PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase.
PHLPP2 suppresses the NF-κB pathway by inactivating IKKβ kinase.
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DOI：
10.18632/oncotarget.1774
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发表时间：
2014-02-15
期刊：
影响因子：
--
通讯作者：
Georgescu MM
中科院分区：
文献类型：
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作者：
Agarwal NK;Zhu X;Gagea M;White CL 3rd;Cote G;Georgescu MM
NF-κB 生长通路在许多癌症中被组成性激活，但在大多数情况下其激活机制尚不清楚。我们发现 PHLPP2 与 IKKβ 激酶相互作用，降低其磷酸化以及随后癌细胞中 NF-κB 的激活。 PHLPP2 在神经胶质瘤和结直肠癌中逐渐丢失，并根据细胞中 IKKβ 的表达发挥真正的肿瘤抑制因子的作用。从生理学角度来说，生长因子激活 IKKβ 需要形成 Bcl10-MALT1 泛素连接酶复合物，从而导致 NEMO/IKKγ 非降解性泛素化和 IKKβ 磷酸化。 PHLPP2 通过与 Bcl10 相互作用以及从 Bcl10 竞争性置换 MALT1 来阻止该复合物的形成。相反，PHLPP2 缺失会增强 Bcl10-MALT1 复合物形成、NEMO 泛素化和随后的 IKKβ 磷酸化，从而导致多个靶基因的 NF-κB 依赖性转录增加。我们的结果表明 PHLPP2 是癌症进展的新生物标志物，并表明它是 NF-κB 信号传导的主要负调节因子。
The NF-κB growth pathway is constitutively activated in many cancers but its activation mechanism is unclear in most cases. We show that PHLPP2 interacts with IKKβ kinase, decreases its phosphorylation and the subsequent NF-κB activation in cancer cells. PHLPP2 is progressively lost in glioma and colorectal cancer and acts as a bona fide tumor suppressor, depending on IKKβ expression in cells. Physiologically, IKKβ activation by growth factors requires the formation of the Bcl10-MALT1 ubiquitin-ligase complex leading to NEMO/IKKγ non-degradative ubiquitination and IKKβ phosphorylation. PHLPP2 opposes the formation of this complex through interaction with Bcl10 and competitive displacement of MALT1 from Bcl10. Conversely, PHLPP2 loss enhances Bcl10-MALT1 complex formation, NEMO ubiquitination and subsequent IKKβ phosphorylation, resulting in increased NF-κB-dependent transcription of multiple target genes. Our results reveal PHLPP2 as a new biomarker of cancer progression, and implicate it as major negative regulator of NF-κB signaling.