Lyn mediates FIP1L1-PDGFRA signal pathway facilitating IL- 5RA intracellular signal through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex in CEL

// Bin Li 1, 2, 3 , Guangsen Zhang 2 , Cui Li 1 , Ruijuan Li 2 , Jingchen Lu 3 , Zhengxi He 3 , Quan Wang 3 , Zhenzi Peng 1 , Jun Wang 1 , Yeping Dong 1 , Chunfang Zhang 1 , Jie Qiong Tan 4 , Nacef Bahri 5 , Yuexiang Wang 5, 6 and Chaojun Duan 1 1 Medical Research Center, Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, People’s Republic of China 2 Division of Hematology, Institute of Molecular Hematology, The Second Xiang Ya Hospital, Central South University, Changsha, People’s Republic of China 3 Division of Oncology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China 4 State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, People’s Republic of China 5 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA 6 The 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 Correspondence to: Chaojun Duan, email: duancjxy@126.com Keywords: Lyn, CEL Received: October 04, 2015      Accepted: July 26, 2016      Published: August 19, 2016 ABSTRACT 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.