Abstract
The disialic acid-containing glycosphingolipid GD3 recruited membrane transglutaminase 2 (TG2) as a signaling molecule for erythroid differentiation in human chronic myelogenous leukemia (CML) K562 cells. The α1-adrenergic receptor (α1-AR)/TG2-mediated signaling pathway regulated GD3 functions, including gene expression and production, to differentiate CML K562 cells into erythroid lineage cells. Epinephrine, an AR agonist, increased membrane recruitment as well as GTP-photoaffinity of TG2, inducing GD3 synthase gene expression. Epinephrine activated PI3K/Akt signaling and GTPase downstream of TG2 activated Akt. The coupling of TG2 and GD3 production was specifically suppressed by prazosin (α1-AR antagonist), but not by propranolol (β-AR antagonist) or rauwolscine (α2-AR antagonist), indicating α1-AR specificity. Small interfering RNA (siRNA) experiment results indicated that the α1-AR/TG2-mediated signaling pathway activated PKCs α and δ to induce GD3 synthase gene expression. Transcription factors CREB, AP-1, and NF-κB regulated GD3 synthase gene expression during α1-AR-induced differentiation in CML K562 cells. In addition, GD3 synthase gene expression was upregulated in TG2-transfected cells via α1-AR with expression of erythroid lineage markers and benzidine-positive staining. α1-AR/TG2 signaling pathway-directed GD3 production is a crucial step in erythroid differentiation of K562 cells and GD3 interacts with α1-AR/TG2, inducing GD3/α1-AR/TG2-mediated erythroid differentiation. These results suggest that GD3, which acts as a membrane mediator of erythroid differentiation in CML cells, provides a therapeutic avenue for leukemia treatment.
Highlights
The adrenergic receptors (ARs) have been known with three subtypes (α1, a2, and b), and a1 AR is further subclassified into 3 subtypes (a1A = C, a1B, and a1D) by parameters of its receptor-ligand interaction and receptor-mediated signaling [1,2,3,4]
GD3 synthase gene expression was upregulated in transglutaminase 2 (TG2)-transfected cells via α1-adrenergic receptor (α1-AR) with expression of erythroid lineage markers and benzidine-positive staining. α1-AR/TG2 signaling pathway-directed GD3 production is a crucial step in erythroid differentiation of K562 cells and GD3 interacts with α1-AR/TG2, inducing GD3/α1-AR/TG2-mediated erythroid differentiation
We demonstrate that up-regulation of GD3 synthase is directly coupled with TG2 and that TG2 is serially coupled with the ARs for erythroid differentiation of chronic myelogenous leukemia (CML) K562 cells
Summary
The adrenergic receptors (ARs) have been known with three subtypes (α1, a2, and b), and a1 AR is further subclassified into 3 subtypes (a1A = C, a1B, and a1D) by parameters of its receptor-ligand interaction and receptor-mediated signaling [1,2,3,4]. ARs are known to couple with the ubiquitous transglutaminase-2 (TG2) [6], and are involved in TG signaling. GTP-bound TG2 mediates signal transductions of membrane receptor to intracellular effectors. The studied example of this phenomenon is the a1-AR-down-streamed enhancement of phospholipase C activity [10, 11], in which the a1-AR activates GTP binding capacity of TG2. A previous study performed by our group suggested that TG2 overexpression as well as membrane recruitment and membrane localization of TG2 accelerate erythroid differentiation of K562 cells [17]
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