Physical and functional interaction of the TPL2 kinase with nucleophosmin.
Physical and functional interaction of the TPL2 kinase with nucleophosmin.
复制标题
TPL2 激酶与核磷蛋白的物理和功能相互作用。
DOI：
10.1038/onc.2014.183
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发表时间：
2015
期刊：
影响因子：
8
通讯作者：
Eliopoulos,AG
中科院分区：
文献类型：
--
作者：
Kanellis,DC;Bursac,S;Tsichlis,PN;Volarevic,S;Eliopoulos,AG
肿瘤进展位点2 （Tumor Progression Locus 2, TPL2）被广泛认为是一种细胞质有丝分裂原激活蛋白3激酶，在炎症和致癌信号转导的调节中发挥着重要作用。在这里，我们报道TPL2也可能作为核磷蛋白（NPM/B23）的物理和功能伙伴在细胞核中起作用，核磷蛋白是一种主要的核仁磷酸化蛋白，具有与恶性肿瘤相关的多种细胞活性。我们证明TPL2介导了一部分NPM苏氨酸199的磷酸化，这是其蛋白酶体降解和维持稳态NPM水平所必需的事件。暴露于紫外线C后，Tpl2是将去磷酸化的NPM从核核转运到核质所必需的。NPM是一种内源性HDM2抑制剂：p53的相互作用和TPL2的敲低被发现导致NPM与HDM2结合减少，并伴随基因毒性或核糖体应激后p53积累的缺陷。这些发现通过定义TPL2激酶在NPM的拓扑隔离中的核作用，将p53信号与苏氨酸199磷酸化NPM的产生联系起来，扩展了我们对TPL2作为致癌负调节因子的功能的理解。
Tumor Progression Locus 2 (TPL2) is widely recognized as a cytoplasmic mitogen-activated protein 3 kinase with a prominent role in the regulation of inflammatory and oncogenic signal transduction. Herein we report that TPL2 may also operate in the nucleus as a physical and functional partner of nucleophosmin (NPM/B23), a major nucleolar phosphoprotein with diverse cellular activities linked to malignancy. We demonstrate that TPL2 mediates the phosphorylation of a fraction of NPM at threonine 199, an event required for its proteasomal degradation and maintenance of steady-state NPM levels. Upon exposure to ultraviolet C, Tpl2 is required for the translocation of de-phosphorylated NPM from the nucleolus to the nucleoplasm. NPM is an endogenous inhibitor of HDM2: p53 interaction and knockdown of TPL2 was found to result in reduced binding of NPM to HDM2, with concomitant defects in p53 accumulation following genotoxic or ribosomal stress. These findings expand our understanding of the function of TPL2 as a negative regulator of carcinogenesis by defining a nuclear role for this kinase in the topological sequestration of NPM, linking p53 signaling to the generation of threonine 199-phosphorylated NPM.