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Cancer Science Volume 109 ,Issue 12 ,2018-11-14
Phosphorylation of serine/arginine‐rich splicing factor 1 at tyrosine 19 promotes cell proliferation in pediatric acute lymphoblastic leukemia
ORIGINAL ARTICLES
Liting Xu 1 Han Zhang 1 Mei Mei 2 Chaohao Du 2 Xiahe Huang 2 Jing Li 1 Yingchun Wang 2 Shilai Bao 2 Huyong Zheng 1
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DOI:10.1111/cas.13834
Received 2018-05-01, accepted for publication 2018-10-04, Published 2018-10-04
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摘要

Serine/arginine‐rich splicing factor 1 (SRSF1) has been linked to various human cancers including pediatric acute lymphoblastic leukemia (ALL). Our previous study has shown that SRSF1 potentially contributes to leukemogenesis; however, its underlying mechanism remains unclear. In this study, leukemic cells were isolated from pediatric ALL bone marrow samples, followed by immunoprecipitation assays and mass spectrometry analysis specific to SRSF1. Subcellular localization of the SRSF1 protein and its mutants were analyzed by immunofluorescence staining. Cell growth, colony formation, cell apoptosis, and the cell cycle were investigated using stable leukemic cell lines generated with lentivirus‐mediated overexpressed WT or mutant plasmids. Cytotoxicity of the Tie2 kinase inhibitor was also evaluated. Our results showed the phosphorylation of SRSF1 at tyrosine 19 (Tyr‐19) was identified in newly diagnosed ALL samples, but not in complete remission or normal control samples. Compared to the SRSF1 WT cells, the missense mutants of the Tyr‐19 phosphorylation affected the subcellular localization of SRSF1. In addition, the Tyr‐19 phosphorylation of SRSF1 also led to increased cell proliferation and enhanced colony‐forming properties by promoting the cell cycle. Remarkably, we further identified the kinase Tie2 as a potential therapeutic target in leukemia cells. In conclusion, we identify for the first time that the phosphorylation state of SRSF1 is linked to different phases in pediatric ALL. The Tyr‐19 phosphorylation of SRSF1 disrupts its subcellular localization and promotes proliferation in leukemia cells by driving cell‐cycle progression. Inhibitors targeting Tie2 kinase that could catalyze Tyr‐19 phosphorylation of SRSF1 offer a promising therapeutic target for treatment of pediatric ALL.

关键词

tyrosine phosphorylation;Tie2 kinase;SRSF;childhood;acute lymphoblastic leukemia

授权许可

© 2018 Japanese Cancer Association
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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通讯作者

1. Shilai Bao.Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.slbao@genetics.ac.cn
2. Huyong Zheng.Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Ministry of Education, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China.slbao@genetics.ac.cn

推荐引用方式

Liting Xu,Han Zhang,Mei Mei,Chaohao Du,Xiahe Huang,Jing Li,Yingchun Wang,Shilai Bao,Huyong Zheng. Phosphorylation of serine/arginine‐rich splicing factor 1 at tyrosine 19 promotes cell proliferation in pediatric acute lymphoblastic leukemia. Cancer Science ,Vol.109, Issue 12(2018)

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参考文献
[1] Cheng CL, Hou HA, Jhuang JY, et al. High bone marrow angiopoietin‐1 expression is an independent poor prognostic factor for survival in patients with myelodysplastic syndromes. Br J Cancer. 2011;105:975‐982.
[2] Cao Z, Fu B, Deng B, Zeng Y, Wan X, Qu L. Overexpression of Chemokine (C‐X‐C) ligand 1 (CXCL1) associated with tumor progression and poor prognosis in hepatocellular carcinoma. Cancer Cell Int. 2014;14:86.
[3] Sanford JR, Gray NK, Beckmann K, Caceres JF. A novel role for shuttling SR proteins in mRNA translation. Genes Dev. 2004;18:755‐768.
[4] Caceres JF, Screaton GR, Krainer AR. A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm. Genes Dev. 1998;12:55‐66.
[5] Zou A, Lambert D, Yeh H, et al. Elevated CXCL1 expression in breast cancer stroma predicts poor prognosis and is inversely associated with expression of TGF‐β signaling proteins. BMC Cancer. 2014;14:781.
[6] Zhang Z, Krainer AR. Involvement of SR proteins in mRNA surveillance. Mol Cell. 2004;16:597‐607.
[7] Li X, Wang J, Manley JL. Loss of splicing factor ASF/SF2 induces G2 cell cycle arrest and apoptosis, but inhibits internucleosomal DNA fragmentation. Genes Dev. 2005;19:2705‐2714.
[8] Sears TK, Angelastro JM. The transcription factor ATF5: role in cellular differentiation, stress responses, and cancer. Oncotarget. 2017;8:84595‐84609.
[9] Malanga M, Czubaty A, Girstun A, Staron K, Althaus FR. Poly(ADP‐ribose) binds to the splicing factor ASF/SF2 and regulates its phosphorylation by DNA topoisomerase I. J Biol Chem. 2008;283:19991‐19998.
[10] Bullock AN, Das S, Debreczeni JE, et al. Kinase domain insertions define distinct roles of CLK kinases in SR protein phosphorylation. Structure. 2009;17:352‐362.
[11] Cartegni L, Chew SL, Krainer AR. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet. 2002;3:285‐298.
[12] Garcia‐Manero G, Khoury HJ, Jabbour E, et al. A phase I study of oral ARRY‐614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate‐1 risk myelodysplastic syndromes. Clin Cancer Res. 2015;21:985‐994.
[13] Liu S, Kang K, Zhang J, et al. A novel Physarum polycephalum SR protein kinase specifically phosphorylates the RS domain of the human SR protein, ASF/SF2. Acta Biochim Biophys Sin. 2009;41:657‐667.
[14] Pui CH, Yang JJ, Hunger SP, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol. 2015;33:2938‐2948.
[15] Shimoni‐Sebag A, Lebenthal‐Loinger I, Zender L, Karni R. RRM1 domain of the splicing oncoprotein SRSF1 is required for MEK1‐MAPK‐ERK activation and cellular transformation. Carcinogenesis. 2013;34:2498‐2504.
[16] Keith T, Araki Y, Ohyagi M, et al. Regulation of angiogenesis in the bone marrow of myelodysplastic syndromes transforming to overt leukaemia. Br J Haematol. 2007;137:206‐215.
[17] Ma CT, Velazquez‐Dones A, Hagopian JC, Ghosh G, Fu XD, Adams JA. Ordered multi‐site phosphorylation of the splicing factor ASF/SF2 by SRPK1. J Mol Biol. 2008;376:55‐68.
[18] Kitajima D, Kasamatsu A, Nakashima D, et al. Tie2 regulates tumor metastasis of oral squamous cell carcinomas. J Cancer. 2016;7:600‐607.
[19] Blume‐Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;411:355‐365.
[20] Olshavsky NA, Comstock CE, Schiewer MJ, et al. Identification of ASF/SF2 as a critical, allele‐specific effector of the cyclin D1b oncogene. Can Res. 2010;70:3975‐3984.
[21] Karni R, Hippo Y, Lowe SW, Krainer AR. The splicing‐factor oncoprotein SF2/ASF activates mTORC1. Proc Natl Acad Sci USA. 2008;105:15323‐15327.
[22] Gonçalves V, Jordan P. Posttranscriptional regulation of splicing factor SRSF1 and its role in cancer cell biology. Biomed Res Int. 2015;2015:1‐10.
[23] Massiello A, Chalfant CE. SRp30a (ASF/SF2) regulates the alternative splicing of caspase‐9 pre‐mRNA and is required for ceramide‐responsiveness. J Lipid Res. 2006;47:892‐897.
[24] Zhang H, Ren Y, Pang D, Liu C. Clinical implications of AGBL2 expression and its inhibitor latexin in breast cancer. World J Surg Oncol. 2014;12:142.
[25] Breckenridge DG, Nguyen M, Kuppig S, Reth M, Shore GC. The procaspase‐8 isoform, procaspase‐8L, recruited to the BAP31 complex at the endoplasmic reticulum. Proc Natl Acad Sci USA. 2002;99:4331‐4336.
[26] Gout S, Brambilla E, Boudria A, et al. Abnormal expression of the pre‐mRNA splicing regulators SRSF1, SRSF2, SRPK1 and SRPK2 in non small cell lung carcinoma. PLoS One. 2012;7:e46539.
[27] Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR. The gene encoding the splicing factor SF2/ASF is a proto‐oncogene. Nat Struct Mol Biol. 2007;14:185‐193.
[28] Huang Y, Gattoni R, Stevenin J, Steitz JA. SR splicing factors serve as adapter proteins for TAP‐dependent mRNA export. Mol Cell. 2003;11:837‐843.
[29] Das S, Krainer AR. Emerging functions of SRSF1, splicing factor and oncoprotein, in RNA metabolism and cancer. Mol Cancer Res. 2014;12:1195‐1204.
[30] Anczuków O, Akerman M, Cléry A, et al. SRSF1‐regulated alternative splicing in breast cancer. Mol Cell. 2015;60:105‐117.
[31] Hubbard SR, Till JH. Protein tyrosine kinase structure and function. Annu Rev Biochem. 2000;69:373‐398.
[32] Gautrey HL, Tyson‐Capper AJ. Regulation of Mcl‐1 by SRSF1 and SRSF5 in cancer cells. PLoS ONE. 2012;7:e51497.
[33] Lievens PMJ, Kuznetsova T, Kochlamazashvili G, et al. ZDHHC3 tyrosine phosphorylation regulates neural cell adhesion molecule palmitoylation. Mol Cell Biol. 2016;36:2208‐2225.
[34] Hunter T. Tyrosine phosphorylation: thirty years and counting. Curr Opin Cell Biol. 2009;21:140‐146.
[35] Anczuków O, Rosenberg AZ, Akerman M, et al. The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation. Nat Struct Mol Biol. 2012;19:220‐228.
[36] Ghigna C, Giordano S, Shen H, et al. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Mol Cell. 2005;20:881‐890.
[37] Mitsutake N, Namba H, Takahara K, et al. Tie‐2 and angiopoietin‐1 expression in human thyroid tumors. Thyroid. 2002;12:95‐99.
[38] Sinha R, Allemand E, Zhang Z, Karni R, Myers MP, Krainer AR. Arginine methylation controls the subcellular localization and functions of the oncoprotein splicing factor SF2/ASF▿†. Mol Cell Biol. 2010;30:2762‐2774.
[39] Del Rosario AM, White FM. Quantifying oncogenic phosphotyrosine signaling networks through systems biology. Curr Opin Genet Dev. 2010;20:23‐30.
[40] Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006;441:424‐430.
[41] Peters KG, Kontos CD, Lin PC, et al. Functional significance of Tie2 signaling in the adult vasculature. Recent Prog Horm Res. 2004;59:51‐71.
[42] Zhou Z, Li M, Zhang L, et al. Oncogenic kinase‐induced PKM2 tyrosine 105 phosphorylation converts non‐oncogenic PKM2 to a tumor promoter and induces cancer stem‐like cells. Can Res. 2018;78:2374.
[43] Shirakawa K, Tsuda H, Heike Y, et al. Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer. Can Res. 2001;61:445‐451.
[44] Ghigna C, De Toledo M, Bonomi S, et al. Pro‐metastatic splicing of Ron proto‐oncogene mRNA can be reversed: therapeutic potential of bifunctional oligonucleotides and indole derivatives. RNA Biol. 2010;7:495‐503.
[45] Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 2006;6:729‐734.
[46] Kurogi Y, Matsuo Y, Mihara Y, et al. Identification of a chemical inhibitor for nuclear speckle formation: implications for the function of nuclear speckles in regulation of alternative pre‐mRNA splicing. Biochem Biophys Res Comm. 2014;446:119‐124.
[47] Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N. mTOR, translation initiation and cancer. Oncogene. 2006;25:6416‐6422.
[48] Leva V, Giuliano S, Bardoni A, et al. Phosphorylation of SRSF1 is modulated by replicational stress. Nucleic Acids Res. 2012;40:1106‐1117.
[49] Blanco FJ, Bernabeu C. The splicing factor SRSF1 as a marker for endothelial senescence. Front Physiol. 2012;3:54.
[50] Goehe RW, Shultz JC, Murudkar C, et al. hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase‐9 pre‐mRNA processing. J Clin Investig. 2010;120:3923‐3939.
[51] Zou L, Zhang H, Du C, et al. Correlation of SRSF1 and PRMT1 expression with clinical status of pediatric acute lymphoblastic leukemia. J Hematol Oncol. 2012;5:42.
[52] Blaustein M, Pelisch F, Tanos T, et al. Concerted regulation of nuclear and cytoplasmic activities of SR proteins by AKT. Nat Struct Mol Biol. 2005;12:1037‐1044.
[53] Kazi JU, Chougule RA, Li T, et al. Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3‐ITD. Cell Mol Life Sci. 2017;74:2679‐2688.
[54] Shultz JC, Goehe RW, Wijesinghe DS, et al. Alternative splicing of caspase 9 is modulated by the phosphoinositide 3‐kinase/Akt pathway via phosphorylation of SRp30a. Can Res. 2010;70:9185‐9196.
[55] Kukk E, Wartiovaara U, Gunji Y, et al. Analysis of Tie receptor tyrosine kinase in haemopoietic progenitor and leukaemia cells. Br J Haematol. 1997;98:195‐203.
[56] Cazalla D, Zhu J, Manche L, Huber E, Krainer AR, Caceres JF. Nuclear export and retention signals in the RS domain of SR proteins. Mol Cell Biol. 2002;22:6871‐6882.
[57] Holland EC, Sonenberg N, Pandolfi PP, Thomas G. Signaling control of mRNA translation in cancer pathogenesis. Oncogene. 2004;23:3138‐3144.
[58] Ye K, Li J, Li X, Chang S, Zhang Z. Ang1/Tie2 induces cell proliferation and migration in human papillary thyroid carcinoma via the PI3K/AKT pathway. Oncol Lett. 2018;15:1313‐1318.
[59] Wang J, Wu K, Zhang D, et al. Expressions and clinical significances of angiopoietin‐1, ‐2 and Tie2 in human gastric cancer. Biochem Biophys Res Comm. 2005;337:386‐393.
[60] De Benedetti A, Harris AL. eIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol. 1999;31:59‐72.
[61] Hunter T, Sefton BM. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc Natl Acad Sci USA. 1980;77:1311‐1315.
[62] Hasenstein JR, Kasmerchak K, Buehler D, et al. Efficacy of Tie2 receptor antagonism in angiosarcoma. Neoplasia. 2012;14:131‐140.
[63] Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342‐4349.
[64] Kim KS, Jeong JY, Kim YC, et al. Predictors of the response to gefitinib in refractory non‐small cell lung cancer. Clin Cancer Res. 2005;11:2244‐2251.
[65] Ben‐Hur V, Denichenko P, Siegfried Z, et al. S6K1 alternative splicing modulates its oncogenic activity and regulates mTORC1. Cell Rep. 2013;3:103‐115.
[66] Michlewski G, Sanford JR, Caceres JF. The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E‐BP1. Mol Cell. 2008;30:179‐189.
[67] Huynh N, Ma CT, Giang N, et al. Allosteric interactions direct binding and phosphorylation of ASF/SF2 by SRPK1. Biochemistry. 2009;48:11432‐11440.
[68] Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR‐ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038‐1042.
[69] Hagopian JC, Ma CT, Meade BR, et al. Adaptable molecular interactions guide phosphorylation of the SR protein ASF/SF2 by SRPK1. J Mol Biol. 2008;382:894‐909.
[70] Gonçalves V, Henriques A, Pereira J, et al. Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor‐related Rac1b in colorectal cells. RNA. 2014;20:474‐482.
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