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首页> 外文期刊>Molecular and Cellular Biology >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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Canonical and Kinase Activity-Independent Mechanisms for Extracellular Signal-Regulated Kinase 5 (ERK5) Nuclear Translocation Require Dissociation of Hsp90 from the ERK5-Cdc37 Complex

机译：胞外信号调节激酶5（ERK5）核易位的规范和激酶活性独立机制需要从ERK5-Cdc37复杂的Hsp90解离。

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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.
机译：丝裂原激活蛋白（MAP）激酶细胞外信号调节激酶5（ERK5）在细胞增殖，调节基因转录中起关键作用。 ERK5具有独特的C末端尾巴，其中包含一个转录激活域，并通过使转录因子磷酸化并充当转录共激活因子来激活转录。但是，尚不清楚调节其核质运输的分子机制。我们已经使用串联亲和纯化来鉴定与ERK5相互作用的蛋白质。我们显示，ERK5与静息细胞中的Hsp90-Cdc37伴侣相互作用，并且对Hsp90或Cdc37的抑制导致ERK5泛素化和蛋白酶体降解。有趣的是，细胞ERK5的激活通过需要在其C末端尾部进行自磷酸化的机制，诱导Hsp90从ERK5-Cdc37复合体解离，从而导致ERK5核易位和转录激活。因此，活性ERK5对Hsp90或Cdc37抑制剂不再敏感。 Cdc37过表达还诱导Hsp90解离和ERK5激酶失活形式的核易位，保留了转录活性。这是第一个显示ERK5转录活性不需要激酶活性的例子。由于Cdc37与ERK5协同促进细胞增殖，因此Cdc37的过度表达（如某些癌症中的发生）可能代表ERK5调节肿瘤增殖的新的非经典机制。

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