The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling
The Pim-1 Protein Kinase Is an Important Regulator of MET Receptor Tyrosine Kinase Levels and Signaling
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DOI：
10.1128/mcb.00147-14
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发表时间：
2014-07-01
影响因子：
5.3
通讯作者：
Kraft, Andrew S.
中科院分区：
文献类型：
--
作者：
Cen, Bo;Xiong, Ying;Kraft, Andrew S.
MET是肝细胞生长因子（HGF）的受体，在正常和肿瘤细胞迁移和侵袭的信号传导中起重要作用。在这里，我们描述了一种以前未被认识到的机制，促进MET在多种肿瘤细胞类型中的表达。Pim-1蛋白激酶的水平与人肿瘤细胞系和患者来源的肿瘤材料中MET蛋白的水平呈正相关。使用小干扰RNA（siRNA），Pim基因敲除小鼠，小分子抑制剂和Pim-1的过表达，我们证实了这种相关性，并发现Pim-1激酶活性调节HGF诱导的肿瘤细胞迁移，侵袭和细胞散射。这些作用的新的生化机制涉及Pim-1通过调节S406上真核起始因子4 B（eIF 4 B）的磷酸化来控制MET翻译的能力。这种靶向磷酸化是eIF 4 B与eIF 3翻译起始复合物结合所必需的。重要的是，Pim-1的作用是通过对来自Pim激酶抑制剂AZD 1208的I期临床试验的患者血液和骨髓的评估来验证的。这些结果表明，Pim抑制剂可能在MET驱动肿瘤生物学的患者的治疗中发挥重要作用。
MET, the receptor for hepatocyte growth factor (HGF), plays an important role in signaling normal and tumor cell migration and invasion. Here, we describe a previously unrecognized mechanism that promotes MET expression in multiple tumor cell types. The levels of the Pim-1 protein kinase show a positive correlation with the levels of MET protein in human tumor cell lines and patient-derived tumor materials. Using small interfering RNA (siRNA), Pim knockout mice, small-molecule inhibitors, and overexpression of Pim-1, we confirmed this correlation and found that Pim-1 kinase activity regulates HGF-induced tumor cell migration, invasion, and cell scattering. The novel biochemical mechanism for these effects involves the ability of Pim-1 to control the translation of MET by regulating the phosphorylation of eukaryotic initiation factor 4B (eIF4B) on S406. This targeted phosphorylation is required for the binding of eIF4B to the eIF3 translation initiation complex. Importantly, Pim-1 action was validated by the evaluation of patient blood and bone marrow from a phase I clinical trial of a Pim kinase inhibitor, AZD1208. These results suggest that Pim inhibitors may have an important role in the treatment of patients where MET is driving tumor biology.