CRBM, CNRS FRE2593, 1919 route de Mende, 34293 Montpellier Cedex 05, France
Author for correspondence (e-mail: serge.roche{at}crbm.cnrs.fr)
Accepted 13 May 2005
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Summary |
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Key words: Src, Abl, PDGF Receptor, Rac, Mitogenesis, Signaling
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Introduction |
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Recently, we and others have identified the cytoplasmic tyrosine kinase Abl as an additional Src mitogenic substrate for PDGF-induced Myc expression and DNA synthesis (Plattner et al., 1999; Furstoss et al., 2002a
). Abl is a non-receptor tyrosine kinase distinct from the Src family, with a dual nuclear and cytoplasmic localization. Nuclear Abl has been implicated in DNA damage response and cell growth inhibition. By contrast, the cytoplasmic kinase has a role in cytoskeletal rearrangement and the promotion of DNA synthesis (Pendergast, 2002
). Abl function implicates Src-induced phosphorylation of Y245 and Y412 for both dorsal ruffles formation and mitogenesis (Furstoss et al., 2002a
). Furthermore, Abl can be regulated by phosphatidylinositol 4,5-bisphosphate (PI4,5P2) for PDGF-induced chemotaxis (Plattner et al., 2003
). The molecular mechanism by which PI4,5P2 modulates catalytic activity in vivo is still obscure. Abl has a related kinase, Arg, that is only present in the cytoplasm and that is also activated by PDGF in a Src-dependent manner (Plattner et al., 2004
). Although not yet unidentified, Arg may have a specific function distinct to Abl (Plattner et al., 2004
).
Downstream targets of Abl during mitogenesis are largely unknown. Recently Pendergast et al. identified the phospholipase C1 as a novel Abl substrate (Plattner et al., 2003
). Although PLC
was shown as an important mediator of PDGF-induced DNA synthesis (Valius and Kazlauskas, 1993
; Roche et al., 1996
), it is not known whether its phosphorylation by Abl plays a role in this biological response. Similarly, Sini et al. identified the GEF SOS1 as an Abl substrate for Rac activation in vitro, but the biological significance of this phosphorylation was not provided (Sini et al., 2004
). Again, whether SOS1 phosphorylation and Rac activation are required for Abl mitogenic function are not known. In this report, we addressed the role of small GTPases of the Rho family in the Abl mitogenic function and we show that Rac is an important mediator of cytoplasmic Abl for PDGF-induced Myc expression and DNA synthesis. Furthermore we identified Jun N-terminal kinases (JNK) and NADPH oxidase (Nox) activities as two important elements of the Abl-Rac signaling cascade for mitogenesis.
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Materials and Methods |
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Cell culture, transfection, infection and DNA synthesis.
Abl.Arg+/+ 3T3, Abl/Arg/3T3, Abl/Arg/3T3 expressing Abl-NLS, NIH3T3, cell culture, transfection and retroviral infections were described previously (Furstoss et al., 2002a; Furstoss et al., 2002b
). For biochemistry, quiescent cells were treated or not with 20 ng/ml of PDGF-BB (UBI) at the indicated times before lysis. DNA synthesis was analysed by BrdU incorporation assays (Furstoss et al., 2002a
). Actinic structure was vizualized using rhodamine phaloidine (Furstoss et al., 2002a
). For cell treatment, inhibitors (or vehicule) were added to the medium 2 hours before stimulation. The percentage of transfected cells that incorporated BrdU was calculated by the following formula:
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Biochemistry and Myc expression
Cells lysis, immunoprecipitation and western blotting were described previously (Furstoss et al., 2002a). In vitro kinase assays for PDGFR and MKK have been described (Roche et al., 1998
; Raingeaud et al., 1996
). GTPase activities were measured as described (Charrasse et al., 2002
) and precipitated using GST fusion proteins containing Ras-binding domain of RalGDS (Ras) (Herrmann et al., 1996
), CRIB domain of PAK (Rac), Cdc42-binding domain of WASP (Cdc42) and RhoA-binding domain of Rhotekin (Rho) (C. Gauthier-Rouviere, CRBM, Montpellier, France). MAPK1 and 2 and JNK activities were assessed by western blotting of the whole cell-lysates using antibodies specific to the phosphorylated kinases.
Myc mRNA level was measured by both northern blotting (Furstoss et al., 2002a) and by real-time quantitative PCR. The following primers were used: Myc forward 5'-CGGAGGAAAACGACAAGAGG-3' and reverse 5'-GTGCTCGTCTGCTTGAATGG-3'; ß-tubulin forward 5'-CGGACAGTGTGGCAACCAGATCGG-3' and reverse 5'-TGGCCAAAAGGACCTGAGCGAACGG-3'. Data were normalized using RT-PCR of the ß-tubulin mRNA as an index of cDNA content after reverse transcription. The results of 2-5 independent experiments have been averaged and the mean±s.d. are shown.
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Results |
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We next addressed whether Rac is a downstream effector to other Src mitogenic substrates, e.g. Stat3 and Shc. We first checked that Rac impinges on the Src mitogenic pathway. As expected, PDGF-induced Rac activation was dependent upon SFK activities (C. Bénistant and S.R., unpublished); furthermore, RacV12 gave a significant mitogenic rescue in cells with inactive SFK although the rescuing effect was not as strong as the one obtained with Abl-PP-K (not shown). We next confirmed that expression of the non-phosphorylatable allele of Src substrates inhibited mitogenesis (Fig. 2B) (Blake et al., 2000; Bowman et al., 2001
). Nevertheless, RacV12 could not overcome those inhibitions. By contrast, constitutive expression of Myc largely restored mitogenic signaling. Note that in our conditions, Myc did not induce mitogenesis in the absence of growth factors, furthermore this was specific to the Src pathway as Myc could not alleviate the G1 block induced by RasN17 (not shown) (Barone and Courtneidge, 1995
). From this set of data we concluded that Rac is a specific effector of the Src substrate Abl for mitogenesis.
The Rac mitogenic rescue requires a JNK and a Nox pathway
We next searched the underlying mechanism for Rac mitogenic rescue. To this end, we took advantage of active RacL61 alleles with point mutation in the effector loop, known to interact with specific effectors (e.g. F37A, D38N, Y40C, N52L, K132E) (Bishop and Hall, 2000). Although a single mutation may affect several signaling cascades, we felt that this may bring some insight into the nature of downstream elements of the Abl-Rac pathway. Similarly to RacV12, all RacL61 alleles were expressed under a retroviral promoter for low expression. In these conditions they induced low Rac activity in cells (Fig. 4E) so that they did not induce DNA synthesis on their own (not shown). We then analyzed their capacity to alleviate the Abl-PP-K G1 block in PDGF-stimulated cells. First, we found that RacL61 was as active as RacV12 in restoring mitogenic signaling (70% of the PDGF response) (Fig. 4A). RacL61/F37A was also fully active. This mutant has been described to affect the capacity of Rac to activate Stat3 (Simon et al., 2000
), indicating that this signaling protein may not impinge on that pathway. In agreement with this notion, we did not observe any reduction in PDGF-induced Stat3 activation in Abl-deficient cells (not shown). By contrast, mutants with reduced JNK (RacL61/Y40C and N52L) (Lambert et al., 2002
) or NADPH oxidase (Nox) activation (RacL61/D38N and K132E) (Nisimoto et al., 1997
; Puceat et al., 2003
) were biologically defective. Again these rescuing effects were not specific to PDGF as similar data were obtained with serum (Fig. 4A). Such defects were not due to a lower enzymatic activity: all of these Rac alleles were as active as RacL61 on their ability to bind GTP in vivo (Fig. 4E). These data suggest that Rac mitogenic function implicates both a JNK and a Nox-dependent pathway. Accordingly, we found that cell treatment with low doses of a JNK inhibitor (SP600125) or compounds that inhibit superoxide accumulation (catalase and diphenylene iodonium, DPI) strongly reduced the RacL61 mitogenic rescue (Fig. 4B). By contrast, SB203580 had no effect, precluding any involvement of p38 kinases
and ß in that biological response (Fig. 4B). Since RacL61/N52L and RacL61/Y40C also exhibited reduced ability to activate p70 S6 kinase (Lambert et al., 2002
), we checked whether the observed biological activity was due to an impairment in JNK activation. We found that co-expression of active JNK kinases MKK4 or MKK7 induced strong JNK activity in vivo (Fig. 4F) and corrected the biological defect observed with RacL61/N52L (Fig. 4C). Similarly, we found that RacL61/D38N rescued mitogenesis when co-expressed with an activator of Nox activity. For this purpose, we used the constitutively active allele p47SD (Wu et al., 2003
) of the Nox2 organizer subunit Noxo2 (originally called p47phox). This allele consists of a replacement of three serines on Noxo2 known to be critically phosphorylated for Nox2 activation, with aspartic acid residues to mimic phosphoserines. This triple mutant has been shown to cause constitutive activation of the NADPH oxidase in a cell-free reconstitution system (Ago et al., 1999
) and in endothelial cells (Wu et al., 2003
). We also found that p47SD induced superoxide production in fibroblasts, although Nox2 was not detected in these cells (not shown). This may reflect the capacity of Noxo2 to activate additional members of the Nox family, including Nox1 and Nox3 (Banfi et al., 2003
; Cheng et al., 2004
). When analysed in our mitogenic assay, we found that p47SD compensated for the inability of RacL61/D38N by rescuing mitogenesis at a similar level to RacL61 (Fig. 4D). Collectively, these data indicate that the loss of mitogenic rescue induced by N52L and D38N mutations is probably due to an impairment in JNK and Nox activation, respectively.
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Abl regulates PDGF-induced JNK and Nox activation
We next addressed whether Abl regulates JNK activity in PDGF-stimulated cells. As shown in Fig. 6A, PDGF-induced a modest but significant JNK activation. This enzymatic response was largely reduced in Abl/Arg-deficient cells. Accordingly, JNK regulates PDGF-induced Ser63 phosphorylation of Jun (not shown) and this was also reduced in Abl/Arg/ cells. Reintroduction of the cytoplasmic Abl allele Abl-NLS significantly rescued JNK activation and Jun phosphorylation in agreement with a role of Abl in this signaling cascade (Fig. 6A). By contrast, Abl deficiency did not affect PDGF-induced early activation of MAPK 1 and 2, showing specificity.
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Myc is an important target for JNK and Nox mitogenic functions
The impact of Rac on Abl-induced Myc expression was next addressed in PDGF-stimulated cells. This growth factor induced a large increase in Myc mRNA levels within 1 hour of stimulation. As previously reported, this response was largely impaired in Abl/Arg-deficient cells and this was largely compensated by Abl expression in the cytoplasm (Furstoss et al., 2002a). Here we found that Myc induction was also restored by retroviral expression of RacV12 (Fig. 7A). This gain of expression was dependent upon a defect in Abl signaling as it was not observed in control cells. We also found that the Myc induction was dependent upon JNK and Nox activities as it was sensitive to specific pharmacological inhibitors (SP600125 for JNK, DPI and N-acetylcysteine NAC for Nox) (Fig. 7B). Interestingly, cell treatment with both types of inhibitors prevented the Myc response, which suggests that JNK and Nox activities are important regulators of Myc mRNA induction. Finally, we evaluated the impact of theses signaling cascades on mitogenesis. We found that the dominant interfering mutant DN-MKK4 (Wu et al., 2003
) blocked cells in G1 in agreement with an important function of JNK for DNA synthesis (Weston and Davis, 2002
; Manning and Davis, 2003
) (Fig. 7C). Importantly, this inhibition was overcome by Myc co-expression confirming this transcription factor as an important target for its mitogenic function. Similarly, we investigated the requirement of Nox activity during mitogenesis (Fig. 7D). For this purpose, we took advantage of the dominant negative allele of the Noxa2, p67V204A (Han et al., 1998
). This mutant still binds active Rac but it has lost the capacity to associate with the catalytic subunit (Nisimoto et al., 1997
). As shown in Fig. 7B, p67V204 induced a G1 block and this inhibition was alleviated by Myc expression. Therefore JNK and Nox are important regulators of mitogenesis and Myc is an important target.
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Discussion |
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Our report identified JNK as a downstream effector of the Abl mitogenic pathway. Indeed various elements of the JNK cascade, including MKK4, JNK-1 and Jun, play important functions for the promotion of cell growth (Weston and Davis, 2002). While JNK has been originally described as a mediator of a stress response (Weston and Davis, 2002
), we believe that a modest activation is used by growth factors for DNA synthesis. Previous reports argued against an important role for JNK in Rac transforming activity (Joneson et al., 1996
; Lamarche et al., 1996
). These data were obtained by expressing a high level of RacL61 so that DNA synthesis was observed in the absence of any growth factors. Therefore JNK requirement may be bypassed by a compensatory signaling or the low JNK activity induced by those Rac alleles was sufficient to ensure the cell response. More recently, the group of Der implicated JNK for mitogenic signaling including cyclin D expression (Westwick et al., 1997
). This is consistent with our data implicating JNK in the Abl-Rac signaling cascade initiated by growth factors. Therefore JNK may be required for Rac signaling at least during mitogenesis. Our report also suggests that Myc is an important target of JNK in this pathway. Myc induction primarily involves mRNA stabilization during early stimulation of growth factors (Blanchard et al., 1985
). This raises the idea that JNK may impact on Myc messenger stability. Additionally, JNK may also affect the rate Myc transcription. This notion would be consistent with a role of JNK in phosphorylation and activation of the AP-1 complex Jun:JunD for expression of this gene (Iavarone et al., 2003
). Therefore Abl may also impact on Myc through activation of an AP-1 complex.
Nox is the other effector identified in the Abl-Rac mitogenic signaling. Accordingly, reactive oxygen species (ROS) are important transducers of the proliferative signals induced by growth factors (Lambeth, 2004) or by active Rac (Joneson and Bar-Sagi, 1998
). Although the Nox involved in fibroblast mitogenic signaling has not been identified, it may probably involve Nox1. Indeed, Nox1 is expressed in fibroblasts and it has been implicated in cell growth promotion induced by growth factors (Kwon et al., 2004
) and oncoproteins (Mitsushita et al., 2004
). Furthermore, Nox1-3 can be activated by Noxo2 and Noxa2 subunits (Banfi et al., 2003
; Cheng et al., 2004
). Whatever the nature of the NADPH oxidase involved in this pathway, our rescue experiments indicate that Myc is an important effector of ROS mitogenic function. The molecular mechanism by which Nox impacts on Myc is, however, not known. It is generally assumed that ROS reversibly inactivates phosphatases for sustained signaling. For example ROS generated by Rac inhibits low molecular weight protein tyrosine phosphatase for sustained p190RhoGAP phosphorylation and Rho downregulation (Nimnual et al., 2003
). Similarly, overexpressed Nox1 also inactivates the lipid phosphatase PTEN, allowing growth factors to induce robust PI3K and Akt activation (Kwon et al., 2004
). Therefore one may surmise that ROS generated upon growth factor stimulation inactivates a specific phosphatase for Myc expression. Finally, the partial rescue (70%) obtained with a constitutively active Rac suggest that Abl may also signal outside Rac. Therefore additional Abl mitogenic effectors must be expected.
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Acknowledgments |
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Footnotes |
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