Redox Regulation of PTEN by Reactive Oxygen Species: Its Role in Physiological Processes

Abstract

Phosphatase and tensin homolog (PTEN) is a tumor suppressor due to its ability to regulate cell survival, growth, and proliferation by downregulating the PI3K/AKT signaling pathway. In addition, PTEN plays an essential role in other physiological events associated with cell growth demands, such as ischemia-reperfusion, nerve injury, and immune responsiveness. Therefore, recently, PTEN inhibition has emerged as a potential therapeutic intervention in these situations. Increasing evidence demonstrates that reactive oxygen species (ROS), especially hydrogen peroxide (H₂O₂), are produced and required for the signaling in many important cellular processes under such physiological conditions. ROS have been shown to oxidize PTEN at the cysteine residue of its active site, consequently inhibiting its function. Herein, we provide an overview of studies that highlight the role of the oxidative inhibition of PTEN in physiological processes.

Keywords: PTEN; ROS; cell signaling; oxidative inhibition; redox regulation.

Figure 1

Oxidation of PTEN in cardiovascular remodeling and myogenic constriction. Ischemia or elevated blood pressure conditions induce the production of ROS. These ROS deactivate PTEN, leading to an increase in the AKT signaling pathway. The activation of the AKT pathway enhances cell survival, proliferation, and differentiation. Furthermore, PTEN-mediated AKT activation upregulates IL-10 expression, promoting cardiac remodeling and preventing apoptosis. It also elevates VEGF expression, facilitating angiogenesis. This mechanism also involves L-type calcium channel activity and the formation of IP3, which stimulates Ca²⁺ secretion, thus increasing intracellular Ca²⁺ levels and promoting myogenic constriction.

Figure 2

Oxidative inactivation of PTEN in nerve survival and regeneration. During neuronal injury, the NOX2-derived ROS concentration increases due to receptor kinase stimulation or extracellular vesicles released by macrophages. These ROS oxidize PTEN, leading to the activation of the PIP3/AKT signaling pathway, which promotes nerve regeneration. This mechanism can also promote self-renewal, proliferation, and differentiation in neuronal stem and progenitor cells. In the context of Alzheimer’s disease, the activation of the AKT pathway can downregulate GSK3β activity and the subsequent phosphorylation of the tau protein, providing neuroprotection.

Figure 3

Oxidative inactivation of PTEN in immune responsiveness: Ischemia or inflammation can lead to elevated plasma cytokines, which stimulate myeloid cells to produce NOX2-derived ROS. These ROS mediate the AKT signaling pathway by inhibiting PTEN and trigger granulopoiesis, promoting the proliferation and differentiation of immune cells. These cells engage in immune reactions while also contributing to anti-apoptosis and remodeling processes.

Figure 4

Oxidative inactivation of PTEN in insulin-related metabolism and muscle differentiation. Stimulation of growth factor receptors induces NOX2 activity and the production of ROS, which can oxidize PTEN and upregulate the PI3K/AKT signaling pathway. As a result, glucose uptake and insulin sensitivity are increased. During muscle differentiation, mitochondria-derived ROS can also oxidize PTEN and promote mTOR-induced myogenic autophagy.

Figure 5

Stimulation of receptor tyrosine kinases can trigger the PI3K/AKT signaling pathway and promote H₂O₂ production via NOX2 activity. H₂O₂ can react with HCO₃⁻ to form HCO₄⁻ and inhibit PTEN, the negative regulator of the PI3K/AKT pathway. This mechanism plays a crucial role in physiological processes such as cardiovascular remodeling, vascular constriction, neuronal regeneration, immune responsiveness, insulin-related metabolism, and myogenesis.