Negative and Positive Regulation of MAPK Phosphatase 3 Controls Platelet-derived Growth Factor-induced Erk Activation
Negative and Positive Regulation of MAPK Phosphatase 3 Controls Platelet-derived Growth Factor-induced Erk Activation
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DOI：
10.1074/jbc.m808490200
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发表时间：
2009-02-13
影响因子：
4.8
通讯作者：
Lennartsson, Johan
中科院分区：
文献类型：
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作者：
Jurek, Aleksandra;Amagasaki, Kenichi;Lennartsson, Johan
MAPK磷酸酶（MKP）是使MAPK去磷酸化并由此使MAPK去磷酸化的双特异性磷酸酶。在本研究中，我们提供了血小板衍生生长因子BB（PDGF-BB）调节MKP 3（DUSP 6）的证据，MKP 3被认为是一种对Erk具有高度选择性的磷酸酶。有趣的是，我们观察到Mek受MKP 3的正调控，而Erk本身受负调控。此外，我们发现PDGF受体α或β的激活导致MKP 3以需要Mek激活的方式快速蛋白酶体降解;发现这种前馈机制对于有效的Erk磷酸化至关重要。我们还可以证明，PDGF-BB刺激诱导MKP 3在Ser-174和Ser-300的磷酸化; Ser-174的磷酸化参与PDGF诱导的MKP 3降解，因为该位点的突变稳定了MKP 3。此外，活化的Erk诱导mkp 3表达，导致1-2小时后MKP 3水平恢复，并伴随具有活化的PDGFR α的细胞中Erk的去磷酸化。通过小干扰RNA降低MKP 3水平导致Erk活化和对PDGF-BB的促有丝分裂反应增加。总之，MKP 3是PDGF诱导的Erk磷酸化的重要调节剂，在快速正反馈和随后的负反馈回路中起作用。
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 PDGFR alpha. 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.