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
  • 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: [email protected].
  • 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: [email protected].
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.