Lyn mediates FIP1L1-PDGFRA signal pathway facilitating IL- 5RA intracellular signal through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex in CEL
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Bin Li1,2,3, Guangsen Zhang2, Cui Li1, Ruijuan Li2, Jingchen Lu3, Zhengxi He3, Quan Wang3, Zhenzi Peng1, Jun Wang1, Yeping Dong1, Chunfang Zhang1, Jie Qiong Tan4, Nacef Bahri5, Yuexiang Wang5,6 and Chaojun Duan1
1Medical Research Center, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
2Division of Hematology, Institute of Molecular Hematology, The Second Xiang Ya Hospital, Central South University, Changsha, People’s Republic of China
3Division of Oncology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China
4State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, People’s Republic of China
5Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
6The Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
Chaojun Duan, email: [email protected]
Keywords: Lyn, CEL
Received: October 04, 2015 Accepted: July 26, 2016 Published: August 19, 2016
The Fip1-like1 (FIP1L1)–platelet-derived growth factor receptor alpha (PDGFRA) (F/P) oncogene can cause chronic eosinophilic leukemia (CEL), but requires IL-5 cytokine participation. In this study, we investigate the mechanism of F/P in collaboration with IL-5 in CEL. The results showed that Lyn, a key effector in the IL-5-motivated eosinophil production, is extensively activated in F/P-positive CEL cells. Lyn can associate and phosphorylate IL-5 receptor α (IL-5RA) in F/P-positive cells. Moreover, the activation of Lyn and IL-5R kinase were strengthened when the cells were stimulated by IL-5. Lyn inhibition in F/P-positive CEL cells attenuated cellular proliferation, induced apoptosis, and blocked cell migration and major basic protein (MBP) release. We identified the FIP1L1-PDGFRA/JAK2/Lyn/Akt complex in the F/P-expressing cells which can be disrupted by dual inhibition of JAK2 and Lyn, repressing cell proliferation in both EOL-1(F/P-positive human eosinophilic cell line) and imatinib-resistance (IR) cells. Altogether, our data demonstrate that Lyn is a vital downstream kinase activated by F/P converged with IL-5 signals in CEL cells. Lyn activate and expand IL-5RA intracellular signaling through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex, provoking eosinophils proliferation and exaggerated activation manifested as CEL.
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