Zama Takeru, Aoki Ryoko, Kamimoto Takahiro, Inoue Koichi, Ikeda Yasuo, Hagiwara Masatoshi
Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan.
J Biol Chem. 2002 Jun 28;277(26):23919-26. doi: 10.1074/jbc.M200838200. Epub 2002 Apr 16.
Stress-activated protein kinase (SAPK) pathway-regulating phosphatase 1 (SKRP1) has been identified as a member of the mitogen-activated protein kinase (MAPK) phosphatase (MKP) family that interacts physically with the MAPK kinase (MAPKK) MKK7, a c-Jun N-terminal kinase (JNK) activator, and inactivates the MAPK JNK pathway. Although these findings indicated that SKRP1 contributes to the precise regulation of JNK signaling, it remains to be elucidated how SKRP1 is integrated into this pathway. We report that SKRP1 also plays a scaffold role for the JNK signaling, judged by the following observations. SKRP1 selectively formed the stable complexes with MKK7 but not with MKK4 and biphasically regulated the MKK7 activity and MKK7-induced gene transcription in vivo. Co-precipitation analysis between SKRP1 and MKK7-activating MAPKK kinases (MAPKKKs) revealed that SKRP1 also interacted with the MAPKKK, apoptosis signal-regulating kinase 1 (ASK1), but not with MAP kinase kinase kinase 1 (MEKK1). Consistent with these findings, SKRP1 expression increased the ASK1-MKK7 complexes in a dose-dependent manner and specifically enhanced the activation of MKK7 by ASK1. Thus, our findings are, to our knowledge, the first evidence to show that an MKP also functions as a scaffold protein for the particular MAPK signaling.
应激激活蛋白激酶（SAPK）途径调节磷酸酶1（SKRP1）已被鉴定为丝裂原活化蛋白激酶（MAPK）磷酸酶（MKP）家族的成员，它与MAPK激酶（MAPKK）MKK7（一种c-Jun氨基末端激酶（JNK）激活剂）发生物理相互作用，并使MAPK JNK途径失活。尽管这些发现表明SKRP1有助于JNK信号的精确调节，但SKRP1如何整合到该途径中仍有待阐明。我们报告称，基于以下观察结果判断，SKRP1在JNK信号传导中也发挥支架作用。SKRP1选择性地与MKK7形成稳定复合物，而不与MKK4形成复合物，并在体内双相调节MKK7活性和MKK7诱导的基因转录。SKRP1与激活MKK7的MAPKK激酶（MAPKKKs）之间的共沉淀分析表明，SKRP1也与MAPKKK凋亡信号调节激酶1（ASK1）相互作用，但不与丝裂原活化蛋白激酶激酶激酶1（MEKK1）相互作用。与这些发现一致，SKRP1的表达以剂量依赖的方式增加了ASK1-MKK7复合物，并特异性增强了ASK1对MKK7的激活。因此，据我们所知，我们的发现是首个表明一种MKP也可作为特定MAPK信号传导的支架蛋白的证据。
