Tyr⁷⁴⁰and Tyr⁷⁵¹residues of platelet-derived growth factor beta receptor are responsible for the redox regulation of phosphatase and tensin homolog in the cells stimulated with platelet-derived growth factor

Abstract

Exposure of cells to hydrogen peroxide or platelet-derived growth factor (PDGF) induced Akt phosphorylation and oxidation of phosphatase and tensin homolog (PTEN). The Cys124 and Cys71 residues of PTEN were critical for the formation of a disulfide bond and the intermediate glutathionylation in the process of reduction of the disulfide bond. To determine which specific tyrosine residues of the PDGF beta receptor (PDGFβR) is involved in PDGF-induced PTEN oxidation and Akt phosphorylation, we investigated a kinase activity-deficient mutant and PDGFβR mutants where the tyrosine residues in the binding site for phosphoinositide 3-kinase (PI3K), GTPase-activating protein of Ras, Src homology 2 domain containing protein-tyrosine phosphatase-2, and phospholipase C-1 were replaced by Phe. Both PTEN oxidation and Akt phosphorylation did not occur in response to PDGF in the kinase-deficient mutant and in the PDGFβR mutant with a mutation in the PI3K binding site (Tyr740 and Tyr751). Thus, the kinase activity and the constituent Tyr740 and Tyr751 residues of PDGFβR in the cells stimulated with PDGF are responsible for the oxidation of PTEN and the Akt phosphorylation.

Principles of Redox Signaling

“…PTEN is sensitive to rapid inactivation by hydrogen peroxide or by S -nitrosothiols, forming a stable intramolecular disulfi de bond between the active site Cys124 and the proximal Cys71 [ 108 ]. PTEN redox-mediated inhibition leads to inability to contrast PI3-kinase and hence helps in sustaining Akt activation, acknowledged to favour proliferation, adhesion, and survival to stresses.…”

Oxidases and reactive oxygen species during hematopoiesis: A focus on megakaryocytes

“…Moreover, glutathione, an antioxidant, most likely regulates the reversibility of LMW‐PTP inactivation (Chiarugi, 2001). Exposure of cells to H 2 O 2 or PDGF induces Akt phosphorylation and oxidation of phosphatase and tensin homolog (PTEN; Kim et al, 2011). The antioxidant PrxII, has been demonstrated to locally regulate PDGF signaling in VSMC by decreasing the oxidation of PTPs, thereby functioning as a negative regulator of PDGF signaling (Choi et al, 2005).…”