Involvement of Phosphatases in Proliferation, Maturation, and Hemoglobinization of Developing Erythroid Cells
Figure 1
The effect of phosphatases on the proliferation/maturation of erythroid precursors and their fetal hemoglobin content. The kinetics of maturation and hemoglobinization in developing erythroid cells depends on the Epo signal. This is modulated by the level of erythropoietin (Epo), produced in response to hypoxic conditions, the number of erythropoietin-receptors (Epo-R), and the balance in the activities of kinases and phosphatases. (a) Binding of Epo causes Epo-R homodimerization and activation of the receptor-bound tyrosine kinase JAK2. Transphosphorylation of JAK2 results in activation of JAK2 and tyrosine phosphorylation (symbolized by the red arrows) of proteins (e.g., STATs), including the cytoplasmic domain of the EPO-R. Negative regulation of the Epo stimulus involves the tyrosine phosphatases CD45, PTP-1B, and Shp1. CIS and SOCS3 compete for STAT5 binding at Y401 whereas SOCS1 and SOCS3 bind to the activation loop of JAK2. Regulation of phosphoinositide metabolism by PI 3-kinase and SHIP1 is also indicated. Activation of the EPO-R supports survival, proliferation, and maturation of erythroid precursors. (b) Early erythroid precursors (left) carrying a large number of Epo-R are stimulated by Epo. The strong Epo-signal drives the cells to undergo proliferation and maturation. As maturation proceeds (right), the cell size and the number of Epo-R decrease, and while total Hb accumulates (red color), the proportion of HbF (%HbF) decreases. Addition of a phosphatase inhibitor (e.g., vanadate) to early erythroid precursors blocks phosphatase activity (lower panel, marked by X), resulting in continuous high Epo signaling and inhibition of cell maturation. The latter is accompanied by a relatively high proportion of HbF.
