title: Mechanisms underlying the inhibitory effects of arsenic compounds on protein tyrosine phosphatase (PTP).
abstract: 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.
authors: Department of Pharmacology, Toxicology, and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors: Kanwal
authors: K
authors: Rehman
authors: Zhe
authors: Z
authors: Chen
authors: Wen Wen
authors: WW
authors: Wang
authors: Yan Wei
authors: YW
authors: Wang
authors: Akira
authors: A
authors: Sakamoto
authors: Yan Fang
authors: YF
authors: Zhang
authors: Hua
authors: H
authors: Naranmandura
authors: Noriyuki
authors: N
authors: Suzuki
mesh_terms: D018053:Arsenites / Q000378:metabolism / Q000633:toxicity*; D001665:Binding Sites; D002101:Cacodylic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D056945:Hep G2 Cells; D006801:Humans; D017493:Leukocyte Common Antigens / Q000037:antagonists & inhibitors; D009942:Organometallic Compounds / Q000633:toxicity*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D018053:Arsenites; D009942:Organometallic Compounds; C472511:dimethylarsinous acid; C406082:monomethylarsonous acid; D002101:Cacodylic Acid; D017493:Leukocyte Common Antigens; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C015001:arsenite