RHEX (regulator of hemoglobinization and erythroid cell expansion) is a primate-specific signaling adaptor protein that regulates erythroid cell differentiation through the EPO-EPOR pathway 1. As a plasma membrane protein, RHEX becomes rapidly phosphorylated (>20-fold) upon EPO stimulation and directly couples to the erythropoietin receptor via GRB2, propagating signals essential for red blood cell production 1. RHEX knockdown in erythroid progenitor cells inhibits EPO-dependent growth and impairs formation of hemoglobinizing erythroblasts, indicating roles in both early expansion and late-stage erythroblast development 1. Notably, RHEX exhibits restricted tissue expression with particular abundance in mast cells, where it unexpectedly functions as a negative regulator of SCF/KIT signaling by suppressing ERK1/2 and p38 activation 2. In the context of EPO signaling, PTPN18 phosphatase negatively regulates RHEX phosphorylation at Y141, representing a regulatory mechanism that modulates EPO-dependent hematopoietic cell growth 3. The human-specific nature of RHEX and its multiple lineage-dependent regulatory roles suggest specialized functions in human erythropoiesis and immune cell biology.