Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders

Abstract

The dynamic coordination between kinases and phosphatases is crucial for cell homeostasis, in response to different stresses. The functional connection between oxidation and the intracellular signaling machinery still remains to be investigated. In the last decade, several studies have highlighted the role of reactive oxygen species (ROS) as modulators directly targeting kinases, phosphatases, and downstream modulators, or indirectly acting on cysteine residues on kinases/phosphatases resulting in protein conformational changes with modulation of intracellular signaling pathway(s). Translational studies have revealed the important link between oxidation and signal transduction pathways in hematological disorders. The intricate nature of intracellular signal transduction mechanisms, based on the generation of complex networks of different types of signaling proteins, revealed the novel and important role of phosphatases together with kinases in disease mechanisms. Thus, therapeutic approaches to abnormal signal transduction pathways should consider either inhibition of overactivated/accumulated kinases or homeostatic signaling resetting through the activation of phosphatases. This review discusses the progress in the knowledge of the interplay between oxidation and cell signaling, involving phosphatase/kinase systems in models of globally distributed hematological disorders.

Tyrosine Phosphorylation Modulates Peroxiredoxin-2 Activity in Normal and Diseased Red Cells

“…However, PP1 and PP2 did not modify the amount of Tyr-phosphorylated Prx2 associated with the membrane of diamide-treated red cells ( Figure 4 a). The oxidative dependent compartmentalization of Prx2 was further supported by the observation that dithiotretol (DTT), a known thiol group donor, prevented the membrane association of Tyr-phosphorylated Prx2 ( Figure 4 b) [ 15 , 21 ]. Noteworthily, Prx2 was associated with the membrane as both a monomer and dimer in diamide-treated red cells, and DTT again prevented Prx2 dimer formation, as previously reported by us [ 13 , 36 ] ( Figure S3b ).…”

“…This is associated with an overactivated Syk kinase-dependent intracellular signaling pathway, ending with the release of erythroid microparticles to clear damaged proteins [ 17 , 18 , 19 , 20 ]. In red cells, the biologic importance of redox-related signaling pathways is supported by studies in red cells from both animal models and human subjects with hemoglobinopathies or glucose 6-phosphate dehydrogenase G6PD deficiency [ 13 , 14 , 15 , 17 , 21 , 22 ]. In response to oxidation, Syk translocates to the membrane and favors band 3 clusterization, resulting in erythroid vesiculation followed by red cell membrane rearrangement [ 17 , 18 , 19 ].…”

Iron chelation improves ineffective erythropoiesis and iron overload in myelodysplastic syndrome mice

“…Further increased ROS leads to senescence and decreased ROS restores differentiation in those conditions ( Ludin et al, 2014 ). In addition, ROS can activate JAK/STAT pathways ( Tibaldi et al, 2020 ) and, therefore, EPO-EPOR mediated cell growth and survival. Recent evidence indicates that EPO and iron are required for ROS generation in erythroblasts, and that ROS are necessary for terminal erythropoiesis [44] while unchecked ROS accumulation results in anemia ( Friedman et al, 2001 ; Hebbel, 1990 ; Kong et al, 2004 ; Lee et al, 2004 ; Neumann et al, 2003 ).…”

Iron Chelation Improves Ineffective Erythropoiesis and Iron Overload in Myelodysplastic Syndrome Mice

“…Further increased ROS leads to senescence and decreased ROS restores differentiation in those conditions [69]. In addition, ROS can activate JAK/STAT pathways [70] and therefore EPO-EPOR mediated cell growth and survival. Recent evidence indicates that EPO and iron are required for ROS generation in erythroblasts, and that ROS are necessary for terminal erythropoiesis [44] while unchecked ROS accumulation results in anemia [71][72][73][74][75].…”