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Article |
Address correspondence to Stefan Offermanns, Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. Tel.: 49-6221-54-8246/7. Fax: 49-6221-54-8549. email: Stefan.Offermanns{at}urz.uni-heidelberg.de
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Abstract |
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Key Words: semaphorins; axonal growth cone; Erk; tyrosine phosphorylation
Abbreviations used in this paper: HEK, human embryonic kidney; His, histidine; LARG, leukemia-associated RhoGEF; OTK, off-track; PDZ, PSD-95/DIg/Z0-1; VSV, vesicular stomatitis virus glycoprotein.
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Introduction |
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Considerable progress has recently been made in understanding the signaling mechanisms used by plexin-B1. Several small GTPases of the Rho family have been involved in plexin-B1mediated signaling. Plexin-B1 can directly interact with the GTP-bound form of Rac (Rohm et al., 2000b; Vikis et al., 2000; Driessens et al., 2001). This interaction inhibits Rac-dependent processes by sequestering the active form of Rac (Vikis et al., 2002). In addition, plexin-B1 forms a complex with PSD-95/Dlg/ZO-1 (PDZ)RhoGEF/leukemia-associated RhoGEF (LARG) through its carboxyl-terminal PDZ domain-binding motif (Aurandt et al., 2002; Driessens et al., 2002; Hirotani et al., 2002; Perrot et al., 2002; Swiercz et al., 2002). Binding of Sema4D to plexin-B1 and activation of chimeric plexin-B2 stimulates PDZ-RhoGEF/LARG activity, resulting in activation of RhoA (Aurandt et al., 2002; Perrot et al., 2002; Swiercz et al., 2002). Dominant-negative forms of PDZ-RhoGEF/LARG block Sema4D-induced growth cone collapse in hippocampal neurons (Swiercz et al., 2002) as well as neurite retraction in PC12 cells (Perrot et al., 2002), thereby demonstrating the role of RhoGEF-mediated RhoA activation in Sema4D-induced cytoskeletal changes. It has been suggested that Rnd1, which binds to the cytoplasmic part of plexin-B1, can promote the interaction between plexin-B1 and PDZ-RhoGEF (Oinuma et al., 2003). However, it remains unclear how the activity of plexin-B1 and its downstream effectors is regulated by Sema4D. It was recently shown that in epithelial cells, plexin-B1 associates with the scatter factor 1/hepatocyte growth factor receptor Met. Binding of Sema4D to plexin-B1 can control the invasive growth of these cells by stimulating the tyrosine kinase activity of Met, which results in the tyrosine phosphorylation of both plexin-B1 and Met (Giordano et al., 2002).
Here, we show that plexin-B family members can also interact with the transmembrane tyrosine kinase ErbB-2. Binding of Sema4D to plexin-B1 induces ErbB-2 activation, which results in the tyrosine phosphorylation of both plexin-B1 and ErbB-2. ErbB-2mediated phosphorylation of plexin-B1 is required for Sema4D-induced RhoA activation as well as for plexin-B1mediated axonal growth cone collapse. This finding suggests that ErbB-2 is part of a signaling complex that is required for plexin-Bmediated regulation of cellular functions by semaphorins.
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Results |
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Expression of an ErbB-2 mutant in which tyrosine 1248 was mutated to phenylalanine (ErbB-2(Y1248P)) completely blocked Sema4D-induced phosphorylation of endogenous ErbB-2 as well as of transfected ErbB-2 at tyrosine 1248 (Fig. 5 A). Consequently, ErbB-2(Y1248P) blocked Sema4D-induced phosphorylation of Shc and also greatly reduced Erk activation by Sema4D (unpublished data). However, the ErbB-2(Y1248P) mutant had no effect on the activation of RhoA produced by Sema4D (Fig. 5 A). Furthermore, although the MEK1/2 inhibitor P98059 blocked Sema4D-induced Erk activation (unpublished data), it failed to affect plexin-B1mediated activation of RhoA.
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Effect of Rac1 and Rnd1 on surface expression and tyrosine phosphorylation of plexin-B1
Both the active GTP-bound form of Rac as well as the small GTPase Rnd1 have been shown to interact with the cytoplasmic portion of plexin-B1 and to modulate plexin-B1 signaling (Vikis et al., 2000, 2002; Oinuma et al., 2003). As described previously, active Rac increased the surface expression of plexin-B1 in cells transfected with plexin-B1 alone (Vikis et al., 2002). However, Rac1 had no effect on surface expression of plexin-B1 in cells coexpressing plexin-B1 and PDZ-RhoGEF (Fig. 6 A). In contrast, Rnd1 increased surface expression of plexin-B1 only in cells coexpressing plexin-B1 and PDZ-RhoGEF (Fig. 6, A and B), which is consistent with the idea that Rnd1 promotes the interaction between plexin-B1 and PDZ-RhoGEF (Oinuma et al., 2003). We asked whether Rac1 or Rnd1 would modulate Sema4D-induced tyrosine phosphorylation of plexin-B1. Interestingly, both constitutively active Rac as well as Rnd1 enhanced Sema4D-induced plexin-B1 phosphorylation in cells coexpressing plexin-B1 and PDZ-RhoGEF (Fig. 6 C). The observed increase in tyrosine phosphorylation of plexin-B1 in the presence of active Rac1 occurred in the absence of any effect of Rac on the surface expression of plexin-B1. In contrast, the increased tyrosine phosphorylation of plexin-B1 in the presence of Rnd1 concurred with and may result from an increased membrane localization of plexin-B1 in cells expressing Rnd1.
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ErbB-2 and Met are involved in Sema4D-induced axonal growth cone collapse
To test whether or not ErbB-2 is involved in the biological effects of Sema4D, we studied its role in plexin-B1mediated axonal growth cone collapse in hippocampal neurons (Swiercz et al., 2002). ErbB-2, which is widely expressed in the central nervous system (Gerecke et al., 2001), was found to be expressed in axonal growth cones of primary hippocampal neurons cultured from E17 rat embryos (Fig. 8, A and B). Based on the finding that Sema4D induced an autophosphorylation of ErbB-2 in HEK293 cells, we tested if ErbB-2 underwent autophosphorylation in response to Sema4D in axonal growth cones of hippocampal neurons. Staining of neurons with an antibody specific for phosphorylated tyrosine 1248 revealed that Sema4D-induced activation of ErbB-2 occurred mainly in the central domain of the growth cone (Fig. 8 B). To test if Met is also expressed in axonal growth cones and becomes activated upon exposure to Sema4D, we stained hippocampal neurons with antibodies recognizing Met phosphorylated at tyrosine residues 1234 and 1235. Sema4D induced phosphorylation of Met in the entire growth cone (Fig. 8 C).
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To test the involvement of receptor tyrosine kinases in Sema4D-induced axonal growth cone collapse, we transfected hippocampal neurons with dominant-negative mutants of ErbB family members and Met lacking their cytoplasmic domains. The C-terminal mutants of ErbB-2 as well as of Met did not alter basal outgrowth of neurites from hippocampal neurons (unpublished data). However, growth cone collapse induced by Sema4D was almost completely abolished in neurons expressing a
C-terminal mutant of ErbB-2 (Fig. 10, A and B). In contrast, in neurons expressing
C-terminal mutants of ErbB-1, ErbB-3, ErbB-4, or a control plasmid, Sema4D significantly decreased the number of axons demonstrating growth cones (Fig. 10 B). Interestingly, a
C-terminal mutant of Met also interfered with Sema4D-induced growth cone collapse (Fig. 10 B).
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Discussion |
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Plexin-B1 has previously been shown to associate with an unidentified tyrosine kinase activity, which can phosphorylate plexin-B1 in vitro (Tamagnone et al., 1999). Genetic data indicate that the Drosophila melanogaster protein off-track (OTK), which is structurally related to receptor kinases, can functionally interact with D. melanogaster plexin-A. Biochemical analysis suggests that OTK coimmunoprecipitates with mammalian plexins including plexin-B1 (Winberg et al., 2001). The functional significance of these findings is not clear because OTK and its mammalian orthologues are unlikely to be enzymatically active (Mossie et al., 1995; Park et al., 1996). More recent studies have shown that the receptor tyrosine kinase Met associates with plexin-B1. Binding of Sema4D to plexin-B1 stimulates the intrinsic tyrosine kinase activity of Met, resulting in the phosphorylation of both receptors and the Met substrate Gab1 (Giordano et al., 2002). Although this paper implicates Met in Sema4D-induced effects on epithelial cell invasive growth, it remained unknown whether or not Met is required for the Sema4D-induced activation of Rho via the plexin-B1/RhoGEF complex.
Our data indicate that after activation, plexin-B1 can also functionally interact with ErbB-2 and that ErbB-2mediated phosphorylation of plexin-B1 is required for signaling of plexin-B1 via RhoGEF proteins. Sema4D-induced tyrosine phosphorylation of plexin-B1 and subsequent RhoA activation were only slightly reduced in the presence of a dominant-negative form of Met. In addition, the Met tyrosine kinase inhibitor K252a had no effect on plexin-B1 phosphorylation in response to Sema4D, indicating that Met is not necessarily required for plexin-B1 activation. In contrast, phosphorylation of plexin-B1 and Sema4D-induced RhoA activation were highly sensitive to the ErbB-specific tyrosine kinase inhibitor AG1478 and to dominant-negative ErbB-2, thereby suggesting that the tyrosine kinase activity of ErbB-2 is involved in ligand-dependent plexin-B1 phosphorylation. This finding is consistent with our finding that plexin-B family members and ErbB-2 can specifically associate.
ErbB-2 is unique among the ErbB family members as it has no known ligand and can be activated only in trans by ErbB-1, ErbB-3, and ErbB-4 or other tyrosine kinases like Jak2 (Olayioye et al., 2000; Yamauchi et al., 2000; Yarden and Sliwkowski, 2001). Recent structural data show that the extracellular portion of ErbB-2 exists in an extended configuration that very likely interferes with ligand binding (Burgess et al., 2003). Therefore, it appears unlikely that Sema4D can directly act on ErbB-2. Consistent with this, we did not observe any direct binding of Sema4D to ErbB-2, nor did we see an activation of ErbB-2 in the absence of plexin-B1. This observation indicates that Sema4D activates ErbB-2 indirectly through plexin-B1. However, the mechanisms through which Sema4D-bound plexin-B1 activates ErbB-2, and in turn becomes phosphorylated, is still not clear. An involvement of other ErbB family members appears unlikely because dominant-negative mutants of ErbB-1, ErbB-3, or ErbB-4 have no effect on Sema4D-induced activation of plexin-B1. Given that ErbB-2 and plexin-B1 associate even in the absence of ligands, it is conceivable that Sema4D-induced clustering of plexin-B1 results in the formation of plexin-B1/ErbB-2 heterooligomers, which then allow ErbB-2 to dimerize and to become activated.
Sema4D-induced activation of ErbB-2 kinase activity also results in the autophosphorylation of ErbB-2. Interestingly, the pattern of ErbB-2 tyrosine residues phosphorylated in response to Sema4D was different from that induced by EGF. In contrast to EGF, Sema4D did not induce phosphorylation of tyrosine residue 1112, which has been shown to provide a docking side for the ubiquitin ligase c-Cbl (Klapper et al., 2000). Binding of c-Cbl to ErbB-2 enhances ubiquitination and degradation of ErbB-2 (Klapper et al., 2000; Levkowitz et al., 2000). Therefore, lack of phosphorylation of ErbB-2 at tyrosine 1112 in response to Sema4D may reduce the propensity of ErbB-2 to become degradated after activation. In addition, Sema4D-induced phosphorylation of tyrosine 1139 occurred with much lower potency than phosphorylation of tyrosine 1248, whereas EGF-induced phosphorylation of both tyrosine residues occurred with very similar potency. These differences between EGF and Sema4D with regard to the phosphorylation of ErbB-2 support the view that both stimuli use different mechanisms and probably also different kinases for ErbB-2 phosphorylation.
Sema4D-induced phosphorylation of tyrosine 1248 and tyrosine 1139, which recruit Shc and Grb2, resulted in the activation of the Erk pathway. However, inhibition of Sema4D-induced Shc phosphorylation and Erk activation using an ErbB-2 mutant lacking tyrosine 1248 or by inhibition of MEK1/2 did not affect Sema4D-induced plexin-B1 phosphorylation and subsequent RhoA activation. This result indicates that phosphorylation of ErbB-2 and activation of downstream signaling pathways is not required for plexin-B1mediated activation of RhoA. Consistent with this finding, EGF-induced ErbB-2 phosphorylation and activation did not result in plexin-B1 phosphorylation and RhoA activation. However, we observed that EGF can inhibit Sema4D-induced plexin-B1 phosphorylation in a concentration-dependent manner. This inhibition is most likely due to the ability of EGF to sequester ErbB-2, making it unavailable to support Sema4D-induced plexin-B1 activation. This finding indicates that plexin-B1 and the EGF receptor ErbB-1 interact with the same pool of ErbB-2 and that also other factors that use ErbB-2mediated signaling pathways may interfere with plexin-B1 activation by Sema4D.
The small GTPases Rac and Rnd1 have been shown to interact with the cytoplasmic portion of plexin-B1 and to enhance plexin-B1mediated signaling (Vikis et al., 2002; Oinuma et al., 2003). Constitutively active Rac is able to increase the surface localization of plexin-B1 in a heterologous expression system as well as to increase its affinity for Sema4D (Vikis et al., 2002). However, active Rac had no effect on plexin-B1 surface expression in HEK293 cells coexpressing plexin-B1 and PDZ-RhoGEF (Fig. 6). In contrast, Rnd1 increased surface expression of plexin-B1 in cells coexpressing plexin-B1 and PDZ-RhoGEF, which is consistent with the idea that Rnd1 promotes the interaction of plexin-B1 and PDZ-RhoGEF (Oinuma et al., 2003). We found that Rnd1 and active Rac also increase Sema4D-induced tyrosine phosphorylation of plexin-B1. Rac-induced increase in tyrosine phosphorylation of plexin-B1 appeared to be stronger than the effect of Rac on surface expression of plexin-B1. This observation suggests that binding of active Rac promotes plexin-B1 activation by increasing the affinity for Sema4D (Vikis et al., 2002) or by other mechanisms that facilitate ligand-induced phosphorylation of plexin-B1. Our data support the view that active Rac is able to modulate plexin-B1mediated signaling.
The observation that Sema4D is able to indirectly activate ErbB-2 and to induce Erk activation raises the interesting possibility that signaling pathways downstream of ErbB-2 mediate some of the biological effects exerted by Sema4D and other potential ligands for plexin-B family members. Besides its role in tumor progression (Holbro et al., 2003), ErbB-2 has been shown to play an important role in various morphogenetic processes during development (Citri et al., 2003). Interestingly, several human fetal tissues like brain, lung, liver, and kidney have been shown to express ErbB-2 as well as plexin-B1 (Coussens et al., 1985; Maestrini et al., 1996). Based on the ability of plexin-B1 to mediate ErbB-2 activation, it will be interesting to explore the potential role of a functional interaction between plexin-B1 and ErbB-2 in tumor progression as well as in various developmental processes.
Recently, the receptor tyrosine kinase Met has been implicated in plexin-B1 signaling. Our data indicate that the relative contribution of Met to plexin-B1mediated effects may be cell specific. For example, in HEK293 cells, Sema4D-induced plexin-B1/RhoGEF activation does not necessarily require Met, whereas ErbB-2 is strictly essential. However, in developing primary hippocampal neurons, Sema4D-induced axonal growth cone collapse could be blocked by dominant-negative mutants of both ErbB-2 and Met, and both tyrosine kinases became phosphorylated in axonal growth cones upon exposure of neurons to Sema4D. This finding suggests that both tyrosine kinases may be involved in morphogenetic effects induced by Sema4D in developing neurons, which is consistent with the finding that plexin-B1 associates with Met (Giordano et al., 2002) as well as with ErbB-2, as shown here, and can signal through both receptor tyrosine kinases. Although an interaction between ErbB-1 and Met has been reported (Jo et al., 2000), a direct interaction between Met and ErbB-2 has not been described yet. Although we have been unable to coimmunoprecipitate both proteins in HEK293 cells, one cannot rule out the possibility that Met and ErbB-2 exist in a heterooligomeric complex with plexin-B1.
In summary, we show that plexin-B family members associate with ErbB-2 and that Sema4D is able to activate ErbB-2 indirectly via plexin-B1. Sema4D may exert some of its activities by downstream signaling of ErbB-2. However, plexin-B1/RhoGEFmediated activation of RhoA only requires phosphorylation of plexin-B1 by ErbB-2. These results provide novel insight into signaling pathways used by semaphorins and plexins and open new vistas for their cellular effects.
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Materials and methods |
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Alkaline phosphatase assay
At 48 h after transfection with VSV-tagged plexin-B1 alone or together with RhoGEF and/or small GTPases, COS7 cells were treated with primary anti-VSV antibody diluted in DME (Invitrogen) containing 5% horse serum for 2 h at 4°C. Cells were washed, fixed with 4% PFA for 10 min, and incubated with the AP-linked antimouse antibody. AP assay reagent A (Gene Hunter Corporation) was used to visualize AP activity.
Purification of Sema4D on (6)His affinity column
Medium from HEK293 cells transfected with His-Sema4D in pBK-CMV vector containing Sema3A signal peptide for secretion was collected 48 h after transfection and purified on a HisTrap Kit following the manufacturer's instructions (Amersham Biosciences).
Determination of activated Rho
The amount of activated RhoA was determined as described previously (Swiercz et al., 2002) by precipitation with a fusion protein consisting of GST and the Rho-binding domain of Rhotekin, as described by Ren and Schwartz (2000).
Erk and Shc phosphorylation studies
HEK293 cells were transfected with plexin-B1 and PDZ-RhoGEF. 48 h after transfection, cells were starved for 12 h and treated for 30 min with purified Sema4D. Cells were lysed, and lysates were separated using SDS-PAGE and transferred on nitrocellulose membrane (Schleicher & Schuell). Phospho-Erk and phospho-Shc were detected by using specific antiphospho-Erk (Santa Cruz Biotechnology, Inc.) and antiphospho-Shc[Y317] (Cell Signaling Technology) antibodies.
Growth cone collapse, immunocytochemistry, and image processing
At 24 h after transfection, neurons were treated with medium derived from either mock-transfected or (myc)Sema4D-transfected HEK293 cells for 1 h at 37°C. Neurons were fixed with 4% PFA and used for immunocytochemistry experiments using fluorescently-conjugated secondary antibodies (Dianova). TRITC-labeled phalloidin was used to detect actin filaments in growth cones. Neurons were scored for the presence of growth cones as described previously (Swiercz et al., 2002). Immunoreactivity for the expressed proteins was analyzed and photographed using a laser-scanning confocal microscope (model TCS AOBS; Leica) using the following objectives: HCXPLAPO 63x/1.32-0.60 oil and HC PL FLUOTAR 20x/0.50. All images were acquired similarly at RT with the same laser output to directly compare the fluorescence signal intensities. Images were processed with the confocal image analysis software package (TCS AOBS; Leica) and imported as TIFF files into Adobe Illustrator® 10.0. In colocalization studies, various fluorophores were scanned in the sequential mode to completely rule out potential overlap of fluorescence spectra.
Online supplemental material
Fig. S1 shows the expression of ErbB family members and Met in HEK 293 cells. Shown are Western blots of reverse transcriptase polymerase chain reaction.
Details regarding the expression plasmids, antibodies, and reagents used for this study are available at http://www.jcb.org/content/full/jcb.200312094/DC1.
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Acknowledgments |
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R. Kuner is a recipient of an Emmy-Noether scholarship of the Deutsche Forschungsgemeinschaft (DFG). This work was supported by the DFG. The authors declare no conflict of interest.
Submitted: 11 December 2003
Accepted: 13 May 2004
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