Canonical and Kinase Activity-Independent Mechanisms for Extracellular Signal-Regulated Kinase 5 (ERK5) Nuclear Translocation Require Dissociation of Hsp90 from the ERK5-Cdc37 Complex
Canonical and Kinase Activity-Independent Mechanisms for Extracellular Signal-Regulated Kinase 5 (ERK5) Nuclear Translocation Require Dissociation of Hsp90 from the ERK5-Cdc37 Complex
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DOI：
10.1128/mcb.01246-12
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发表时间：
2013-04-01
影响因子：
5.3
通讯作者：
Lizcano, Jose M.
中科院分区：
文献类型：
--
作者：
Erazo, Tatiana;Moreno, Ana;Lizcano, Jose M.
丝裂原活化蛋白（MAP）激酶细胞外信号调节激酶5（ERK 5）在细胞增殖中起着至关重要的作用，调节基因转录。ERK 5具有独特的C-末端尾，其含有转录激活结构域，并且通过磷酸化转录因子和自身作为转录共激活因子来激活转录。然而，调节其核质运输的分子机制尚不清楚。我们已经使用串联亲和纯化来鉴定与ERK 5相互作用的蛋白质。我们发现，ERK 5与Hsp 90-Cdc 37分子伴侣在静息细胞中相互作用，抑制Hsp 90或Cdc 37导致ERK 5泛素化和蛋白酶体降解。有趣的是，细胞ERK 5的激活诱导Hsp 90从ERK 5-Cdc 37复合物中解离，导致ERK 5核转位和转录激活，其机制需要在其C-末端尾部的自磷酸化。因此，活性ERK 5不再对Hsp 90或Cdc 37抑制剂敏感。Cdc 37过表达还诱导Hsp 90解离和保留转录活性的激酶失活形式的ERK 5的核转位。这是第一个显示ERK 5转录活性不需要激酶活性的例子。由于Cdc 37与ERK 5合作促进细胞增殖，Cdc 37过表达（如在某些癌症中发生的）可能代表ERK 5调节肿瘤增殖的一种新的非经典机制。
The mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase 5 (ERK5) plays a crucial role in cell proliferation, regulating gene transcription. ERK5 has a unique C-terminal tail which contains a transcriptional activation domain, and activates transcription by phosphorylating transcription factors and acting itself as a transcriptional coactivator. However, the molecular mechanisms that regulate its nucleocytoplasmatic traffic are unknown. We have used tandem affinity purification to identify proteins that interact with ERK5. We show that ERK5 interacts with the Hsp90-Cdc37 chaperone in resting cells, and that inhibition of Hsp90 or Cdc37 results in ERK5 ubiquitylation and proteasomal degradation. Interestingly, activation of cellular ERK5 induces Hsp90 dissociation from the ERK5-Cdc37 complex, leading to ERK5 nuclear translocation and activation of transcription, by a mechanism which requires the autophosphorylation at its C-terminal tail. Consequently, active ERK5 is no longer sensitive to Hsp90 or Cdc37 inhibitors. Cdc37 overexpression also induces Hsp90 dissociation and the nuclear translocation of a kinase-inactive form of ERK5 which retains transcriptional activity. This is the first example showing that ERK5 transcriptional activity does not require kinase activity. Since Cdc37 cooperates with ERK5 to promote cell proliferation, Cdc37 overexpression (as happens in some cancers) might represent a new, noncanonical mechanism by which ERK5 regulates tumor proliferation.