Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling

Noda, Saori; Takahashi, Atsushi; Hayashi, Takeru; Tanuma, Sei-ichi; Hatakeyama, Masanori

doi:10.1016/J.BBRC.2015.12.117

Title: Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling

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Abstract

SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2-mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. - Highlights:more »« less

Authors:

Noda, Saori ^[1]; Takahashi, Atsushi; Hayashi, Takeru ^[1]; Tanuma, Sei-ichi ^[2]; Hatakeyama, Masanori ^[1]

Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan)
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba (Japan)

Publication Date:: Fri Jan 22 00:00:00 EST 2016

OSTI Identifier:: 22594202

Resource Type:: Journal Article

Journal Name:: Biochemical and Biophysical Research Communications

Additional Journal Information:: Journal Volume: 469; Journal Issue: 4; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; CONGENITAL DISEASES; IN VITRO; MUTANTS; MUTATIONS; PATIENTS; PHOSPHORYLATION; PROTEINS; SUBSTRATES; SYMPTOMS; TYROSINE

Citation Formats


                    Noda, Saori, Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Takahashi, Atsushi, Hayashi, Takeru, Tanuma, Sei-ichi, and Hatakeyama, Masanori. Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling.  United States: N. p., 2016. 
        Web.  doi:10.1016/J.BBRC.2015.12.117.

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                    Noda, Saori, Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Takahashi, Atsushi, Hayashi, Takeru, Tanuma, Sei-ichi, & Hatakeyama, Masanori. Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling.  United States.  https://doi.org/10.1016/J.BBRC.2015.12.117

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                    Noda, Saori, Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Takahashi, Atsushi, Hayashi, Takeru, Tanuma, Sei-ichi, and Hatakeyama, Masanori. 2016.  
        "Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling".  United States.  https://doi.org/10.1016/J.BBRC.2015.12.117.

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@article{osti_22594202,

  title        = {Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling},

  author       = {Noda, Saori and Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba and Takahashi, Atsushi and Hayashi, Takeru and Tanuma, Sei-ichi and Hatakeyama, Masanori},

  abstractNote = {SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2-mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. - Highlights: • LS-associated SHP2 mutants dephosphorylate parafibromin on Y290, Y293, and Y315. • LS-associated SHP2 mutants display a reduced tyrosine phosphatase activity. • LS-specific SHP2-Y279C is catalytically less active than LS-specific SHP2-T468M. • NS/LS-associated SHP2-Q506P has both hyper- and hypomorphic enzymatic properties.},

  doi          = {10.1016/J.BBRC.2015.12.117},

  url          = {https://www.osti.gov/biblio/22594202},
  journal      = {Biochemical and Biophysical Research Communications},

  issn         = {0006-291X},

  number       = 4,

  volume       = 469,

  place        = {United States},

  year         = {Fri Jan 22 00:00:00 EST 2016},

  month        = {Fri Jan 22 00:00:00 EST 2016}

}

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