SRSF2

Primary Author(s)*

Paul De Fazio, MSc, Monash Health

Synonyms

• Splicing Factor, Arginine/Serine-Rich 2
• Serine And Arginine Rich Splicing Factor 2
• Splicing Component, 35 KDa
• Splicing Factor SC35
• SC35

Genomic Location

Cytoband: 17q25.1

Genomic Coordinates:

chr17:74,730,197-74,733,493 [hg19]

chr17:76,734,115-76,737,629 [hg38]

Cancer Category/Type

Myelodysplastic Syndromes (MDS)

SRSF2 is mutated in approximately 14% of MDS patients (Papaemmanuil et al., 2013). SRSF2 variants are mutually exclusive to EZH2 variants, SF3B1 variants, and pathogenic variants in other splicing factors, but are positively correlated with IDH1, IDH2, and RUNX1 mutations (Papaemmanuil et al., 2013; Thol et al., 2012; Yoshida et al., 2011). SRSF2 variants typically originate early in the generation of dysplastic lineages (Papaemmanuil et al., 2013). SRSF2 variants correlate with shorter overall survival and more frequent progression to acute myeloid leukemia (AML) (Thol et al., 2012). These variants are almost always missense mutations in proline residue 95 (NM_003016.4) (Yoshida et al., 2011).

Chronic Myelomonocytic Leukemia (CMML)

SRSF2 variants, predominantly missense mutations affecting the proline 95 (NM_003016.4) residue, are seen in approximately 32-47% of chronic myelomonocytic leukemia (CMML) cases but rarely in juvenile myelomonocytic leukemia (Kar et al., 2013; Meggendorfer et al., 2012). SRSF2 variants are positively correlated with higher age, less pronounced anemia, and a normal karyotype. The prognostic impact is unclear, although SRSF2 and RUNX1 co-mutation may correlate with an improved overall survival (Itzykson et al., 2013; Meggendorfer et al., 2012). EZH2 and SRSF2 variants are mutually exclusive (Meggendorfer et al., 2012).

Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms

Mutations in SRSF2, mostly affecting proline 95 (NM_003016.4), are found in ~7% of acute myeloid leukemia (AML) with myelodysplasia-related changes but rarely (<1%) in patients with de novo AML (Yoshida et al., 2011). One study found that SRSF2 variants correlated with older age but no other prognostic markers in AML; however, AML sub-types were not separated (Yang et al., 2016). Another study reported decreased survival in patients with SRSF2-mutated AML, and concurrent SRSF2 and ASXL1 variants resulted in poorer probability of survival than either variant alone (Papaemmanuil et al., 2016).

Gene Overview

SRSF2 is a member of the SR superfamily of proteins defined by an Arginine/Serine-rich domain (or RS domain) at their C terminus and invariably an N-terminal RNA recognition motif (Zhou and Fu, 2013). SRSF2 and other SR family members are able to auto- and cross-regulate themselves through ‘unproductive splicing’ (Lareau et al., 2007). The SR proteins are functionally distinct (Zahler et al., 1993). Unlike other SR proteins which are shuttled in and out of the nucleus continuously, SRSF2 remains exclusively in the nucleus (Cáceres et al., 1998).

SRSF2 is involved in constitutive splicing (Fu and Maniatis, 1990) by promoting U1 snRNP binding to the 5’ splice site and U2 snRNP binding to the 3’ splice site of immature mRNA, and facilitating spliceosome recruitment, the latter of which requires SR phosphorylation (Fu and Maniatis, 1992; Roscigno and Garcia-Blanco, 1995).

Acetylation and phosphorylation are important regulatory modifications of SR family proteins (reviewed in Zhou and Fu, 2013). SRSF2 specifically is acetylated by TIP60 and deacetylated by HDAC6 on lysine residue 52, which mediates its RNA-binding and proteasomal degradation; treatment of cells with cisplatin inhibits TIP60 and therefore stabilises SRSF2 (Edmond et al., 2011). Phosphorylation occurs primarily through SR-protein specific kinases (SRPKs) and CDC-2 like kinases (CLKs), which function symbiotically in phosphorylating and dephosphorylating SR proteins at the SR domain (Aubol et al., 2016). This function appears to be necessary for spliceosome progression from assembly to catalysis and, in SR proteins other than SRSF2, for intracellular trafficking (reviewed in Zhou and Fu, 2013). The AKT-SRPK-SR protein axis is a major pathway for EGF signalling to regulate alternative splicing, whereby activated AKT enhances SRPK nuclear localisation with involvement from heat shock proteins Hsp70 and Hsp90 and 14-3-3 proteins (Zhou et al., 2012). SR protein function is also regulated by their competition with heterogeneous nuclear ribonucleoproteins (hnRNPs) for RNA binding (Lin and Fu, 2007).

SR proteins are essential for development in a tissue specific manner, with SRSF2 in particular playing roles in heart development, T-cell development through alternative splicing of CD45, and haematopoiesis (Ding et al., 2004; Komeno et al., 2015; Wang et al., 2001). In angiogenesis SRSF2 promotes the alternative splicing of an anti-angiogenic form of vascular endothelial growth factor (VEGF) (Merdzhanova et al., 2010). In cancer, SRSF2 variants have been implicated in leukemia and myeloid disorders (Meggendorfer et al., 2012; Yoshida et al., 2011). These variants, predominantly affecting proline residue 95 (NM_003016.4), alter splicing of SRSF2 targets by impairing RNA binding, likely explaining their pathogenicity (Kim et al., 2015; Zhang et al., 2015). SRSF2 mutations are associated with age-related clonal hematopoiesis (Mason et al., 2016; McKerrell et al., 2015).

Common Alteration Types

SRSF2 variants almost exclusively affect proline residue 95 (NM_003016.4), which lies between the RNA-binding and RS domains.

Copy Number Loss	Copy Number Gain	LOH	Loss-of-Function Mutation	Gain-of-Function Mutation	Translocation/Fusion
EXAMPLE: X	EXAMPLE: X	EXAMPLE: X	EXAMPLE: X	EXAMPLE: X	EXAMPLE: X

Internal Pages

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External Links

SRSF2 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information

SRSF2 by COSMIC - sequence information, expression, catalogue of mutations

SRSF2 by CIViC - general knowledge and evidence-based variant specific information

SRSF2 by St. Jude ProteinPaint mutational landscape and matched expression data.

SRSF2 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs

SRSF2 by Cancer Index - gene, pathway, publication information matched to cancer type

SRSF2 by OncoKB - mutational landscape, mutation effect, variant classification

SRSF2 by My Cancer Genome - brief gene overview

SRSF2 by UniProt - protein and molecular structure and function

SRSF2 by Pfam - gene and protein structure and function information

SRSF2 by GeneCards - general gene information and summaries

References

• Aubol, B.E., Wu, G., Keshwani, M.M., Movassat, M., Fattet, L., Hertel, K.J., Fu, X.-D., and Adams, J.A. (2016). Release of SR Proteins from CLK1 by SRPK1: A Symbiotic Kinase System for Phosphorylation Control of Pre-mRNA Splicing. Mol. Cell 63, 218–228. PMID: 27397683

• Cáceres, J.F., Screaton, G.R., and Krainer, A.R. (1998). A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm. Genes Dev. 12, 55–66. PMID: 9420331

• Ding, J.H., Xu, X., Yang, D., Chu, P.H., Dalton, N.D., Ye, Z., Yeakley, J.M., Cheng, H., Xiao, R.-P., Ross, J., et al. (2004). Dilated cardiomyopathy caused by tissue-specific ablation of SC35 in the heart. EMBO J. 23, 885–896. PMID: 14963485

• Edmond, V., Moysan, E., Khochbin, S., Matthias, P., Brambilla, C., Brambilla, E., Gazzeri, S., and Eymin, B. (2011). Acetylation and phosphorylation of SRSF2 control cell fate decision in response to cisplatin. EMBO J. 30, 510–523. PMID: 21157427

• Erkelenz, S., Mueller, W.F., Evans, M.S., Busch, A., Schöneweis, K., Hertel, K.J., and Schaal, H. (2013). Position-dependent splicing activation and repression by SR and hnRNP proteins rely on common mechanisms. RNA N. Y. N 19, 96–102. PMID: 23175589

• Fu, X.D., and Ares, M. (2014). Context-dependent control of alternative splicing by RNA-binding proteins. Nat. Rev. Genet. 15, 689–701. PMID: 25112293

• Fu, X.D., and Maniatis, T. (1990). Factor required for mammalian spliceosome assembly is localized to discrete regions in the nucleus. Nature 343, 437–441. PMID: 2137203

• Fu, X.D., and Maniatis, T. (1992). The 35-kDa mammalian splicing factor SC35 mediates specific interactions between U1 and U2 small nuclear ribonucleoprotein particles at the 3’ splice site. Proc. Natl. Acad. Sci. U. S. A. 89, 1725–1729. PMID: 1531875

• Han, J., Ding, J.H., Byeon, C.W., Kim, J.H., Hertel, K.J., Jeong, S., and Fu, X.-D. (2011). SR proteins induce alternative exon skipping through their activities on the flanking constitutive exons. Mol. Cell. Biol. 31, 793–802. PMID: 21135118

• Itzykson, R., Kosmider, O., Renneville, A., Gelsi-Boyer, V., Meggendorfer, M., Morabito, M., Berthon, C., Adès, L., Fenaux, P., Beyne-Rauzy, O., et al. (2013). Prognostic Score Including Gene Mutations in Chronic Myelomonocytic Leukemia. J. Clin. Oncol. 31, 2428–2436. PMID: 23690417

• Kar, S.A., Jankowska, A., Makishima, H., Visconte, V., Jerez, A., Sugimoto, Y., Muramatsu, H., Traina, F., Afable, M., Guinta, K., et al. (2013). Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia. Haematologica 98, 107–113. PMID: 22773603

• Kim, E., Ilagan, J.O., Liang, Y., Daubner, G.M., Lee, S.C.W., Ramakrishnan, A., Li, Y., Chung, Y.R., Micol, J.-B., Murphy, M., et al. (2015). SRSF2 Mutations Contribute to Myelodysplasia Through Mutant-Specific Effects on Exon Recognition. Cancer Cell 27, 617–630. PMID: 25965569

• Komeno, Y., Huang, Y.J., Qiu, J., Lin, L., Xu, Y., Zhou, Y., Chen, L., Monterroza, D.D., Li, H., DeKelver, R.C., et al. (2015). SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative Pre-mRNA Splicing. Mol. Cell. Biol. 35, 3071–3082. PMID: 26124281

• Lareau, L.F., Inada, M., Green, R.E., Wengrod, J.C., and Brenner, S.E. (2007). Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 446, 926–929. PMID: 17361132

• Lin, S., and Fu, X.D. (2007). SR proteins and related factors in alternative splicing. Adv. Exp. Med. Biol. 623, 107–122. PMID: 18380343

• Lin, S., Coutinho-Mansfield, G., Wang, D., Pandit, S., and Fu, X.-D. (2008). The splicing factor SC35 has an active role in transcriptional elongation. Nat. Struct. Mol. Biol. 15, 819–826. PMID: 18641664

• Liu, H.X., Chew, S.L., Cartegni, L., Zhang, M.Q., and Krainer, A.R. (2000). Exonic splicing enhancer motif recognized by human SC35 under splicing conditions. Mol. Cell. Biol. 20, 1063–1071. PMID: 10629063

• Mason, C.C., Khorashad, J.S., Tantravahi, S.K., Kelley, T.W., Zabriskie, M.S., Yan, D., Pomicter, A.D., Reynolds, K.R., Eiring, A.M., Kronenberg, Z., et al. (2016). Age-related mutations and chronic myelomonocytic leukemia. Leukemia 30, 906–913. PMID: 26648538

• McKerrell, T., Park, N., Moreno, T., Grove, C.S., Ponstingl, H., Stephens, J., Crawley, C., Craig, J., Scott, M.A., Hodkinson, C., et al. (2015). Leukemia-Associated Somatic Mutations Drive Distinct Patterns of Age-Related Clonal Hemopoiesis. Cell Rep. 10, 1239–1245. PMID: 25732814

• Meggendorfer, M., Roller, A., Haferlach, T., Eder, C., Dicker, F., Grossmann, V., Kohlmann, A., Alpermann, T., Yoshida, K., Ogawa, S., et al. (2012). SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood 120, 3080–3088. PMID: 22919025

• Merdzhanova, G., Gout, S., Keramidas, M., Edmond, V., Coll, J.-L., Brambilla, C., Brambilla, E., Gazzeri, S., and Eymin, B. (2010). The transcription factor E2F1 and the SR protein SC35 control the ratio of pro-angiogenic versus antiangiogenic isoforms of vascular endothelial growth factor-A to inhibit neovascularization in vivo. Oncogene 29, 5392–5403. PMID: 20639906

• Papaemmanuil, E., Gerstung, M., Malcovati, L., Tauro, S., Gundem, G., Loo, P.V., Yoon, C.J., Ellis, P., Wedge, D.C., Pellagatti, A., et al. (2013). Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122, 3616–3627. PMID: 24030381

• Roscigno, R.F., and Garcia-Blanco, M.A. (1995). SR proteins escort the U4/U6.U5 tri-snRNP to the spliceosome. RNA N. Y. N 1, 692–706. PMID: 7585254

• Thol, F., Kade, S., Schlarmann, C., Löffeld, P., Morgan, M., Krauter, J., Wlodarski, M.W., Kölking, B., Wichmann, M., Görlich, K., et al. (2012). Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 119, 3578–3584. PMID: 22389253

• Wang, H.Y., Xu, X., Ding, J.H., Bermingham, J.R., and Fu, X.D. (2001). SC35 plays a role in T cell development and alternative splicing of CD45. Mol. Cell 7, 331–342. PMID: 11239462

• Xiao, R., Sun, Y., Ding, J.-H., Lin, S., Rose, D.W., Rosenfeld, M.G., Fu, X.-D., and Li, X. (2007). Splicing Regulator SC35 Is Essential for Genomic Stability and Cell Proliferation during Mammalian Organogenesis. Mol. Cell. Biol. 27, 5393–5402. PMID: 17526736

• Yang, J., Yao, D., Ma, J., Yang, L., Guo, H., Wen, X., Xiao, G., Qian, Z., Lin, J., and Qian, J. (2016). The prognostic implication of SRSF2 mutations in Chinese patients with acute myeloid leukemia. Tumor Biol. 37, 10107–10114. PMID: 26820131

• Yoshida, K., Sanada, M., Shiraishi, Y., Nowak, D., Nagata, Y., Yamamoto, R., Sato, Y., Sato-Otsubo, A., Kon, A., Nagasaki, M., et al. (2011). Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64–69. PMID: 21909114

• Zahler, A.M., Neugebauer, K.M., Lane, W.S., and Roth, M.B. (1993). Distinct functions of SR proteins in alternative pre-mRNA splicing. Science 260, 219–222. PMID: 8385799

• Zhang, J., Lieu, Y.K., Ali, A.M., Penson, A., Reggio, K.S., Rabadan, R., Raza, A., Mukherjee, S., and Manley, J.L. (2015). Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities. Proc. Natl. Acad. Sci. U. S. A. 112, E4726–E4734. PMID: 26261309

• Zhou, Z., and Fu, X.D. (2013). Regulation of Splicing by SR proteins and SR Protein-Specific Kinases. Chromosoma 122, 191–207. PMID: 23525660

• Zhou, Z., Qiu, J., Liu, W., Zhou, Y., Plocinik, R.M., Li, H., Hu, Q., Ghosh, G., Adams, J.A., Rosenfeld, M.G., et al. (2012). The Akt-SRPK-SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus. Mol. Cell 47, 422–433. PMID: 22727668

Notes

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