PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation.
PKCε phosphorylates MIIP and promotes colorectal cancer metastasis through inhibition of RelA deacetylation.
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PKCepsilon 磷酸化 MIIP，并通过抑制 RelA 脱乙酰化促进结直肠癌转移。
DOI：
10.1038/s41467-017-01024-2
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发表时间：
2017-10-16
影响因子：
16.6
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Chen T;Li J;Xu M;Zhao Q;Hou Y;Yao L;Zhong Y;Chou PC;Zhang W;Zhou P;Jiang Y
表皮生长因子受体信号转导参与了核因子-κB的激活。然而，NF-κB信号通路的核心转导通路RelA/p65在表皮生长因子受体激活下的具体调控机制仍有待进一步阐明。在这里，我们发现，表皮生长因子刺激诱导依赖于PKCε的迁移和侵袭抑制蛋白(MIIP)在Ser303的磷酸化；这种磷酸化促进MIIP和RelA在细胞核中的相互作用，MIIP通过阻止组蛋白脱乙酰酶6(HDAC6)介导的RELA去乙酰化，从而增强RELA的转录活性，促进肿瘤转移。同时，PP1作为一种磷酸酶参与了MIIP-S303的去磷酸化，其表达水平与肿瘤细胞的转移能力呈负相关。此外，临床研究表明MIIP-S303的磷酸化水平与结直肠癌的转移和预后有关。这些发现揭示了表皮生长因子对NF-κB的精确调控的未知机制，并强调了核MIIP在肿瘤转移中的关键作用。在结直肠癌中，EGFR信号与转移有关。在这里，作者揭示了一种机制，即EGF刺激诱导MIIP磷酸化，导致MIIP与RelA相互作用，从而防止RelA去乙酰化，增强转录活性，促进转移。
EGFR signaling is implicated in NF-κB activation. However, the concrete mechanisms by which the core transducer of NF-κB signaling pathway, RelA/p65 is regulated under EGFR activation remains to be further clarified. Here, we show that EGF stimulation induces PKCε-dependent phosphorylation of migration and invasion inhibitory protein (MIIP) at Ser303; this phosphorylation promotes the interaction between MIIP and RelA in the nucleus, by which MIIP prevents histone deacetylase 6 (HDAC6)-mediated RelA deacetylation, and thus enhances transcriptional activity of RelA and facilitates tumor metastasis. Meanwhile PP1, which functions as a phosphatase, is found to mediate MIIP-S303 dephosphorylation and its expression level inversely correlates with metastatic capability of tumor cells. Moreover, clinical analyses indicate the level of MIIP-S303 phosphorylation correlates with colorectal cancer (CRC) metastasis and prognosis. These findings uncover an unidentified mechanism underlying the precise regulation of NF-κB by EGF, and highlight the critical role of nuclear MIIP in tumor metastasis. In colorectal cancer, EGFR signalling is implicated in metastasis. Here, the authors unravel a mechanism through which EGF stimulation induces MIIP phosphorylation, leading to MIIP interacting with RelA—this prevents RelA deactylation and enhances transcriptional activity, facilitating metastasis.
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MIIP 单倍体不足诱导染色体不稳定并促进结直肠癌肿瘤进展
DOI：
10.1002/path.4823
发表时间：
2017-01
期刊：
The Journal of pathology
影响因子：
--
作者：
Sun Y;Ji P;Chen T;Zhou X;Yang D;Guo Y;Liu Y;Hu L;Xia D;Liu Y;Multani AS;Shmulevich I;Kucherlapati R;Kopetz S;Sood AK;Hamilton SR;Sun B;Zhang W
通讯作者：
Zhang W
影响因子：
5.3
作者：
Hoberg, JE;Popko, AE;Mayo, MW
通讯作者：
Mayo, MW
影响因子：
64.5
作者：
Kawahara TL;Michishita E;Adler AS;Damian M;Berber E;Lin M;McCord RA;Ongaigui KC;Boxer LD;Chang HY;Chua KF
通讯作者：
Chua KF
影响因子：
8
作者：
Ji, P.;Smith, S. M.;Zhang, W.
通讯作者：
Zhang, W.
影响因子：
64.5
作者：
Ogryzko, VV;Schiltz, RL;Nakatani, Y
通讯作者：
Nakatani, Y