title: Src-like adaptor protein 2 (SLAP2) binds to and inhibits FLT3 signaling.
abstract: 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.
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Sausan A
authors.initials: SA
authors.lastname: Moharram
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Rohit A
authors.initials: RA
authors.lastname: Chougule
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.|School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Xianwei
authors.initials: X
authors.lastname: Su
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Tianfeng
authors.initials: T
authors.lastname: Li
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, P. R. China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Sun
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Translational Cancer Research, Lund University, Skåne University Hospital, Department of Oncology, Lund, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnstrand
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Julhash U
authors.initials: JU
authors.lastname: Kazi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry; D054875:Ubiquitination; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C486695:Sla2 protein, mouse; D014443:Tyrosine; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; D016392:Proto-Oncogene Proteins pp60(c-src)
keywords: 32D; AKT; AML; Ba/F3; SLA2