Opposing regulation of megakaryopoiesis by LPA receptors 2 and 3 in K562 human erythroleukemia cells

Erythrocytes and megakaryocytes (MK) are derived from a common progenitor that undergoes lineage specification. Lysophosphatidic acid (LPA), a lipid growth factor was previously shown to be a regulator for erythropoietic process through activating LPA receptor 3 (LPA(3)). However, whether LPA affects megakaryopoiesis remains unclear. In this study, we used K562 leukemia cell line as a model to investigate the roles of LPA in MK differentiation. We demonstrated that K562 cells express both LPA(2) and LPA(3), and the expression levels of LPA(2) are higher than LPA(3). Treatment with phorbol 12-myristate 13-acetate, a commonly used inducer of megakaryopoiesis, reciprocally regulates the expressions of LPA(2) and LPA(3). By pharmacological blockers and knockdown experiments, we showed that activation of LPA(2) suppresses whereas, LPA(3) promotes megakaryocytic differentiation in K562. The LPA(2)-mediated inhibition is dependent on beta-catenin translocation, whereas reactive oxygen species (ROS) generation is a downstream signal for activation of LPA(3). Furthermore, the hematopoietic transcriptional factors GATA-1 and FLI-1, appear to be involved in these regulatory mechanisms. Taken together, our results suggested that LPA(2) and LPA(3) may function as a molecular switch and play opposing roles during megakaryopoiesis of K562 cells. (C) 2014 Elsevier B.V. All rights reserved.