Stat5 Signaling Specifies Basal versus Stress Erythropoietic Responses through Distinct Binary and Graded Dynamic Modalities

Abstract

Author SummaryHormone signaling through the erythropoietin (Epo) pathway is required both for the continuous replacement of red blood cells (RBCs) that are lost through aging (a process known as "basal erythropoiesis") and to boost tissue oxygen when bleeding, in anemia or at high altitude ("stress erythropoiesis"). A key challenge lies in understanding how extracellular Epo concentration is translated into different intracellular signals that promote transcription of proteins that are specific to basal versus stress erythropoiesis. Binding of Epo to its receptor EpoR on the surface of an erythroblast (the precursors of RBCs) triggers the addition of phosphates to a target protein Stat5; the phosphorylated Stat5 becomes activated and induces transcription. We show that the dynamic properties of the Stat5 activation signal convey additional information that specifies either basal or stress responses. During basal conditions, the Stat5 signal is low and binary in nature—an on/off switch-like response. Stress, on the other hand, triggers a distinct Stat5 response consisting of a highintensity signal that increases in a graded fashion with rising Epo concentration. We found that a mouse bearing a truncated EpoR is restricted to the low-intensity binary Stat5 signal and correspondingly fails to initiate stress erythropoiesis. Ultimately, it is the Stat5 protein level in erythroblasts that determines their ability to generate the high-intensity graded Stat5 signal in response to high Epo. These findings have therapeutic potential: targeting Stat5's high-intensity graded signal may inhibit its aberrant function in blood cell cancers without affecting its important binary response in normal cells.