p90 RSK2 Mediates Antianoikis Signals by both Transcription-Dependent and -Independent Mechanisms
p90 RSK2 Mediates Antianoikis Signals by both Transcription-Dependent and -Independent Mechanisms
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DOI：
10.1128/mcb.01677-12
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发表时间：
2013-07-01
影响因子：
5.3
通讯作者：
Kang, Sumin
中科院分区：
文献类型：
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作者：
Jin, Lingtao;Li, Dan;Kang, Sumin
侵袭性和转移性肿瘤细胞如何逃避失巢凋亡诱导仍不清楚。我们发现，RSK 2的敲低使不同的癌细胞对失巢凋亡诱导敏感，失巢凋亡诱导是通过磷酸化靶点介导的，包括凋亡信号调节激酶1（ASK 1）和环AMP（cAMP）反应元件结合蛋白（CREB）。我们提供的证据表明，RSK 2通过磷酸化S83，T1109和T1326抑制ASK 1，通过一种新的机制，其中磷酸-T1109/T1326抑制ATP与ASK 1的结合，而磷酸-S83减弱ASK 1底物MKK 6的结合。此外，RSK 2-> CREB信号通路通过调节参与细胞死亡调节的蛋白效应物的基因表达提供抗失巢凋亡保护，所述蛋白效应物包括抗凋亡因子蛋白酪氨酸激酶6（PTK 6）和促凋亡因子生长因子3（ING 3）。PTK 6过表达或ING 3敲低以及ASK 1敲低进一步挽救了RSK 2敲低细胞中对失巢凋亡诱导的敏感性增加。这些数据共同表明，RSK 2作为信号整合剂发挥作用，以转录非依赖性和转录依赖性方式向癌细胞提供抗失巢凋亡保护，部分通过ASK 1和CREB进行信号传导，并有助于癌细胞侵袭和肿瘤转移。
How invasive and metastatic tumor cells evade anoikis induction remains unclear. We found that knockdown of RSK2 sensitizes diverse cancer cells to anoikis induction, which is mediated through phosphorylation targets including apoptosis signal-regulating kinase 1 (ASK1) and cyclic AMP (cAMP) response element-binding protein (CREB). We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. Moreover, the RSK2 -> CREB signaling pathway provides antianoikis protection by regulating gene expression of protein effectors that are involved in cell death regulation, including the antiapoptotic factor protein tyrosine kinase 6 (PTK6) and the proapoptotic factor inhibitor-of-growth protein 3 (ING3). PTK6 overexpression or ING3 knockdown in addition to ASK1 knockdown further rescued the increased sensitivity to anoikis induction in RSK2 knockdown cells. These data together suggest that RSK2 functions as a signal integrator to provide antianoikis protection to cancer cells in both transcription-independent and -dependent manners, in part by signaling through ASK1 and CREB, and contributes to cancer cell invasion and tumor metastasis.