Metal-dependent protein phosphatase 1A functions as an extracellular signal-regulated kinase phosphatase

Authors

  • Rong Li,

    1. Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, China
    2. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
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    • These authors contributed equally to this work
  • Zheng Gong,

    1. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    2. Weihai Campus, Shandong University, China
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    • These authors contributed equally to this work
  • Chang Pan,

    1. Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, China
    2. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    3. Qilu Hospital, Shandong University, Jinan, China
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    • These authors contributed equally to this work
  • Di-Dong Xie,

    1. Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, China
    2. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    3. Shandong Provincial Hospital, Shandong University, Jinan, China
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  • Jun-Yi Tang,

    1. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    2. Department of Physiology, School of Medicine, Shandong University, Jinan, China
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  • Min Cui,

    1. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    2. Department of Physiology, School of Medicine, Shandong University, Jinan, China
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  • Yun-Fei Xu,

    1. Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, China
    2. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    3. Qilu Hospital, Shandong University, Jinan, China
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  • Wei Yao,

    1. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    2. Department of Physiology, School of Medicine, Shandong University, Jinan, China
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  • Qi Pang,

    1. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    2. Shandong Provincial Hospital, Shandong University, Jinan, China
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  • Zhi-gang Xu,

    1. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    2. School of Life Science, Shandong University, Jinan, China
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  • Min-yong Li,

    1. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmacy, Shandong University, Jinan, China
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  • Xiao Yu,

    Corresponding author
    1. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    2. Department of Physiology, School of Medicine, Shandong University, Jinan, China
    • Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, China
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  • Jin-Peng Sun

    Corresponding author
    1. Shandong Provincial School Key Laboratory for Protein Science of Chronic Degenerative Diseases, Jinan, China
    2. Shandong Provincial Hospital, Shandong University, Jinan, China
    • Key Laboratory of Experimental Teratology of the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Medicine, Shandong University, Jinan, China
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Correspondence

J.-P. Sun and X. Yu, Building 6, Shandong University, School of medicine; 44 Wenhua Xi Road, Jinan, 250012

Fax: 86-531-88382502

Tel: 86-531-88381910

E-mail: sunjinpeng@sdu.edu.cn; yuxiao@sdu.edu.cn

Abstract

Protein phosphorylation is an important post-translational modification that regulates almost every aspect of signal transduction in cells. Activation of the mitogen-activated protein kinase (MAPK) family kinase extracellular signal-regulated kinase (ERK) is a point of convergence for many cellular activities in response to external stimulation. With stimuli, ERK activity is significantly increased by the phosphorylation of Thr202 and Tyr204 at its activation loop. Downregulation of ERK phosphorylation at these two sites by several phosphatases, such as protein phosphatase 2A, HePTP and MAPK phosphatase 3, is essential for maintaining appropriate ERK function in different cellular processes. However, it is unknown whether metal-dependent protein phosphatase (PPM) family phosphatases directly dephosphorylate ERK. In this study, we found that PPM1A negatively regulated ERK by directly dephosphorylating its pThr202 position early in EGF stimulation. Additional kinetic studies revealed that key residues participated in phospho-ERK recognition by PPM1A. Importantly, PPM1A preferred the phospho-ERK peptide sequence over a panel of other phosphopeptides through the interactions of basic residues in the active site of PPM1A with the pThr-Glu-pTyr motif of ERK. Whereas Lys165 and Arg33 were required for efficient catalysis or phosphosubstrate binding of PPM1A, Gln185 and Arg186 were determinants of PPM1A substrate specificity. The interaction between Arg186 of PPM1A and Glu203 and pTyr204 of phospho-ERK was identified as a hot-spot for phospho-ERK–PPM1A interaction.

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