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词条 Serine/arginine-rich splicing factor 1
释义

  1. Structure

  2. Splicing

  3. Post-splicing

  4. Regulation through phosphorylation

  5. Biological importance

      Stability and fidelity    Development and growth  

  6. Clinical significance

  7. Interactions

  8. References

{{Infobox_gene}}Serine/arginine-rich splicing factor 1 (SRSF1) also known as alternative splicing factor 1 (ASF1), pre-mRNA-splicing factor SF2 (SF2) or ASF1/SF2 is a protein that in humans is encoded by the SRSF1 gene.[1] ASF/SF2 is an essential sequence specific splicing factor involved in pre-mRNA splicing.[2][3][4] SRSF1 is the gene that codes for ASF/SF2[5] and is found on chromosome 17. The resulting splicing factor is a protein of approximately 33 kDa.[6] ASF/SF2 is necessary for all splicing reactions to occur, and influences splice site selection in a concentration-dependent manner, resulting in alternative splicing.[3] In addition to being involved in the splicing process, ASF/SF2 also mediates post-splicing activities, such as mRNA nuclear export and translation.[7]

Structure

ASF/SF2 is an SR protein, and as such, contains two functional modules: an arginine-serine rich region (RS domain), where the bulk of ASF/SF2 regulation takes place, and two RNA recognition motifs (RRMs), through which ASF/SF2 interacts with RNA and other splicing factors.[8][9] These modules have different functions within general splicing factor function.[9]

{{Gallery
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|Image:RRM2domain.png|NMR structure of the second RRM domain of ASF/SF2 based on the {{PDB|2O3D}} coordinates.[10]
|Image:ASF-SF2.png|ASF/SF2 (left: red/orange/yellow) complexed with SRPK1 (right: blue/green/yellow) based on the {{PDB2|3BEG}} crystallographic coordinates.[8]
}}

Splicing

ASF/SF2 is an integral part of numerous components of the splicing process. ASF/SF2 is required for 5’ splice site cleavage and selection, and is capable of discriminating between cryptic and authentic splice sites.[6] Subsequent lariat formation during the first chemical step of pre-mRNA splicing also requires ASF/SF2.[6] ASF/SF2 promotes recruitment of the U1 snRNP to the 5’ splice site, and bridges the 5’ and 3’ splice sites to facilitate splicing reactions.[4] ASF/SF2 also associates with the U2 snRNP.[11] During the reaction, ASF/SF2 promotes the use of intron proximal sites and hinders the use of intron distal sites, affecting alternative splicing.[12][13] Alternative splicing is affected by ASF/SF2 in a concentration-dependent manner; differing concentrations of ASF/SF2 is a mechanism for alternative splicing regulation, and will result in differing amounts of product isoforms.[2] ASF/SF2 accomplishes this regulation through direct or indirect binding to exonic splicing enhancer (ESE) sequences.[12]

Post-splicing

ASF/SF2, in the presence of elF4E, promotes the initiation of translation of ribosome-bound mRNA by suppressing the activity of 4E-BP and recruiting molecules for further regulation of translation.[7] ASF/SF2 interacts with the nuclear export protein TAP in a regulated manner, controlling the export of mature mRNA from the nucleus.[14] An increase in cellular ASF/SF2 also will increase the efficiency of nonsense-mediated mRNA decay (NMD), favoring NMD that occurs before mRNA release from the nucleus over NMD that occurs after mRNA export from the nucleus to the cytoplasm.[15] This shift in NMD caused by increased ASF/SF2 is accompanied by overall enhancement of the pioneer round of translation, through elF4E-bound mRNA translation and subsequent translationally active ribosomes, increased association of pioneer translation initiation complexes with ASF/SF2, and increased levels of active TAP.[15]

Regulation through phosphorylation

ASF/SF2 has the ability to be phosphorylated at the serines in its RS domain by the SR specific protein kinase, SRPK1.[9] SRPK1 and ASF/SF2 form an unusually stable complex of apparent Kd of 50nM.[8][14] SRPK1 selectively phosphorylates up to twelve serines in the RS domain of ASF/SF2 through a directional and processive mechanism, moving from the C terminus to the N terminus.[9] This multi-phosphorylation directs ASF/SF2 to the nucleus, influencing a number of protein-protein interactions associated with splicing.[9] ASF/SF2’s function in export of mature mRNA from the nucleus is dependent on its phosphorylation state; dephosphorylation of ASF/SF2 facilitates binding to TAP,[9] while phosphorylation directs ASF/SF2 to nuclear speckles.[14] Both phosphorylation and dephosphorylation of ASF/SF2 are important and necessary for proper splicing to occur, as sequential phosphorylation and dephosphorylation marks the transitions between stages in the splicing process.[16] In addition, hypophosphorylation and hyperphosphorylation of ASF/SF2 by Clk/Sty can lead to inhibition of splicing.[9]

Biological importance

Stability and fidelity

ASF/SF2 is involved in genomic stability; it is thought that RNA Polymerase recruits ASF/SF2 to nascent RNA transcripts to impede formation of mutagenic DNA:RNA hybrid R loop structures between the transcript and the template DNA.[4] In this way, ASF/SF2 is protecting cells from the potential deleterious effects of transcription itself.[4] ASF/SF2 is also implicated in cellular mechanisms to hinder exon skipping and to ensure splicing is occurring accurately and correctly.[6]

Development and growth

ASF/SF2 has been shown to have a critical function in heart development,[8] embryogenesis, tissue formation, cell motility, and cell viability in general.[17][18]

Clinical significance

SFRS1 is a proto-oncogene, and thus ASF/SF2 can act as an oncoprotein; it can alter the splicing patterns of crucial cell cycle regulatory genes and suppressor genes.[9] ASF/SF2 controls the splicing of various tumor suppressor genes, kinases, and kinase receptors, all of which have the potential to be alternatively spliced into oncogenic isoforms.[19] As such, ASF/SF2 is an important target for cancer therapy, as it is over-expressed in many tumors.[9]

Modifications and defects in the alternative splicing pathway are associated with a variety of human diseases.[20]

ASF/SF2 is involved in the replication of HIV-1, as HIV-1 needs a delicate balance of spliced and unspliced forms of its viral DNA.[21] ASF/SF2 action in the replication of HIV-1 is a potential target for HIV therapy.[21] ASF/SF2 is also implicated in the production of T cell receptors in Systemic Lupus Erythematosus, altering specific chain expression in T cell receptors through alternative splicing.[22][23]

Interactions

ASF/SF2 has been shown to interact with:

{{div col|colwidth=20em}}
  • CDC5L,[24]
  • CLK1,[25][26]
  • PSIP1,[27]
  • SFRS2,[53]
  • SRPK1,[26][28][29][30]
  • SRPK2,[26][29][30]
  • TOP1,[31][32]
  • U2 small nuclear RNA auxiliary factor 1,[33][64] and
  • snRNP70.[34][35]
{{Div col end}}

References

1. ^{{cite web | title = Entrez Gene: SFRS1 splicing factor, arginine/serine-rich 1 (splicing factor 2, alternate splicing factor)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6426| accessdate = }}
2. ^1 {{cite journal | vauthors = Kim DJ, Oh B, Kim YY | title = Splicing factor ASF/SF2 and transcription factor PPAR-gamma cooperate to directly regulate transcription of uncoupling protein-3 | journal = Biochemical and Biophysical Research Communications | volume = 378 | issue = 4 | pages = 877–82 | date = Jan 2009 | pmid = 19073146 | doi = 10.1016/j.bbrc.2008.12.009 }}
3. ^1 {{cite journal | vauthors = Zuo P, Manley JL | title = Functional domains of the human splicing factor ASF/SF2 | journal = The EMBO Journal | volume = 12 | issue = 12 | pages = 4727–37 | date = Dec 1993 | pmid = 8223481 | pmc = 413918 | doi = }}
4. ^1 2 3 {{cite journal | vauthors = Li X, Manley JL | title = Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability | journal = Cell | volume = 122 | issue = 3 | pages = 365–78 | date = Aug 2005 | pmid = 16096057 | doi = 10.1016/j.cell.2005.06.008 }}
5. ^{{cite journal | vauthors = Bermingham JR, Arden KC, Naumova AK, Sapienza C, Viars CS, Fu XD, Khotz J, Manley JL, Rosenfeld MG | title = Chromosomal localization of mouse and human genes encoding the splicing factors ASF/SF2 (SFRS1) and SC-35 (SFRS2) | journal = Genomics | volume = 29 | issue = 1 | pages = 70–9 | date = Sep 1995 | pmid = 8530103 | doi = 10.1006/geno.1995.1216 }}
6. ^1 2 3 {{cite journal | vauthors = Krainer AR, Conway GC, Kozak D | title = The essential pre-mRNA splicing factor SF2 influences 5' splice site selection by activating proximal sites | journal = Cell | volume = 62 | issue = 1 | pages = 35–42 | date = Jul 1990 | pmid = 2364434 | doi = 10.1016/0092-8674(90)90237-9 }}
7. ^1 {{cite journal | vauthors = Michlewski G, Sanford JR, Cáceres JF | title = The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1 | journal = Molecular Cell | volume = 30 | issue = 2 | pages = 179–89 | date = Apr 2008 | pmid = 18439897 | doi = 10.1016/j.molcel.2008.03.013 }}
8. ^1 2 3 {{cite journal | vauthors = Ngo JC, Giang K, Chakrabarti S, Ma CT, Huynh N, Hagopian JC, Dorrestein PC, Fu XD, Adams JA, Ghosh G | title = A sliding docking interaction is essential for sequential and processive phosphorylation of an SR protein by SRPK1 | journal = Molecular Cell | volume = 29 | issue = 5 | pages = 563–76 | date = Mar 2008 | pmid = 18342604 | pmc = 2852395 | doi = 10.1016/j.molcel.2007.12.017 }}
9. ^1 2 3 4 5 6 7 8 {{cite journal | vauthors = Hagopian JC, Ma CT, Meade BR, Albuquerque CP, Ngo JC, Ghosh G, Jennings PA, Fu XD, Adams JA | title = Adaptable molecular interactions guide phosphorylation of the SR protein ASF/SF2 by SRPK1 | journal = Journal of Molecular Biology | volume = 382 | issue = 4 | pages = 894–909 | date = Oct 2008 | pmid = 18687337 | pmc = 2741138 | doi = 10.1016/j.jmb.2008.07.055 }}
10. ^{{cite journal | vauthors = Tintaru AM, Hautbergue GM, Hounslow AM, Hung ML, Lian LY, Craven CJ, Wilson SA | title = Structural and functional analysis of RNA and TAP binding to SF2/ASF | journal = EMBO Rep. | volume = 8 | issue = 8 | pages = 756–62 |date=August 2007 | pmid = 17668007 | pmc = 1978082 | doi = 10.1038/sj.embor.7401031 | url = | issn = }}
11. ^{{cite journal | vauthors = Masuyama K, Taniguchi I, Okawa K, Ohno M | title = Factors associated with a purine-rich exonic splicing enhancer sequence in Xenopus oocyte nucleus | journal = Biochemical and Biophysical Research Communications | volume = 359 | issue = 3 | pages = 580–5 | date = Aug 2007 | pmid = 17548051 | doi = 10.1016/j.bbrc.2007.05.144 }}
12. ^1 {{cite journal | vauthors = Zhang X, Merkler KA, McLean MP | title = Characterization of regulatory intronic and exonic sequences involved in alternative splicing of scavenger receptor class B gene | journal = Biochemical and Biophysical Research Communications | volume = 372 | issue = 1 | pages = 173–8 | date = Jul 2008 | pmid = 18477479 | doi = 10.1016/j.bbrc.2008.05.007 }}
13. ^{{cite journal | vauthors = Wang Z, Xiao X, Van Nostrand E, Burge CB | title = General and specific functions of exonic splicing silencers in splicing control | journal = Molecular Cell | volume = 23 | issue = 1 | pages = 61–70 | date = Jul 2006 | pmid = 16797197 | pmc = 1839040 | doi = 10.1016/j.molcel.2006.05.018 }}
14. ^1 2 {{cite journal | vauthors = Ma CT, Velazquez-Dones A, Hagopian JC, Ghosh G, Fu XD, Adams JA | title = Ordered multi-site phosphorylation of the splicing factor ASF/SF2 by SRPK1 | journal = Journal of Molecular Biology | volume = 376 | issue = 1 | pages = 55–68 | date = Feb 2008 | pmid = 18155240 | doi = 10.1016/j.jmb.2007.08.029 }}
15. ^1 {{cite journal | vauthors = Sato H, Hosoda N, Maquat LE | title = Efficiency of the pioneer round of translation affects the cellular site of nonsense-mediated mRNA decay | journal = Molecular Cell | volume = 29 | issue = 2 | pages = 255–62 | date = Feb 2008 | pmid = 18243119 | doi = 10.1016/j.molcel.2007.12.009 }}
16. ^{{cite journal | vauthors = Cao W, Jamison SF, Garcia-Blanco MA | title = Both phosphorylation and dephosphorylation of ASF/SF2 are required for pre-mRNA splicing in vitro | journal = RNA | volume = 3 | issue = 12 | pages = 1456–67 | date = Dec 1997 | pmid = 9404896 | pmc = 1369586 | doi = | url = http://rnajournal.cshlp.org/content/3/12/1456.abstract }}
17. ^{{cite journal | vauthors = Ghigna C, Giordano S, Shen H, Benvenuto F, Castiglioni F, Comoglio PM, Green MR, Riva S, Biamonti G | title = Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene | journal = Molecular Cell | volume = 20 | issue = 6 | pages = 881–90 | date = Dec 2005 | pmid = 16364913 | doi = 10.1016/j.molcel.2005.10.026 }}
18. ^{{cite journal | vauthors = Lin S, Xiao R, Sun P, Xu X, Fu XD | title = Dephosphorylation-dependent sorting of SR splicing factors during mRNP maturation | journal = Molecular Cell | volume = 20 | issue = 3 | pages = 413–25 | date = Nov 2005 | pmid = 16285923 | doi = 10.1016/j.molcel.2005.09.015 }}
19. ^{{cite journal | vauthors = Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D, Krainer AR | title = The gene encoding the splicing factor SF2/ASF is a proto-oncogene | journal = Nature Structural & Molecular Biology | volume = 14 | issue = 3 | pages = 185–93 | date = Mar 2007 | pmid = 17310252 | doi = 10.1038/nsmb1209 | pmc = 4595851 }}
20. ^{{cite journal | vauthors = Watanuki T, Funato H, Uchida S, Matsubara T, Kobayashi A, Wakabayashi Y, Otsuki K, Nishida A, Watanabe Y | title = Increased expression of splicing factor SRp20 mRNA in bipolar disorder patients | journal = Journal of Affective Disorders | volume = 110 | issue = 1–2 | pages = 62–9 | date = Sep 2008 | pmid = 18281098 | doi = 10.1016/j.jad.2008.01.003 }}
21. ^1 {{cite journal | vauthors = Tange TØ, Kjems J | title = SF2/ASF binds to a splicing enhancer in the third HIV-1 tat exon and stimulates U2AF binding independently of the RS domain | journal = Journal of Molecular Biology | volume = 312 | issue = 4 | pages = 649–62 | date = Sep 2001 | pmid = 11575921 | doi = 10.1006/jmbi.2001.4971 }}
22. ^{{cite journal | vauthors = Moulton V, Perl M, Tsokos G | title = Alternative splicing factor/splicing factor 2 (ASF/SF2) regulates the expression of T cell receptor ζ chain | journal = Clinical Immunology | volume = 127 | page = S95 | year=2008 | doi=10.1016/j.clim.2008.03.266 }}
23. ^{{cite journal | vauthors = Moulton VR, Grammatikos AP, Fitzgerald LM, Tsokos GC | title = Splicing factor SF2/ASF rescues IL-2 production in T cells from systemic lupus erythematosus patients by activating IL-2 transcription | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 5 | pages = 1845–50 | date = Jan 2013 | pmid = 23319613 | doi = 10.1073/pnas.1214207110 | pmc=3562779}}
24. ^{{cite journal | vauthors = Ajuh P, Kuster B, Panov K, Zomerdijk JC, Mann M, Lamond AI | title = Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry | journal = The EMBO Journal | volume = 19 | issue = 23 | pages = 6569–81 | date = Dec 2000 | pmid = 11101529 | pmc = 305846 | doi = 10.1093/emboj/19.23.6569 }}
25. ^{{cite journal | vauthors = Colwill K, Feng LL, Yeakley JM, Gish GD, Cáceres JF, Pawson T, Fu XD | title = SRPK1 and Clk/Sty protein kinases show distinct substrate specificities for serine/arginine-rich splicing factors | journal = The Journal of Biological Chemistry | volume = 271 | issue = 40 | pages = 24569–75 | date = Oct 1996 | pmid = 8798720 | doi = 10.1074/jbc.271.40.24569}}
26. ^1 2 {{cite journal | vauthors = Umehara H, Nishii Y, Morishima M, Kakehi Y, Kioka N, Amachi T, Koizumi J, Hagiwara M, Ueda K | title = Effect of cisplatin treatment on speckled distribution of a serine/arginine-rich nuclear protein CROP/Luc7A | journal = Biochemical and Biophysical Research Communications | volume = 301 | issue = 2 | pages = 324–9 | date = Feb 2003 | pmid = 12565863 | doi = 10.1016/s0006-291x(02)03017-6}}
27. ^{{cite journal | vauthors = Ge H, Si Y, Wolffe AP | title = A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2 | journal = Molecular Cell | volume = 2 | issue = 6 | pages = 751–9 | date = Dec 1998 | pmid = 9885563 | doi = 10.1016/s1097-2765(00)80290-7}}
28. ^{{cite journal | vauthors = Lukasiewicz R, Velazquez-Dones A, Huynh N, Hagopian J, Fu XD, Adams J, Ghosh G | title = Structurally unique yeast and mammalian serine-arginine protein kinases catalyze evolutionarily conserved phosphorylation reactions | journal = The Journal of Biological Chemistry | volume = 282 | issue = 32 | pages = 23036–43 | date = Aug 2007 | pmid = 17517895 | doi = 10.1074/jbc.M611305200 }}
29. ^1 {{cite journal | vauthors = Wang HY, Lin W, Dyck JA, Yeakley JM, Songyang Z, Cantley LC, Fu XD | title = SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells | journal = The Journal of Cell Biology | volume = 140 | issue = 4 | pages = 737–50 | date = Feb 1998 | pmid = 9472028 | pmc = 2141757 | doi = 10.1083/jcb.140.4.737}}
30. ^1 {{cite journal | vauthors = Koizumi J, Okamoto Y, Onogi H, Mayeda A, Krainer AR, Hagiwara M | title = The subcellular localization of SF2/ASF is regulated by direct interaction with SR protein kinases (SRPKs) | journal = The Journal of Biological Chemistry | volume = 274 | issue = 16 | pages = 11125–31 | date = Apr 1999 | pmid = 10196197 | doi = 10.1074/jbc.274.16.11125}}
31. ^{{cite journal | vauthors = Labourier E, Rossi F, Gallouzi IE, Allemand E, Divita G, Tazi J | title = Interaction between the N-terminal domain of human DNA topoisomerase I and the arginine-serine domain of its substrate determines phosphorylation of SF2/ASF splicing factor | journal = Nucleic Acids Research | volume = 26 | issue = 12 | pages = 2955–62 | date = Jun 1998 | pmid = 9611241 | pmc = 147637 | doi = 10.1093/nar/26.12.2955}}
32. ^{{cite journal | vauthors = Andersen FF, Tange TØ, Sinnathamby T, Olesen JR, Andersen KE, Westergaard O, Kjems J, Knudsen BR | title = The RNA splicing factor ASF/SF2 inhibits human topoisomerase I mediated DNA relaxation | journal = Journal of Molecular Biology | volume = 322 | issue = 4 | pages = 677–86 | date = Sep 2002 | pmid = 12270705 | doi = 10.1016/s0022-2836(02)00815-x}}
33. ^1 {{cite journal | vauthors = Zhang WJ, Wu JY | title = Functional properties of p54, a novel SR protein active in constitutive and alternative splicing | journal = Molecular and Cellular Biology | volume = 16 | issue = 10 | pages = 5400–8 | date = Oct 1996 | pmid = 8816452 | pmc = 231539 | doi = }}
34. ^1 {{cite journal | vauthors = Xiao SH, Manley JL | title = Phosphorylation-dephosphorylation differentially affects activities of splicing factor ASF/SF2 | journal = The EMBO Journal | volume = 17 | issue = 21 | pages = 6359–67 | date = Nov 1998 | pmid = 9799243 | pmc = 1170960 | doi = 10.1093/emboj/17.21.6359 }}
35. ^{{cite journal | vauthors = Cao W, Garcia-Blanco MA | title = A serine/arginine-rich domain in the human U1 70k protein is necessary and sufficient for ASF/SF2 binding | journal = The Journal of Biological Chemistry | volume = 273 | issue = 32 | pages = 20629–35 | date = Aug 1998 | pmid = 9685421 | doi = 10.1074/jbc.273.32.20629}}
{{DEFAULTSORT:ASF SF2}}

3 : Gene expression|Human proteins|Biology of bipolar disorder
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