title: Cadmium is a potent inhibitor of PPM phosphatases and targets the M1 binding site.
abstract: The heavy metal cadmium is a non-degradable pollutant. By screening the effects of a panel of metal ions on the phosphatase activity, we unexpectedly identified cadmium as a potent inhibitor of PPM1A and PPM1G. In contrast, low micromolar concentrations of cadmium did not inhibit PP1 or tyrosine phosphatases. Kinetic studies revealed that cadmium inhibits PPM phosphatases through the M1 metal ion binding site. In particular, the negative charged D441 in PPM1G specific recognized cadmium. Our results suggest that cadmium is likely a potent inhibitor of most PPM family members except for PHLPPs. Furthermore, we demonstrated that cadmium inhibits PPM1A-regulated MAPK signaling and PPM1G-regulated AKT signaling potently in vivo. Cadmium reversed PPM1A-induced cell cycle arrest and cadmium insensitive PPM1A mutant rescued cadmium induced cell death. Taken together, these findings provide a better understanding of the effects of the toxicity of cadmium in the contexts of human physiology and pathology.
authors.affiliation: Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University, School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Pan
authors.forename: Hong-Da
authors.initials: HD
authors.lastname: Liu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Gong
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.forename: Xu-Ben
authors.initials: XB
authors.lastname: Hou
authors.forename: Di-Dong
authors.initials: DD
authors.lastname: Xie
authors.forename: Xi-Bin
authors.initials: XB
authors.lastname: Zhu
authors.forename: Hao-Wen
authors.initials: HW
authors.lastname: Li
authors.forename: Jun-Yi
authors.initials: JY
authors.lastname: Tang
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Xu
authors.forename: Jia-Qi
authors.initials: JQ
authors.lastname: Yu
authors.forename: Lian-Ying
authors.initials: LY
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Fang
authors.forename: Kun-Hong
authors.initials: KH
authors.lastname: Xiao
authors.forename: Yu-Guo
authors.initials: YG
authors.lastname: Chen
authors.forename: Jiang-Yun
authors.initials: JY
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Pang
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Jin-Peng
authors.initials: JP
authors.lastname: Sun
mesh_terms: D001665:Binding Sites; D002104:Cadmium / Q000737:chemistry* / Q000493:pharmacokinetics*; D003198:Computer Simulation; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011485:Protein Binding; D000071636:Protein Phosphatase 2C
chemical_list: D002104:Cadmium; C000607456:PPM1A protein, human; C000607460:PPM1G protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
references.citation: Toxicol Lett. 2010 Oct 5;198(2):152-8
references.pmid: 20600713
references.citation: Am Surg. 2009 Jul;75(7):592-5; discussion 595-7
references.pmid: 19655603
references.citation: Crit Rev Toxicol. 2011 Jan;41(1):75-82
references.pmid: 21073263
references.citation: Toxicol Appl Pharmacol. 2009 Aug 1;238(3):240-9
references.pmid: 19236889
references.citation: Science. 1982 Mar 26;215(4540):1622-5
references.pmid: 7071581
references.citation: Toxicol Sci. 2010 Jan;113(1):127-37
references.pmid: 19887573
references.citation: Nat Neurosci. 2003 Jan;6(1):34-42
references.pmid: 12483215
references.citation: Chem Biol Interact. 2010 Nov 5;188(2):267-75
references.pmid: 20347726
references.citation: Cell. 2009 Jan 23;136(2):352-63
references.pmid: 19167335
references.citation: J Biol Chem. 1999 Jul 16;274(29):20336-43
references.pmid: 10400656
references.citation: EMBO J. 1996 Dec 16;15(24):6798-809
references.pmid: 9003755
references.citation: PLoS One. 2012;7(8):e43631
references.pmid: 22952725
references.citation: Biochemistry. 2003 Jul 22;42(28):8513-21
references.pmid: 12859198
references.citation: Proc Natl Acad Sci U S A. 1989 Mar;86(5):1736-40
references.pmid: 2537985
references.citation: Am J Hum Genet. 2000 Feb;66(2):378-92
references.pmid: 10677297
references.citation: Sheng Li Xue Bao. 2010 Apr 25;62(2):179-89
references.pmid: 20401454
references.citation: Tech Bull Regist Med Technol. 1964 Aug;34:134-7
references.pmid: 14199731
references.citation: PLoS One. 2012;7(2):e32438
references.pmid: 22384250
references.citation: J Neurochem. 2008 Apr;105(1):251-61
references.pmid: 18021293
references.citation: J Biol Chem. 2003 Apr 18;278(16):14299-305
references.pmid: 12514180
references.citation: J Biol Chem. 2007 Sep 28;282(39):29043-29051
references.pmid: 17656357
references.citation: Toxicol Lett. 2010 Feb 1;192(2):115-8
references.pmid: 19853025
references.citation: Nature. 2005 May 5;435(7038):42
references.pmid: 15875011
references.citation: J Inorg Biochem. 2012 Jul;112:32-8
references.pmid: 22542594
references.citation: FASEB J. 2008 Apr;22(4):954-65
references.pmid: 18039929
references.citation: PLoS One. 2011 Apr 22;6(4):e19052
references.pmid: 21544200
references.citation: Science. 2009 Aug 28;325(5944):1134-8
references.pmid: 19713527
references.citation: FEBS J. 2013 Jun;280(11):2700-11
references.pmid: 23560844
references.citation: Biometals. 2004 Oct;17(5):581-7
references.pmid: 15688869
references.citation: J Biol Chem. 2002 Aug 30;277(35):31818-25
references.pmid: 12082107
references.citation: Free Radic Biol Med. 2008 Oct 1;45(7):1035-44
references.pmid: 18703135
references.citation: EMBO J. 1998 Aug 17;17(16):4744-52
references.pmid: 9707433
references.citation: FEBS J. 2009 Mar;276(6):1667-79
references.pmid: 19220852
references.citation: Toxicology. 2012 Oct 28;300(3):103-11
references.pmid: 22659318
references.citation: Cell. 2009 Oct 30;139(3):468-84
references.pmid: 19879837
references.citation: Mol Cell Biochem. 2004 Jan;255(1-2):93-101
references.pmid: 14971650
references.citation: J Biol Chem. 2011 Sep 2;286(35):30526-30534
references.pmid: 21719704
references.citation: FEBS J. 2010 Jan;277(1):39-46
references.pmid: 19843171
references.citation: Biochem Biophys Res Commun. 2009 Aug 28;386(3):467-70
references.pmid: 19538940
references.citation: Environ Monit Assess. 2012 Apr;184(4):2261-73
references.pmid: 21573711
references.citation: J Mol Biol. 2007 Dec 7;374(4):890-8
references.pmid: 17961594