2. Academic Validation
  3. Cellular phosphatase activity of C1-Ten/Tensin2 is controlled by Phosphatidylinositol-3,4,5-triphosphate binding through the C1-Ten/Tensin2 SH2 domain

Cellular phosphatase activity of C1-Ten/Tensin2 is controlled by Phosphatidylinositol-3,4,5-triphosphate binding through the C1-Ten/Tensin2 SH2 domain

  • Cell Signal. 2018 Nov;51:130-138. doi: 10.1016/j.cellsig.2018.07.009.
Eui Kim 1,  Do-Hyeon Kim 2,  Indira Singaram 3,  Heeyoon Jeong 4,  Ara Koh 2,  Jiyoun Lee 4,  Wonhwa Cho 5,  Sung Ho Ryu 6
Affiliations

Affiliations

  • 1 Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 37673, South Korea; Brain Korea 21 PLUS project of Bio-Molecular Function, Pohang University of Science and Technology, Pohang 37673, South Korea.
  • 2 Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, South Korea.
  • 3 Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
  • 4 Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, South Korea; Brain Korea 21 PLUS project of Bio-Molecular Function, Pohang University of Science and Technology, Pohang 37673, South Korea.
  • 5 Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA. Electronic address: wcho@uic.edu.
  • 6 Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 37673, South Korea; Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, South Korea; Brain Korea 21 PLUS project of Bio-Molecular Function, Pohang University of Science and Technology, Pohang 37673, South Korea. Electronic address: sungho@postech.ac.kr.
PMID: 30092354 DOI: 10.1016/j.cellsig.2018.07.009
Abstract

Regulation of tyrosine phosphorylation on Insulin Receptor substrate-1 (IRS-1) is essential for Insulin signaling. The protein tyrosine Phosphatase (PTP) C1-Ten/Tensin2 has been implicated in the regulation of IRS-1, but the molecular basis of this dephosphorylation is not fully understood. Here, we demonstrate that the cellular Phosphatase activity of C1-Ten/Tensin2 on IRS-1 is mediated by the binding of the C1-Ten/Tensin2 Src-homology 2 (SH2) domain to phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). We show that the role of C1-Ten/Tensin2 is dependent on insulin-induced phosphoinositide 3-kinase activity. The C1-Ten/Tensin2 SH2 domain showed strong preference and high affinity for PtdIns(3,4,5)P3. Using site-directed mutagenesis, we identified three basic residues in the C1-Ten/Tensin2 SH2 domain that were critical for PtdIns(3,4,5)P3 binding but were not involved in phosphotyrosine binding and PTP activity. Using a PtdIns(3,4,5)P3 binding-deficient mutant, we showed that the specific binding of the C1-Ten/Tensin2 SH2 domain to PtdIns(3,4,5)P3 allowed C1-Ten/Tensin2 to function as a PTP in cells. Collectively, our findings suggest that the interaction between the C1-Ten/Tensin2 SH2 domain and PtdIns(3,4,5)P3 produces a negative feedback loop of Insulin signaling through IRS-1.

Keywords

C1-Ten/Tensin2; Insulin receptor substrate-1; Phosphatidylinositol-3,4,5-triphosphate binding; Protein tyrosine phosphatase; Src-homology 2 domain.

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