View source for Serine/arginine-rich splicing factor 1

{{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]].<ref name="entrez">{{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 = }}</ref> ASF/SF2 is an essential sequence specific [[splicing factor]] involved in [[RNA splicing|pre-mRNA splicing]].<ref name="kim">{{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 }}</ref><ref name="zuo">{{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 =  }}</ref><ref name="li">{{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 }}</ref> SRSF1 is the gene that codes for ASF/SF2<ref name="bermingham">{{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 }}</ref> and is found on [[chromosome 17]].  The resulting splicing factor is a protein of approximately 33 [[Dalton (unit)|kDa]].<ref name="krainer">{{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 }}</ref> ASF/SF2 is necessary for all splicing reactions to occur, and influences splice site selection in a concentration-dependent manner, resulting in [[alternative splicing]].<ref name="zuo" /> In addition to being involved in the splicing process, ASF/SF2 also mediates post-splicing activities, such as [[mRNA]] nuclear export and [[Translation (biology)|translation]].<ref name="michlewski">{{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 }}</ref>

== 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.<ref name="ngo">{{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 }}</ref><ref name="hagopian">{{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 }}</ref> These modules have different functions within general splicing factor function.<ref name="hagopian" />
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|Image:RRM2domain.png|[[Protein nuclear magnetic resonance spectroscopy|NMR]] structure of the second RRM domain of ASF/SF2 based on the {{PDB|2O3D}} coordinates.<ref name="pmid17668007">{{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 = }}</ref>
|Image:ASF-SF2.png|ASF/SF2 (left: red/orange/yellow) complexed with [[SRPK1]] (right: blue/green/yellow) based on the {{PDB2|3BEG}} [[X-ray crystallography#Protein crystallography|crystallographic]] coordinates.<ref name="ngo" />
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== 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.<ref name="krainer" /> Subsequent lariat formation during the first chemical step of pre-mRNA splicing also requires ASF/SF2.<ref name="krainer" /> ASF/SF2 promotes recruitment of the [[U1 snRNA|U1]] snRNP to the 5’ splice site, and bridges the 5’ and 3’ splice sites to facilitate splicing reactions.<ref name="li" /> ASF/SF2 also associates with the [[U2 snRNA|U2]] snRNP.<ref name="masuyama">{{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 }}</ref> During the  reaction, ASF/SF2 promotes the use of [[intron]] proximal sites and hinders the use of intron distal sites, affecting [[alternative splicing]].<ref name="zhang">{{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 }}</ref><ref name="wang">{{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 }}</ref> 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 [[protein isoform|isoforms]].<ref name="kim" /> ASF/SF2 accomplishes this regulation through direct or indirect binding to [[exonic splicing enhancer]] (ESE) sequences.<ref name="zhang" />

== Post-splicing ==

ASF/SF2, in the presence of [[eukaryotic initiation factor|elF4E]], promotes the initiation of translation of [[ribosome]]-bound mRNA by suppressing the activity of [[EIF4EBP1|4E-BP]] and recruiting molecules for further regulation of translation.<ref name="michlewski" /> ASF/SF2 interacts with the nuclear export protein TAP in a regulated manner, controlling the export of mature mRNA from the [[cell nucleus|nucleus]].<ref name="ma">{{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 }}</ref> An increase in cellular ASF/SF2 also will increase the efficiency of [[nonsense mediated decay|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.<ref name="sato">{{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 }}</ref> 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.<ref name="sato" />

== 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]].<ref name="hagopian" /> SRPK1 and ASF/SF2 form an unusually stable complex of apparent [[dissociation constant|K<sub>d</sub>]] of 50nM.<ref name="ngo" /><ref name="ma" /> 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]].<ref name="hagopian" /> This multi-phosphorylation directs ASF/SF2 to the nucleus, influencing a number of protein-protein interactions associated with splicing.<ref name="hagopian" /> ASF/SF2’s function in export of [[mature messenger RNA|mature mRNA]] from the nucleus is dependent on its phosphorylation state; dephosphorylation of ASF/SF2 facilitates binding to TAP,<ref name="hagopian" /> while phosphorylation directs ASF/SF2 to [[splicing speckles|nuclear speckles]].<ref name="ma" /> 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.<ref name="pmid9404896">{{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 }}</ref> In addition, hypophosphorylation and hyperphosphorylation of ASF/SF2 by [[CLK1|Clk/Sty]] can lead to inhibition of splicing.<ref name="hagopian" />

== 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.<ref name="li" /> In this way, ASF/SF2 is protecting cells from the potential deleterious effects of transcription itself.<ref name="li" /> ASF/SF2 is also implicated in cellular mechanisms to hinder exon skipping and to ensure splicing is occurring accurately and correctly.<ref name="krainer" />

=== Development and growth ===

ASF/SF2 has been shown to have a critical function in heart development,<ref name="ngo" /> embryogenesis, tissue formation, cell motility, and cell viability in general.<ref name="ghigna">{{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 }}</ref><ref name="pmid16285923">{{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 }}</ref>

== Clinical significance ==

SFRS1 is a [[oncogene|proto-oncogene]], and thus ASF/SF2 can act as an oncoprotein; it can alter the splicing patterns of crucial [[cell cycle|cell cycle regulatory genes]] and [[tumor suppressor gene|suppressor genes]].<ref name="hagopian" /> ASF/SF2 controls the splicing of various tumor suppressor genes, [[kinase]]s, and [[receptor tyrosine kinase|kinase receptors]], all of which have the potential to be alternatively spliced into oncogenic isoforms.<ref name="pmid17310252">{{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 }}</ref> As such, ASF/SF2 is an important target for cancer therapy, as it is over-expressed in many [[tumor]]s.<ref name="hagopian" />

Modifications and defects in the alternative splicing pathway are associated with a variety of human diseases.<ref name="pmid18281098">{{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 }}</ref>

ASF/SF2 is involved in the replication of [[subtypes of HIV|HIV-1]], as HIV-1 needs a delicate balance of spliced and unspliced forms of its viral DNA.<ref name="tange">{{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 }}</ref> ASF/SF2 action in the replication of HIV-1 is a potential target for HIV therapy.<ref name="tange" /> ASF/SF2 is also implicated in the production of T cell receptors in [[Systemic lupus erythematosus|Systemic Lupus Erythematosus]], altering specific chain expression in T cell receptors through alternative splicing.<ref>{{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 }}</ref><ref>{{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}}</ref>

== Interactions ==

ASF/SF2 has been shown to [[Protein-protein interaction|interact]] with:
{{div col|colwidth=20em}}
* [[CDC5L]],<ref name = pmid11101529>{{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 }}</ref>
* [[CLK1]],<ref name = pmid8798720>{{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}}</ref><ref name = pmid12565863>{{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}}</ref> 
* [[PSIP1]],<ref name = pmid9885563>{{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}}</ref> 
* [[SFRS2]],<ref name = pmid8816452/> 
* [[SRPK1]],<ref name = pmid12565863/><ref name = pmid17517895>{{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 }}</ref><ref name = pmid9472028>{{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}}</ref><ref name = pmid10196197>{{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}}</ref> 
* [[SRPK2]],<ref name = pmid12565863/><ref name = pmid9472028/><ref name = pmid10196197/> 
* [[TOP1]],<ref name = pmid9611241>{{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}}</ref><ref name = pmid12270705>{{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}}</ref> 
* [[U2 small nuclear RNA auxiliary factor 1]],<ref name = pmid8816452>{{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 =  }}</ref><ref name = pmid9799243/>  and
* [[snRNP70]].<ref name = pmid9799243>{{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 }}</ref><ref name = pmid9685421>{{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}}</ref> 
{{Div col end}}

== References ==
{{reflist|33em}}

{{DEFAULTSORT:ASF SF2}}
[[Category:Gene expression]]
[[Category:Human proteins]]
[[Category:Biology of bipolar disorder]]