MEKK1 PHD 通过泛素化 TAB1 来激活 MAPKs 以响应细胞因子。

The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines.

机构信息

Department of Medicine, Imperial College London, London, UK.

Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine, San Diego, CA, USA.

出版信息

EMBO J. 2014 Nov 3;33(21):2581-96. doi: 10.15252/embj.201488351. Epub 2014 Sep 26.

Unlike the other MAP3Ks, MEKK1 (encoded by Map3k1) contains a PHD motif. To understand the role of this motif, we have created a knockin mutant of mouse Map3k1 (Map3k1(m) (PHD)) with an inactive PHD motif. Map3k1(m) (PHD) ES cells demonstrate that the MEKK1 PHD controls p38 and JNK activation during TGF-β, EGF and microtubule disruption signalling, but does not affect MAPK responses to hyperosmotic stress. Protein microarray profiling identified the adaptor TAB1 as a PHD substrate, and TGF-β- or EGF-stimulated Map3k1(m) (PHD) ES cells exhibit defective non-canonical ubiquitination of MEKK1 and TAB1. The MEKK1 PHD binds and mediates the transfer of Lys63-linked poly-Ub, using the conjugating enzyme UBE2N, onto TAB1 to regulate TAK1 and MAPK activation by TGF-β and EGF. Both the MEKK1 PHD and TAB1 are critical for ES-cell differentiation and tumourigenesis. Map3k1(m) (PHD) (/+) mice exhibit aberrant cardiac tissue, B-cell development, testis and T-cell signalling.

与其他 MAP3Ks 不同，MEKK1（由 Map3k1 编码）含有一个 PHD 结构域。为了了解该结构域的作用，我们创建了一个具有失活 PHD 结构域的小鼠 Map3k1（Map3k1(m)（PHD））的基因敲入突变体。Map3k1(m)（PHD）ES 细胞表明，MEKK1 的 PHD 在 TGF-β、EGF 和微管破坏信号转导过程中控制 p38 和 JNK 的激活，但不影响 MAPK 对高渗应激的反应。蛋白质微阵列分析鉴定出衔接蛋白 TAB1 是 PHD 的底物，TGF-β 或 EGF 刺激的 Map3k1(m)（PHD）ES 细胞表现出 MEKK1 和 TAB1 的非典型泛素化缺陷。MEKK1 的 PHD 结合并介导 Lys63 连接的多聚泛素的转移，使用连接酶 UBE2N，将其转移到 TAB1 上，以调节 TGF-β 和 EGF 对 TAK1 和 MAPK 的激活。MEKK1 的 PHD 和 TAB1 对于 ES 细胞分化和肿瘤发生都是至关重要的。Map3k1(m)（PHD）（+/+）小鼠表现出心脏组织、B 细胞发育、睾丸和 T 细胞信号的异常。