Research Papers:

Induction of GD3/α1-adrenergic receptor/transglutaminase 2-mediated erythroid differentiation in chronic myelogenous leukemic K562 cells

Sun-Hyung Ha, Sung-Koo Kang, Hyunju Choi, Choong-Hwan Kwak, Fukushi Abekura, Jun-Young Park, Kyung-Min Kwon, Hyeun-Wook Chang, Young-Choon Lee, Ki-Tae Ha, Bo Kyeng Hou, Tae-Wook Chung and Cheorl-Ho Kim _

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Oncotarget. 2017; 8:72205-72219. https://doi.org/10.18632/oncotarget.20080

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Sun-Hyung Ha1,*, Sung-Koo Kang1,*, Hyunju Choi1, Choong-Hwan Kwak1, Fukushi Abekura1, Jun-Young Park1, Kyung-Min Kwon1,2, Hyeun-Wook Chang3, Young-Choon Lee4, Ki-Tae Ha5, Bo Kyeng Hou6, Tae-Wook Chung5 and Cheorl-Ho Kim1,7

1Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, Seoburo, Jangan-Gu, Kyunggi-Do, Korea

2Research Institute, Davinch-K Co., Ltd., Geumcheon-gu, Seoul, Korea

3College of Pharmacy, Yeungnam University, Gyeongsan, Korea

4Faculty of Medicinal Biotechnology, Dong-A University, Busan, Korea

5Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan City, Gyeongsangnam-Do, Korea

6Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea

7Department of Medical Device Management and Research, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea

*These authors contributed equally to this work and share co-first authors

Correspondence to:

Cheorl-Ho Kim, email: [email protected]

Tae-Wook Chung, email: [email protected]

Keywords: adrenergic receptor, transglutaminase 2, ganglioside GD3, erythroid differentiation, human chronic myelogenous leukemia K562 cell

Received: July 05, 2016     Accepted: July 18, 2017     Published: August 09, 2017


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.

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PII: 20080