the caveolin family members function as scaffolding proteins (Sargiacomo et al. 1995) to organize and concentrate specific lipids (cholesterol and glycosphingolipids) (Fra et al. 1995; Murata et al. 1995; Li et al. 1996c) and lipid-modified signaling molecules (Src-like kinases, H-Ras, eNOS, and G-proteins) (Garcia-Cardena et al. 1996; Li et al. 1996b; Shaul et al. 1996; Song et al. 1996) within caveola membranes. Each caveolin-interacting protein binds to the same membrane-proximal cytoplasmic region of Cav-1, called the caveolin-scaffolding domain (CSD, residues 82-101) (Li et al. 1996a; Couet et al. 1997); thereby, their enzymatic activity was suppressed.
In this study, we examined the role of caveolin-1 on the ERK-inhibitory activity of Spred-1. We found that Spred-1 and caveolin-1 associated with each other and caveolin-1 synergistically increased the inhibitory effect of Spred-1 for ERK. In the presence of caveolin, a larger amount of Spred-1 was localized in the lipid raft/caveola fraction. Thus, caveolin-1 serves as a scaffold protein for Spred-1.
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Results |
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To define the function of the C-terminal CR domain, we generated a series of deletion constructs and examined the effect on ERK activation. First, we performed a transient reporter assay using HEK293 cells. One of the nuclear targets of ERK is Elk-1, a transcription factor of the Ets family. Thus, activation of ERK can be monitored by measuring the Elk-1-dependent luciferase reporter activity. HEK293 cells were transfected with wild-type or various C-terminal-deletion mutant constructs of Spred-1 and Elk-1 reporter plasmids and then stimulated with EGF for 6 h. As shown in Fig. 1A, the wild-type and 10-amino acid deletion mutant dc10 suppressed ERK activation, while the suppressive function of Spred-1 was strongly impaired in dc26, dc56 and dc80 mutants. Similar results were obtained by monitoring the phosphorylation of ERK. HEK293 cells were transfected with C-terminal-deletion mutants of Spred-1 and GFP-ERK and then stimulated with EGF. The phosphorylation of ERK was suppressed by wild-type and dc10 Spred-1, but not by dc26, 56 or 80 Spred-1. These data indicate that the C-terminal 10 amino acids were dispensable for the Spred-1 function, but the deletion of 26 amino acids severely impaired it.
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Effect of caveolin-1 expression on ERK activation in BaF/kit cells
In human or murine lymphocyte cell lines, caveolae or caveolin has not been found, except for some specific cases (Harris et al. 2002). The BaF/3 cell is a murine pro B cell-derived cell line and does not have endogenous caveolin-1, as shown Fig. 2B. To examine the effect of newly introduced caveolin-1 on the ERK activation and function of Spred-1, we used this cell line. As reported before (Fra et al. 1995), when caveolin-1 was over-expressed by electroporation to BaF-kit cells, caveola were formed (BaF-kit-caveolin-1 cells), as shown in Fig. 2A, and the expression of caveolin-1 was confirmed by Western blotting (Fig. 2B).
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Co-localization of Spred-1 and caveolin-1 on caveola membrane in BaF-kit-caveolin-Spred cells
Next, to clarify the functional relationship between Spred-1 and caveolin-1, we established a cell line expressing wild-type Spred-1 by introducing wild-type Spred-1 cDNA into Ba/F3-kit-caveolin-1 cells with enhanced green fluorescent protein (EGFP) using a bicistronic retrovirus vector, pMY-IRES-EGFP. After establishing clones by limiting dilution, the localization of Spred-1 and caveolin-1 was determined by immunohistochemical staining using confocal microscopy. As shown in Fig. 3A, in BaF-kit-caveolin-Spred-1 cells, Spred-1 and caveolin-1 mostly co-localized at the plasma membrane.
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Synergistic inhibitory effect of caveolin-1 and Spred-1 on ERK activation
Next, to investigate the role of caveolin-1 in the function of Spred-1, Ba/F3-kit-caveolin-1 was infected with the retrovirus vector carrying Spred-1. Since the infected cells expressed both EGFP and Flag-tagged Spred-1, the percentage of infected cells was determined as the EGFP-positive rate by flow cytometry. We have reported that, when Ba/F3-kit cells were cultured in a medium containing IL-3 or SCF, the proportion of control IRES-EGFP-infected cells was not changed; however, that of wild-type Spred-1-infected cells decreased (Nonami et al. 2004). As shown in Fig. 4A,B, while the proportion of control-infected BaF-kit-caveolin-1 cells was not changed, that of wild-type Spred-1-infected BaF-kit-caveolin cells cultured in a medium containing SCF or IL-3 dramatically decreased.
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Discussion |
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We have shown that Spreds localize in the plasma membrane using its C-terminals (Wakioka et al. 2001). It has been reported that Sprouty-1 and Sprouty-2 are anchored to membranes by palmitoylation and associated with caveolin-1 (Impagnatiello et al. 2001). Considering the homology of the C-terminal of Spreds with Sprouty, it is likely that the CR domain of Spreds is also palmitoylated and associates with caveolin-1, like Sproutys. As shown in Fig. 1D,E, when the C-terminal of Spred-1 was deleted, Spred-1 could neither localize in the lipid raft nor associate with caveolin-1. In addition, the C-terminal deletion abrogated its inhibitory function (Fig. 1A,B). On the other hand, caveolin-1 concentrates lipid-modified signaling molecules, such as Ha-Ras (Song et al. 1996) and MEK/ERK, through the caveolin-scaffolding domain (Li et al. 1996b; Couet et al. 1997). It has been reported that caveolae is implicated in the p42/44 MAP kinase pathway (Engelman et al. 1998; Galbiati et al. 1998; Wary et al. 1998; Park et al. 2000). Components of this pathway such as Grb2 (Liu et al. 1996), H-Ras (Song et al. 1996; Rizzo et al. 2001), Raf (Mineo et al. 1996; Hekman et al. 2002), and 14-3-3 proteins (Mineo et al. 1996) are suggested to be localized within caveolae membranes. In our experiment, when Spred-1 was over-expressed in HEK293 cells, accumulation of not only Ras, but also Raf were enhanced in the raft (Fig. 1F). Thus, we propose that Spred-1 is recruited to the lipid raft/caveola and efficiently interacts with Ras and Raf-1 by interacting with caveolin-1, resulting in strong inhibition of Ras/ERK pathway. Therefore, caveolin-1 may function as a scaffold protein for growth factor receptors, Spred-1, and Ras.
When we over-expressed caveolin-1 in BaF-kit cells, which originally do not have caveolin-1, the amount of Spred-1 localized in the lipid raft fraction increased (Fig. 3B). Furthermore, the inhibitory function of Spred-1 was dramatically potentiated by caveolin-1 over-expression (Fig. 4C,D). Since caveolin-1 itself can suppress the activation of ERK, it can be considered that this potentiation is only a result of the additive effect of Spred-1 and caveolin-1. However, considering that caveolin-1 only suppresses the activation of ERK induced by SCF or IL-3 only 60 min after stimulation (Fig. 2B,C), it is highly probable that Spred-1 functions synergistically with Caveolin-1.
There are three Spred family proteins in mammals (Kato et al. 2003). Gene targeting studies demonstrated the important roles of Spred-1 and Spred-2 on hematopoiesis through regulating the signaling of hematopoietic cytokines (Nobuhisa et al. 2004; Nonami et al. 2004; Inoue et al. 2005). As Spred inhibits active-Ras-induced ERK activation, Spred might modulate the unidentified activation steps of Raf by a novel mechanism. However, the details of the mechanism and physiological functions of each member remain to be investigated. Apparently, Spred-1 can function in the cells without caveolin-1 like hematopoietic cells. However, even in caveola-deficient hematopoietic cells, cholesterol-rich membrane Raft is present. Some molecules in the raft may be able to replace the function of caveolin-1 in these cells. A new class of proteins with the ability to alter the morphology and/or function of raft membrane domain (modifiers of raft function (MORFs)) is emerging (Quest et al. 2004). Among them are flotillin-1, flotillin-2, stomatin and raftlin (Saeki et al. 2003). Flotillin-1, 2 and stomatin are the most abundant integral proteins in the human erythrocytes apart from the GPI-anchored proteins. They are present as high-order oligomers, suggesting that flotillins/stomatin act as scaffolding components at the cytoplasmic face of erythrocyte lipid rafts (Salzer & Prohaska 2001). Raftlin is an abundant protein in the lipid raft fraction of B cells, and has been suggested to contribute to the integrity of the raft (Saeki et al. 2003). Since signaling molecules, such as PTK and Ras, are concentrated in the caveola membrane, the localization of Spred-1 in the caveola membrane could facilitate the suppression of Ras-mediated Raf activation. A more precise analysis of interaction between lipid raft/caveola and Spred-1 will uncover the regulatory mechanism of the Ras/Erk pathway on the plasma membrane.
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Experimental procedures |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
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HEK293 cells and the retrovirus packaging cell line Plat-E were maintained in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum (FBS). A murine pro-B cell-derived cell line, Ba/F3, was cultured in an RPMI medium containing 10% FBS and 10% conditioned medium from WEHI-3B cells as a source of IL-3. Ba/F3 cells expressing c-kit (Ba/F3-kit) had been previously established (Nonami et al. 2004). In addition, BaF/kit cells expressing caveolin-1 (Ba/F3-kit-caveolin-1) were established by the same method (Yoshimura et al. 1995).
Plasmids, transfection, and infection
Wild-type Spred-1 was subcloned into pCDNA3 for the 6XMyc epitope tag or pMY-IRES-EGFP for retrovirus infection as described (Sasaki et al. 2001). Caveolin-1 was subcloned into a pcDNA4/To vector. pCDNA3 vectors were transfected into HEK293 cells on 6-well dishes by the calcium-phosphate method. BaF/3-kit cells or Ba/F3-kit-caveolin-1 cells expressing wild-type Spred-1 were established as described (Sasaki et al. 2003) using pMY-IRES-EGFP vectors. Briefly, pMY-IRES-EGFP vectors were transfected into a PLAT-E packaging cell line using the FUGENE6 (Boehringer Mannheim, Mannheim, Germany) to obtain the viruses. Ba/F3-kit cells or Ba/F3-kit-caveolin-1 cells (2 x 105 cells) were infected with viruses on a RetroNectin (Takara Bio Inc., Shiga, Japan)-coated plate for 24 h in the presence of 5 ng/mL IL-3. Cells were washed three times with PBS, resuspended in RPMI-10% FBS containing 5 ng/mL IL-3 or 100 ng/mL SCF, and incubated for the indicated times. Then, cells (1 x 104) were analyzed for EGFP fluorescence on a COULTER EPICS-XL flow cytometer.
Immunochemical analysis
Immunoprecipitation and immunoblotting were done as described (Sasaki et al. 2001). We used anti-Myc, anti-c-kit, anti-STAT5, anti-ERK2 (Santa Cruz Biotechnology, Santa Cruz, CA, USA), anti-Flag (SIGMA, St. Louis, MO, USA), anti-phospho STAT5, anti-phospho ERK2, and anti-Caveolin-1 (Cell Signaling). For detecting lipid raft, we used horseradish peroxidase (HRP)-conjugated cholera toxin B (CTB) (Sigma). Anti-Spred-1 antibodies were prepared by immunizing rabbits. Immunofluorescence staining was done as described (Saeki et al. 2003) using Alexa546-conjugated rabbit anti-mouse IgG and Alexa633-conjugated anti-rabbit IgG and observed by confocal microscopy using an LSM 5 Pascal (Carl Zeiss).
Electron microscopy
BaF-kit-caveolin-1 cells were fixed with 0.4% gluteraldehyde (GA) and 2% paraformaldehyde in a 0.1 M cacodylate buffer (PH 7.4) containing 3.4% sucrose and 3 mM CaCl2 at room temperature (RT) for 30 min. They were then blocked with 0.05 M NH4Cl in PBS at RT for 10 min and washed with PBS. Next, they were dehydrated sequentially with 50, 70, 90, and 95% ethanol for 10 min each and substituted with LR white/absolute and ethanol (1 : 1) for 2 h and LR white for 16 h. These samples were embedded in LR/white with benzoin ethylether and incubated at 50 °C for 24 h. Ultrathin-sectioned samples were stained with anti-caveolin antibody (polyclonal) and then Protein A gold 15 nm (EY-LAB, San Mateo, CA, USA) and fixed with 2.5% Ga and 0.5% OSO4. They were stained with uranyle acetate and observed by JEM 2000EX electron microscope with accelerating voltage of 100 kv.
Subcellular fractionation of HEK293 cells
Cell fractionation was performed as described (Saeki et al. 2003). Briefly, HEK293 cells, Ba/F3-kit-Spred-1 cells and Ba/F3-kit-caveolin-Spred-1 cells (1 x 107 cells) were lyzed in 2.5 mL of a Triton X-100 lysis buffer (50 mM Tris-HCl pH 8.0, 10 mM MgCl2, 150 mM NaCl, 20 mM NaF, 1 mM Na3VO4, 1% Triton X-100, 5 mM 2-mercaptoethanol, 5% glycerol, and a protease inhibitor cocktail; Roche-Boehringer), incubated on ice for 1 h, and mixed with an equal volume of 80% sucrose in buffer A (50 mM Tris-HCl pH 7.4, 50 mM NaCl, 10 mM MgCl2, 1 mM Na3VO4, and a protease inhibitor cocktail). The mixture was transferred to a centrifuge tube and sequentially overlaid with 5 mL of 35% sucrose in buffer A and 1.2 mL of 5% sucrose in buffer A. After centrifugation at 100 000 g at 4 °C for 16 h, the fractions between the 5% and 35% sucrose interface (raft fraction) and between the 35% and 80% sucrose interface (non-raft fraction) were collected.
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Acknowledgements |
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Footnotes |
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* Correspondence: E-mail: yakihiko{at}bioreg.kyushu-u.ac.jp
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References |
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Received: 29 March 2005
Accepted: 4 June 2005
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