Mechanisms underlying the inhibitory effects of arsenic compounds on protein tyrosine phosphatase (PTP)
Mechanisms underlying the inhibitory effects of arsenic compounds on protein tyrosine phosphatase (PTP)
复制标题
砷化合物抑制蛋白酪氨酸磷酸酶（PTP）的机制
DOI：
10.1016/j.taap.2012.06.019
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发表时间：
2012-09-15
影响因子：
3.8
通讯作者：
Suzuki, Noriyuki
中科院分区：
文献类型：
--
作者：
Rehman, Kanwal;Chen, Zhe;Suzuki, Noriyuki
砷与生物分子的结合被认为是主要的毒性机制之一，这也可能与砷在人体中的致癌风险有关。与此同时，砷还已知激活磷酸化依赖的信号通路，包括表皮生长因子受体、促分裂原活化蛋白激酶和胰岛素/胰岛素样生长因子-1通路。这些信号传导途径起源于受体酪氨酸激酶水平，其磷酸化状态由相反的蛋白酪氨酸磷酸酶（PTP）活性调节。可逆酪氨酸磷酸化受蛋白酪氨酸激酶和磷酸酶的平衡作用控制，调节参与控制细胞增殖、粘附和迁移的重要信号传导途径。在本研究中，我们重点研究了细胞PTP与毒性三价砷（iAs（III））及其中间代谢产物如甲基亚胂酸（MMA（III））和二甲基亚胂酸（DMA（III））的体外相互作用，然后利用重组PTP（例如，PTP 1B和CD 45）。有趣的是，观察到PTP 1B（细胞质形式）或CD 45（受体连接形式）的活性被两种甲基化代谢物强烈抑制（即，MMA（III）和DMA（III）），但不通过iAs（III）。基质辅助激光解吸电离-飞行时间质谱（MALDI-TOF MS）已明确证实为有机中间体。DMA（III）直接结合到PTP 1B的活性位点半胱氨酸残基（例如，Cys 215），导致酶活性的抑制。这些结果表明，砷暴露可能通过PTP失活干扰细胞信号通路。(C)2012 Elsevier Inc. All rights reserved.
Arsenic binding to biomolecules is considered one of the major toxic mechanisms, which may also be related to the carcinogenic risks of arsenic in humans. At the same time, arsenic is also known to activate the phosphorylation-dependent signaling pathways including the epidermal growth factor receptor, the mitogen-activated protein kinase and insulin/insulin-like growth factor-1 pathways. These signaling pathways originate at the level of receptor tyrosine kinases whose phosphorylation status is regulated by opposing protein tyrosine phosphatase (PTP) activity. Reversible tyrosine phosphorylation, which is governed by the balanced action of protein tyrosine kinases and phosphatases, regulates important signaling pathways that are involved in the control of cell proliferation, adhesion and migration. In the present study, we have focused on the interaction of cellular PTPs with toxic trivalent arsenite (iAs(III)) and its intermediate metabolites such as monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)) in vitro, and then determined the arsenic binding site in PTP by the use of recombinant PTPs (e.g., PTP1B and CD45). Interestingly, the activities of PTP1B (cytoplasm-form) or CD45 (receptor-linked form) were observed to be strongly inhibited by both methylated metabolites (i.e., MMA(III) and DMA(III)) but not by iAs(III). Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) has clearly confirmed that the organic intermediate. DMA(III) directly bound to the active site cysteine residue of PTP1B (e.g., Cys215), resulting in inhibition of enzyme activity. These results suggest that arsenic exposure may disturb the cellular signaling pathways through PTP inactivation. (C) 2012 Elsevier Inc. All rights reserved.