Src-like adaptor protein 2 (SLAP2) binds to and inhibits FLT3 signaling
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Sausan A. Moharram1,2, Rohit A. Chougule1,2, Xianwei Su4,5, Tianfeng Li5, Jianmin Sun1,2,6, Hui Zhao5, Lars Rönnstrand1,2,3, Julhash U. Kazi1,2
1Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden
2Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden
3Translational Cancer Research, Lund University, Skåne University Hospital, Department of Oncology, Lund, Sweden
4Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
5School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
6Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, P. R. China
Julhash U. Kazi, email: email@example.com
Keywords: SLA2, Ba/F3, 32D, AML, AKT
Received: May 27, 2016 Accepted: July 13, 2016 Published: July 21, 2016
Fms-like tyrosine kinase (FLT3) is a frequently mutated oncogene in acute myeloid leukemia (AML). FLT3 inhibitors display promising results in a clinical setting, but patients relapse after short-term treatment due to the development of resistant disease. Therefore, a better understanding of FLT3 downstream signal transduction pathways will help to identify an alternative target for the treatment of AML patients carrying oncogenic FLT3. Activation of FLT3 results in phosphorylation of FLT3 on several tyrosine residues that recruit SH2 domain-containing signaling proteins. We screened a panel of SH2 domain-containing proteins and identified SLAP2 as a potent interacting partner of FLT3. We demonstrated that interaction occurs when FLT3 is activated, and also, an intact SH2 domain of SLAP2 is required for binding. SLAP2 binding sites in FLT3 mainly overlap with those of SRC. SLAP2 over expression in murine proB cells or myeloid cells inhibited oncogenic FLT3-ITD-mediated cell proliferation and colony formation in vitro, and tumor formation in vivo. Microarray analysis suggests that higher SLAP2 expression correlates with a gene signature similar to that of loss of oncogene function. Furthermore, FLT3-ITD positive AML patients with higher SLAP2 expression displayed better prognosis compared to those with lower expression of SLAP2. Expression of SLAP2 blocked FLT3 downstream signaling cascades including AKT, ERK, p38 and STAT5. Finally, SLAP2 accelerated FLT3 degradation through enhanced ubiquitination. Collectively, our data suggest that SLAP2 acts as a negative regulator of FLT3 signaling and therefore, modulation of SLAP2 expression levels may provide an alternative therapeutic approach for FLT3-ITD positive AML.
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