Abstract
MAPK phosphatases (MKPs) are dual specificity phosphatases that dephosphorylate and thereby inactivate MAPKs. In the present study, we provide evidence that platelet-derived growth factor BB (PDGF-BB) regulates MKP3 (DUSP6), which is considered to be a phosphatase highly selective for Erk. Intriguingly, we observed that Mek is positively regulated by MKP3, whereas Erk itself is negatively regulated. In addition, we found that activation of PDGF receptor alpha or beta leads to a rapid proteasomal degradation of MKP3 in a manner that requires Mek activation; this feed-forward mechanism was found to be essential for efficient Erk phosphorylation. We could also demonstrate that PDGF-BB stimulation induces phosphorylation of MKP3 at Ser-174 and Ser-300; phosphorylation of Ser-174 is involved in PDGF-induced MKP3 degradation, since mutation of this site stabilized MKP3. Moreover, activated Erk induces mkp3 expression, leading to restoration of MKP3 levels after 1-2 h and a concomitant dephosphorylation of Erk in cells with activated PDGFRalpha. Reducing the MKP3 level by small interfering RNA leads to an increased Erk activation and mitogenic response to PDGF-BB. In conclusion, MKP3 is an important regulator of PDGF-induced Erk phosphorylation acting in both a rapid positive feed-forward and a later negative feed-back loop.
Highlights
Erk phosphorylation, which is compatible with the observation that after the initial MKP3 degradation, the protein level remained low with only a minor transient increase after 2 h of platelet-derived growth factor BB (PDGF-BB) stimulation (Fig. 2A, lower panel)
MKP3 normally seen after 2 h of PDGF-BB stimulation did not occur in the presence of U0126, and we found a decrease in MKP3 level (Fig. 2E)
In cells with enhanced Erk activation after silencing of MKP3, we observed a significant increase in the mitogenic response to PDGF-BB in both PAE/PDGFR␣ and PAE/ PDGFR cells, in accordance with a critical role of Erk in mediating proliferative signals (Fig. 6)
Summary
MKP3 Regulates PDGF-induced Erk Activation to control different MAPK pathways [14]. Erk phosphorylation, which is compatible with the observation that after the initial MKP3 degradation, the protein level remained low with only a minor transient increase after 2 h of PDGF-BB stimulation (Fig. 2A, lower panel). Both PDGFR␣- and PDGFR-expressing cells; after 1–2 h of was no longer able to induce a robust Erk activation (Fig. 2D).
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