Sub-family selective actions in the ability of Erk2 MAP kinase to phosphorylate and regulate the activity of PDE4 cyclic AMP-specific phosphodiesterases
Sub-family selective actions in the ability of Erk2 MAP kinase to phosphorylate and regulate the activity of PDE4 cyclic AMP-specific phosphodiesterases
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DOI：
10.1038/sj.bjp.0703636
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发表时间：
2000-10-01
影响因子：
7.3
通讯作者：
Houslay, MD
中科院分区：
文献类型：
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作者：
Baillie, GS;MacKenzie, SJ;Houslay, MD
1在完整细胞和体外表达的环核苷酸磷酸二酯酶（PDE）的PDE 4 B和PDE 4C同工酶与PDE 4D同工酶一样，显示为细胞外信号调节激酶Erk 2的C末端催化单元磷酸化提供底物（p42（MAPK））。2相反，PDE 4A同工酶不为C-通过Erk2.3产生的末端催化单元磷酸化突变PDE 4酶显示Erk 2磷酸化发生在单个，同源丝氨酸残基位于PDE 4催化单元的C-末端部分。4 PDE 4长型同工酶被Erk 2磷酸化显著抑制。5短型丝氨酸残基位于PDE 4催化单元的C-末端部分。PDE 4 B2型同工酶被Erk 2磷酸化激活。6 PDE活性的这些功能变化通过Erk 2磷酸化的靶丝氨酸突变为带负电荷的氨基酸，表皮生长因子（EGF）与表达短PDE 4 B2同工酶的细胞相比，在转染表达长PDE 4 B1同工酶的COS 1细胞中，激发引起了环AMP水平的截然相反的变化。8我们认为，PDE 4酶可能为整合细胞中的环AMP和Erk信号转导提供了一个关键点，其中4种基因编码的酶是对Erk 2作用不敏感，或者可以被激活或抑制。这表明PDE 4同工酶具有不同的功能作用，从而证实了使用PDE 4亚家族或同工酶选择性抑制剂可以产生不同的治疗益处的观点。
1 Expressed in intact cells and in vitro, PDE4B and PDE4C isoenzymes of cyclic nucleotide phosphodiesterase (PDE), in common with PDE4D isoenzymes, are shown to provide substrates for C-terminal catalytic unit phosphorylation by the extracellular signal-regulated kinase Erk2 (p42(MAPK)).2 In contrast, PDE4A isoenzymes do not provide substrates for C-terminal catalytic unit phosphorylation by Erk2.3 Mutant PDE4 enzymes were generated to show that Erk2 phosphorylation occurs at a single, cognate serine residue located within the C-terminal portion of the PDE4 catalytic unit.4 PDE4 long-form isoenzymes were markedly inhibited by Erk2 phosphorylation.5 The short-form PDE4B2 isoenzyme was activated by Erk2 phosphorylation.6 These functional changes in PDE activity were mimicked by mutation of the target serine for Erk2 phosphorylation to the negatively charged amino acid, aspartic acid.7 Epidermal growth factor (EGF) challenge caused diametrically opposed changes in cyclic AMP levels in COS1 cells transfected to express the long PDE4B1 isoenzyme compared to cells expressing the short PDE4B2 isoenzyme.8 We suggest that PDE4 enzymes may provide a pivotal point for integrating cyclic AMP and Erk signal transduction in cells with 4 genes encoding enzymes that are either insensitive to Erk2 action or may either be activated or inhibited. This indicates that PDE4 isoenzymes have distinct Functional roles, giving credence to the notion that distinct therapeutic benefits may accrue using either PDE4 subfamily or isoenzyme-selective inhibitors.