Compartment-specific regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) by ERK-dependent and non-ERK-dependent inductions of MAPK phosphatase (MKP)-3 and MKP-1 in differentiating P19 cells
Compartment-specific regulation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) by ERK-dependent and non-ERK-dependent inductions of MAPK phosphatase (MKP)-3 and MKP-1 in differentiating P19 cells
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DOI：
10.1042/0264-6021:3520701
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发表时间：
2000-12-15
影响因子：
4.1
通讯作者：
Schlegel, W
中科院分区：
文献类型：
--
作者：
Reffas, S;Schlegel, W
在小鼠胚胎干细胞系P19中研究了有丝分裂原活化蛋白激酶（MAPKs）及其上游激活剂MAPK激酶（MAPKK或MEK）的激活以及MKP-1（CL 100/3CH 134）和MKP-3（Past 1/rVH 6）双特异性MAPK磷酸酶（MKP）的诱导。在聚集和维甲酸触发的神经元分化的7天诱导过程中。ERK（细胞外信号调节激酶），但不是JNK（c-Jun N-末端激酶），被发现激活与双相动力学：第一个短暂的阶段，在第1和第2天，其次是第二次激活，持续到出现的神经元表型。MEK激活与ERK激活同时出现。细胞溶质MKP-3与ERK活化平行诱导，诱导依赖于ERK活化，如使用MEK-1抑制剂PD 98059所示。相反，核MKP-1在48小时瞬时升高，与ERK失活一致，独立于ERK活性。如细胞分级分离所示，活化的ERK易位到细胞核。ERK特异性磷酸酶MKP-1和MKP-3的互补诱导允许精确和独立地控制细胞质和细胞核ERK活性，这很可能是正确诱导复杂的细胞分化程序所需的。
Activation of mitogen-activated protein kinases (MAPKs), their upstream activators MAPK kinases (MAPKKs or MEKs) and induction of MKP-1 (CL100/3CH134) and MKP-3 (Pyst1/rVH6) dual-specificity MAPK phosphatases (MKPs) were studied in the mouse embryonic stem cell line P19 during the 7 day induction of neuronal differentiation triggered by aggregation and retinoic acid. ERK (extracellular signal-regulated kinase), but not JNK (c-Jun N-terminal kinase), was found activated with biphasic kinetics: a first transient phase on days 1 and 2, followed by a second activation that was sustained until the appearance of a neuronal phenotype. MEK activation appeared coincident with ERK activation. Cytosolic MKP-3 was induced in parallel to ERK activation, the induction being dependent on ERK activation, as was shown using the MEK-1 inhibitor PD98059. In contrast, nuclear MKP-1 was transiently elevated at 48 h, coincident with ERK inactivation and independently of ERK activity. As shown by cell fractionation, activated ERK is translocated to the nucleus. The complementary induction of ERK-specific phosphatases MKP-1 and MKP-3 permits precise and independent control of cytoplasmic and nuclear ERK activity, most probably required to properly induce a complex cellular programme of differentiation.