The expression of Gangioside GD3 by a1‐Adrenergic receptor/Transglutaminase 2 mediated‐signaling pathway induces erythroid differentiation of K562 cells.

Sialic acid containing glycosphingolipids (gangliosides) have been proposed to play a role in the regulation of a variety of biological phenomena, including cell differentiation. We previously reported the role of transglutaminase 2 (TG2) in the acceleration of erythroid differentiation in K562 cells and modulation of its recruitment into membranes. In this study, we study that a1‐Adrenergic receptor (AR) mediated‐signaling pathway regulates expression of Ganglioside GD3. Epinephrine induced membrane recruitment of TG2 and activated PI3K/Akt signaling at low calcium levels in the medium, but transglutaminase activity was increased at high calcium concentration, indicating that GTPase of TG2 functions primarily on the Akt activation. On the other hand, ERK phosphorylation was down‐regulated by treatment of epinephrine. The membrane recruitment of TG2 as well as the expression of GD3 synthase gene was decreased by prazocin, but not by propranolol and rawolscene, suggesting a1‐AR specific. siRNA result indicated that a1‐AR/TG2 mediated signaling pathway activated PKC a and d to induce GD3 synthase expression. Results of RT‐PCR and promotor luciferase assay and EMSA suggested that full promotor regions containing AP‐1 transcription factor binding site is mainly influenced on the GD3 expression. TG2 transfected cells showed increase of GD3 synthase gene expression via a1‐AR. Moreover, both GD3 synthase and TG2 transfected cells induced several erythroid lineage marker genes. Therefore, this study suggests for the first time that a1‐AR mediated‐signaling pathway induces the erythroid differentiation of K562 cells by induction of GD3 synthase gene expression as well as membrane recruitment of TG2.