Leukocyte Cell-Derived Chemotaxin 2 Antagonizes MET Receptor Activation to Suppress Hepatocellular Carcinoma Vascular Invasion by Protein Tyrosine Phosphatase 1B Recruitment
Leukocyte Cell-Derived Chemotaxin 2 Antagonizes MET Receptor Activation to Suppress Hepatocellular Carcinoma Vascular Invasion by Protein Tyrosine Phosphatase 1B Recruitment
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DOI：
10.1002/hep.26738
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发表时间：
2014-03-01
期刊：
影响因子：
13.5
通讯作者：
Kuo, Min-Liang
中科院分区：
文献类型：
--
作者：
Chen, Chi-Kuan;Yang, Ching-Yao;Kuo, Min-Liang
白细胞源性化学毒素2（LECT 2）已被证明是肝细胞癌（HCC）的肿瘤抑制因子。然而，其基本机制尚未完全确定。在这里，我们采用LECT 2亲和柱加上液相色谱串联质谱法来鉴定LECT 2结合蛋白，发现MET受体与LECT 2蛋白强烈相互作用。尽管存在肝细胞生长因子，但LECT 2结合通过募集蛋白酪氨酸磷酸酶1B对MET受体活化产生拮抗作用。LECT 2对MET活化的拮抗作用也主要有助于阻断HCC的血管侵袭和转移。此外，LECT 2的连续缺失和突变表明，HxGxD基序主要负责MET受体结合及其拮抗作用。结论：这些发现揭示了LECT 2在HCC中通过直接结合和失活MET而具有的新的特异性抑制功能，为治疗MET相关肝癌开辟了潜在途径。（肝病学2014;59：974-985）
Leukocyte cell-derived chemotoxin 2 (LECT2) has been shown to act as a tumor suppressor in hepatocellular carcinoma (HCC). However, the underlying mechanism has not yet been completely defined. Here, we employ a LECT2-affinity column plus liquid chromatography coupled with tandem mass spectrometry to identify LECT2-binding proteins and found that MET receptor strongly interacted with LECT2 protein. Despite the presence of hepatocyte growth factor, the LECT2 binding causes an antagonistic effect to MET receptor activation through recruitment of protein tyrosine phosphatase 1B. The antagonistic effect of LECT2 on MET activation also mainly contributes to the blockage of vascular invasion and metastasis of HCC. Furthermore, serial deletions and mutations of LECT2 showed that the HxGxD motif is primarily responsible for MET receptor binding and its antagonistic effects. Conclusion: These findings reveal a novel, specific inhibitory function of LECT2 in HCC by the direct binding and inactivation of MET, opening a potential avenue for treating MET-related liver cancer. (Hepatology 2014;59:974-985)