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Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-ß-dependent responses in human mesangial cells¹

Department of Pediatrics, The Feinberg School of Medicine, Northwestern University, Chicago Illinois, USA; and
^* Department of Medicine/Hypertension and Nephrology, Vanderbilt University, Nashville, Tennessee, USA

²Correspondence: The Feinberg School of Medicine, Northwestern University, W-140, Pediatrics, 303 E Chicago Ave., Ward 12-112, Chicago IL, 60611-3008, USA. E-mail: hayashida{at}northwestern.edu

SPECIFIC AIMS

To determine the mechanism by which ERK activity enhances TGF-ß-induced collagen expression in human mesangial cells, the effects of ERK inhibition on Smad signaling were evaluated. Based on our findings that suggest differential phosphorylation of sequences in receptor-regulated Smads (R-Smads), roles for different phospho-acceptor sites in R-Smad were evaluated using site-specific mutated Smad3 constructs.

PRINCIPAL FINDINGS

1. TGF-ß induction of Smad3 transcriptional activity is decreased by ERK inhibition
Previously we reported that TGF-ß1 activates human mesangial cell extracellular signal-regulated kinase (ERK) and c-Jun NH₂-terminal kinase (JNK), but not p38 MAP kinase. Further, TGF-ß stimulation of p3TP-Lux, a construct that contains TGF-ß-responsive elements and AP-1 consensus sites derived from a portion of the type 1 plasminogen activator inhibitor promoter, is decreased by cotransfected ERK1 dominant negative mutant construct in mesangial cells. To rule out the possibility that the inhibitory effect of ERK blockade on TGF-ß1-stimulated transcription is mediated by the AP-1 site, we analyzed Smad-dependent transcription using a heterologous transcription assay with Gal4-Smad3. ERK blockade by a biochemical inhibitor, U0126 (25 µM), or overexpression of an ERK1 dominant negative mutant decreased ligand-dependent trans-activation of Gal4-Smad3 (fold induction over the control: 2.84 vs. 1.48 x or 2.35 vs. 1.65x, respectively). Thus, TGF-ß-initiated transcription through ERK activity does not require interaction with AP-1 consensus sites.

2. ERK blockade inhibits TGF-ß stimulation of R-Smad serine phosphorylation and hetero-multimerization with Smad4
R-Smad phosphorylation by the type I TGF-ß receptor at the extreme carboxyl-terminal site (SS^pXS^p) has been shown to be critical for hetero-multimerization with Smad4. Total serine phosphorylation of Smad2/3 detected by anti-phosphoserine antibodies in Smad2/3-immunoprecipitated samples was decreased by pretreatment with a MEK/ERK inhibitor, PD98059 (10 µM, Fig. 1 , third panel). The decrease in phosphorylation of Smad2/3 paralleled a reduction in Smad2/3 association with Smad4. The inhibitory effect was significant only when cells were exposed to the inhibitor at least 30 min before stimulation with TGF-ß1, even though ERK activity was suppressed immediately after addition of the inhibitor. Some degree of ERK activity is detectable in our cells even after incubation in serum-free conditions for 20 h. These results imply that Smads require a certain level of ERK activity in order to be maximally activated by TGF-ß.

View larger version (32K): [in this window] [in a new window]   Figure 1. Effect of ERK blockade on Smad phosphorylation and association. After 20 h in serum-free medium, cells were preincubated with either 10 µM PD98059, 25 µM U0126, or DMSO as a vehicle for 60 min, then treated with 1.0 ng/mL TGF-ß1 for 30 min. Cell lysates were immunoprecipitated with anti-Smad2/3 antibody (N-19) and analyzed for total serine phosphorylation (third panel). The blots were stripped and reblotted with anti-Smad2/3 antibody (second and bottom panels). Whole cell lysates were analyzed in parallel to determine carboxyl-terminal Smad2 phosphorylation (top panel). Graph shows relative change for TGF-ß signal by MEK/ERK inhibitors (solid bar, PD98059, shaded bar, U0126) to control (open bar, DMSO) after correction for loading.

3. The effect of ERK inhibition on Smad signaling is cell type-specific
Results from previous studies, which report that the interaction between ERK and Smad could alter signaling in either positive or negative manner, suggest that the phenomenon varies according to the cell type studied. Therefore, we performed the same experiments with mouse mammary epithelial NMuMG cells. ERK inhibition did not affect Smad2/3 phosphorylation or association with Smad4 in those cells. Gal4-Smad3 trans-activation by TGF-ß was not affected in NMuMG cells.

4. R-Smad phosphorylation is differentially regulated by TGF-ß-induced ERK activity
In addition to the directly receptor-regulated carboxyl-terminal SS^pXS^p motif, recent reports suggest that other phospho-acceptor sites in R-Smad may play regulatory role in TGF-ß signaling. Pretreatment with two MEK/ERK inhibitors, PD98059 (10 µM) or U0126 (25 µM), resulted in decreased total serine phosphorylation of Smad2/3 (Fig. 1 , third panel). On the other hand, the inhibitor did not affect phosphorylation on carboxyl-terminal SS^pXS^p motif as determined by immunoblotting with an antibody that specifically recognizes Smad2 phosphorylated on this site (Fig. 1 , top panel). These results suggest that TGF-ß phosphorylates R-Smad outside of the carboxyl-terminal SS^pXS^p motif and that ERK mediates for that specific phosphorylation.

5. TGF-ß phosphorylates R-Smad linker region serines through ERK activity
Next we evaluated TGF-ß stimulation of differential R-Smad phosphorylation. In the R-Smad linker region, there are several proline-rich repeats that are a consensus for ERK-mediated phosphorylation sites. Wild-type Smad3 introduced into the mesangial cells showed a basal level of serine phosphorylation. TGF-ß1 treatment induced further phosphorylation of wild-type Smad3, and both the basal and stimulated phosphorylation levels were proportionally reduced when the cells were pretreated with the MEK/ERK inhibitor. The Flag-N-Smad3A construct, in which three serines in the carboxyl-terminal SSXS motif are replaced with alanines, showed serine phosphorylation upon TGF-ß1 treatment, supporting the presence of a phosphorylation site outside of the carboxyl terminus. ERK blockade decreased the phosphorylation of Smad3A induced by TGF-ß1. In contrast, ERK inhibition did not decrease TGF-ß1-stimulated phosphorylation of Smad3 EPSM in which all of the putative ERK-dependent phospho-acceptor sites in the linker region of Smad3 are mutated to alanines (6x His Smad3 ESPM). These data indicate that TGF-ß stimulates phosphorylation of Smad linker region serines in addition to the classically described carboxyl-terminal serines in Smad3 and that the linker region phosphorylation is mediated by TGF-ß-dependent ERK activation.

6. ERK induction of –0.42(I) collagen promoter activity is mediated by the linker region phospho-acceptor site
To investigate the functional role for ERK-mediated Smad activation in transcriptional activation of the type I collagen promoter in human mesangial cells, we overexpressed a constitutively active MEK1 mutant (caMEK) along with the 2(I) collagen promoter reporter and analyzed the effects of caMEK on basal and TGF-ß-dependent reporter activity (Fig. 2 A). TGF-ß1 treatment stimulated the promoter by 1.9 ± 0.5-fold. caMEK enhanced basal and ligand-dependent reporter activity (1.9±0.5 and 4.6±1.5x, respectively). Consistent with our previous observations, transfection of Smad3A or Smad3 EPSM resulted in elevated basal collagen promoter activity. Ligand-dependent activation of the collagen promoter reporter was blunted by overexpression of the Smad3A mutant (1.3±0.1x), which blocks receptor-mediated activation of endogenous Smad3, whereas caMEK induction of the reporter activity was not affected by the Smad3A construct (2.3±0.7x). Thus, caMEK does not act through the carboxyl-terminal phosphorylation site of Smad3. In contrast, overexpression of the Smad3EPSM mutant had no effect on ligand-dependent reporter gene activation (2.4±0.4x), but blocked caMEK-dependent stimulation of the reporter activity (1.2±0.5x). Expression levels of Smad3 construct as determined by immunoblot with antibodies for appropriate tagged protein were not significantly affected by cotransfection of caMEK (Fig. 2B ). No significant variance was detected in absolute ß-galactosidase expression among the conditions either (Fig. 2C ). Therefore, the changes in 2(I) collagen promoter activities were not due to differences in Smad3 construct expression or transfection efficiency in general. Taken together, these findings indicate that the direct effects of TGF-ß and those mediated through ERK act through different phospho-acceptor sites on the Smad molecule to enhance the expression of this TGF-ß target gene.

View larger version (23K): [in this window] [in a new window]   Figure 2. Role for differential phosphorylation of Smad3 in 2(I) collagen promoter activity. A) Constructs expressing either Smad3A, Smad3EPSM, or their empty vector were transfected and TGF-ß induction of cotransfected –0.42(I) collagen promoter activity was evaluated in either the presence or absence of overexpressed constitutively active MEK (caMEK). Construct that expresses caMEK or its empty vector was transfected to directly activate ERK pathway. Three hours later, cells were treated with 1.0 ng/mL TGF-ß1 or vehicle for 24 h. Data shown are the mean ± SE of luciferase activity corrected for ß-galactosidase activity from a representative experiment performed in triplicate. Similar results were obtained from 3 independent experiments. Open bars, controls; solid and shaded bars; TGF-ß1-treated cells in the absence or presence of ca MEK, respectively. B) Aliquots of the lysates from transfected cells were subjected to electrophoresis and the expression levels of Smad3 constructs were determined with an antibody for the tagged protein anti-flag and –His for Smad3A and Smad3EPSM, respectively. C) Expression levels of ß-galactosidase (x10-2, mean±SE) are shown in the table.

CONCLUSIONS AND SIGNIFICANCE

Whereas the TGF-ß receptors classically transduce the signal through serine/threonine kinase activity that phosphorylates the Smad proteins, evidence has accumulated that TGF-ß1 also activates MAP kinase pathways and a complex interaction involving several MAP kinase pathways in regulating Smad activity has been suggested. Direct activation of Smads by MEKK family members was reported. Some of the events initiated by TGF-ß could be Smad independent.

The effect of interaction between ERKs and Smads is the subject of some controversy, with data suggesting that such an interaction either enhances or inhibits downstream events. There are several potential explanations for this differential response. One is cellular origin: cells of mesenchymal origin appear to show synergy in ERK-Smad interaction whereas epithelial cells generally appear to show inhibition. In support of this notion, we did not see the same inhibitory effect by ERK blockade in mouse mammary epithelial NMuMG cells, as opposed to mesangial cells that are of mesenchymal origin. A second possibility is the method of ERK activation by TGF-ß itself as opposed to by overexpression of activated molecules upstream of ERK, such as oncogenic Ras. Although receptor phosphorylation of R-Smad on the carboxyl-terminal SS^pXS^p motif is critical for activation of TGF-ß signaling, possible regulatory roles for several other phosphorylation sites mediated by several pathways, such as ERK MAP kinases, protein kinase C, or Ca²⁺ calmodulin-dependent protein kinase II, have been suggested. The net effect of these events on Smad activity could be enhancing or inhibitory. A previous report indicated that the Smad3 EPSM construct (lacking linker region phospho-acceptor sites) prevented oncogenic Ras-driven inhibition of Smad nuclear localization. In other experimental systems, however, overexpression of constitutively active Raf or oncogenic N-Ras^K61 failed to affect Smad localization or transcriptional activity. In our system, TGF-ß phosphorylates the R-Smad linker region by TGF-ß-induced ERK activity, and this additional phosphorylation is required for optimal Smad activation (Fig. 3 a).

View larger version (18K): [in this window] [in a new window]   Figure 3. Schematic diagram showing the possible mechanism of the cross-talk between the ERK and Smad pathways.

Direct activation of ERK by caMEK induced 2(I) collagen promoter activity additive to TGF-ß stimulation. We cannot exclude the possibility that caMEK acts on the promoter independent of Smads. However, since caMEK was unable to initiate the transcription in the presence of Smad3EPSM with its linker region phospho-acceptor sites mutated, ERK activity likely works on the promoter at least partially through R-Smad activity (Fig. 3b ). Therefore, our findings provide a model in which differential R-Smad phosphorylations, one mediated directly through the receptor and the other via activation of ERK pathway, cooperatively regulate TGF-ß-responsive reporter promoter activity.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0037fje; doi: 10.1096/fj.03-0037fje

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