Abstract
In eukaryotic cells, RNA binding proteins (RBPs) play critical roles in regulating almost every aspect of gene expression, often shuttling between the nucleus and the cytoplasm. They are also key determinants in cell fate via controlling the target mRNAs under the regulation of various signaling pathways in response to environmental stresses. Therefore, understanding the mechanisms that couple the location of mRNA and RBPs is a major challenge in the field of gene expression and signal responses. In fission yeast, a KH-type RBP Rnc1 negatively regulates MAPK signaling activation via mRNA stabilization of the dual-specificity MAPK phosphatase Pmp1, which dephosphorylates MAPK Pmk1. Rnc1 also serves as a target of MAPK phosphorylation, which makes a feedback loop mediated by an RBP. We recently discovered that the nuclear export of Rnc1 requires mRNA-binding ability and the mRNA export factor Rae1. This strongly suggested the presence of an mRNA-export system, which recognizes the mRNA/RBP complex and dictates the location and post-transcriptional regulation of mRNA cargo. Here, we briefly review the known mechanisms of general nuclear transporting systems, with an emphasis on our recent findings on the spatial regulation of Rnc1 and its impact on the regulation of the MAPK signal transduction cascade.
Similar content being viewed by others
References
Alessi DR, Smythe C, Keyse SM (1993) The human CL100 gene encodes a Tyr/Thr-protein phosphatase which potently and specifically inactivates MAP kinase and suppresses its activation by oncogenic ras in Xenopus oocyte extracts. Oncogene 8:2015–2020
Bakheet T, Frevel M, Williams BR, Greer W, Khabar KS (2001) ARED: human AU-rich element-containing mRNA database reveals an unexpectedly diverse functional repertoire of encoded proteins. Nucleic Acids Res 29:246–254
Bharathi A, Ghosh A, Whalen WA, Yoon JH, Pu R, Dasso M, Dhar R (1997) The human RAE1 gene is a functional homologue of Schizosaccharomyces pombe rae1 gene involved in nuclear export of Poly(A)+ RNA. Gene 198:251–258
Brennan CM, Gallouzi IE, Steitz JA (2000) Protein ligands to HuR modulate its interaction with target mRNAs in vivo. J Cell Biol 151:1–14
Brown JA, Bharathi A, Ghosh A, Whalen W, Fitzgerald E, Dhar R (1995) A mutation in the Schizosaccharomyces pombe rae1 gene causes defects in poly(A)+ RNA export and in the cytoskeleton. J Biol Chem 270:7411–7419
Calado A, Kutay U, Kühn U, Wahle E, Carmo-Fonseca M (2000) Deciphering the cellular pathway for transport of poly(A)-binding protein II. RNA 6:245–256
Charles CH, Sun H, Lau LF, Tonks NK (1993) The growth factor-inducible immediate-early gene 3CH134 encodes a protein-tyrosine-phosphatase. Proc Natl Acad Sci U S A 90:5292–5296
Chen CY, Shyu AB (1995) AU-rich elements: characterization and importance in mRNA degradation. Trends Biochem Sci 20:465–470
Chen CY, Chen TM, Shyu AB (1994) Interplay of two functionally and structurally distinct domains of the c-fos AU-rich element specifies its mRNA-destabilizing function. Mol Cell Biol 14:416–426
Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, Lapuk A, Neve RM, Qian Z, Ryder T, Chen F, Feiler H, Tokuyasu T, Kingsley C, Dairkee S, Meng Z, Chew K, Pinkel D, Jain A, Ljung BM, Esserman L, Albertson DG, Waldman FM, Gray JW (2006) Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10:529–541
Chong H, Vikis HG, Guan KL (2003) Mechanisms of regulating the Raf kinase family. Cell Signal 15:463–469
Chu Y, Solski PA, Khosravi-Far R, Der CJ, Kelly K (1996) The mitogen-activated protein kinase phosphatases PAC1, MKP-1, and MKP-2 have unique substrate specificities and reduced activity in vivo toward the ERK2 sevenmaker mutation. J Biol Chem 271:6497–6501
Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL (2006) eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 175:415–426
Cullen BR (2000) Nuclear RNA export pathways. Mol Cell Biol 20:4181–4187
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954
Dowd S, Sneddon AA, Keyse SM (1998) Isolation of the human genes encoding the pyst1 and Pyst2 phosphatases: characterisation of Pyst2 as a cytosolic dual-specificity MAP kinase phosphatase and its catalytic activation by both MAP and SAP kinases. J Cell Sci 111:3389–3399
Fan XC, Steitz JA (1998) HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc Natl Acad Sci USA 95:15293–15298
Funasaka T, Nakano H, Wu Y, Hashizume C, Gu L, Nakamura T, Wang W, Zhou P, Moore MA, Sato H, Wong RW (2011) RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis. Cell Cycle 10:1456–1467
Görlich D, Kutay U (1999) Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol 15:607–660
Gray NK, Hrabálková L, Scanlon JP, Smith RW (2015) Poly(A)-binding proteins and mRNA localization: who rules the roost? Biochem Soc Trans 43:1277–1284
Grzybowska EA, Wilczynska A, Siedlecki JA (2001) Regulatory functions of 3’UTRs. Biochem Biophys Res Commun 288:291–295
Güttinger S, Mühlhäusser P, Koller-Eichhorn R, Brennecke J, Kutay U (2004) Transportin2 functions as importin and mediates nuclear import of HuR. Proc Natl Acad Sci USA 101:2918–2923
Ho YH, Gasch AP (2015) Exploiting the yeast stress-activated signaling network to inform on stress biology and disease signaling. Curr Genet 61:503–511
Hoffman CS, Wood V, Fantes PA (2015) An ancient yeast for young geneticists: a primer on the schizosaccharomyces pombe model system. Genetics 201(2):403–423
Hohmann S (2015) An integrated view on a eukaryotic osmoregulation system. Curr Genet 61:373–382
Huang G, Shi LZ, Chi H (2009) Regulation of JNK and p38 MAPK in the immune system: signal integration, propagation and termination. Cytokine 48:161–169
Jang BC, Muñoz-Najar U, Paik JH, Claffey K, Yoshida M, Hla T (2003) Leptomycin B, an inhibitor of the nuclear export receptor CRM1, inhibits COX-2 expression. J Biol Chem 278:2773–2776
Jans DA, Xiao CY, Lam MH (2000) Nuclear targeting signal recognition: a key control point in nuclear transport? BioEssays 22:532–544
Jeffrey KL, Brummer T, Rolph MS, Liu SM, Callejas NA, Grumont RJ, Gillieron C, Mackay F, Grey S, Camps M, Rommel C, Gerondakis SD, Mackay CR (2006) Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol 7:274–283
Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802:396–405
Kimura T, Hashimoto I, Nagase T, Fujisawa J (2004) CRM1-dependent, but not ARE-mediated, nuclear export of IFN-α1 mRNA. J Cell Sci 117:2259–2270
Kovanen PE, Rosenwald A, Fu J, Hurt EM, Lam LT, Giltnane JM, Wright G, Staudt LM, Leonard WJ (2003) Analysis of γc-family cytokine target genes: identification of dual-specificity phosphatase 5 (DUSP5) as a regulator of mitogen-activated protein kinase activity in interleukin-2 signaling. J Biol Chem 278:5205–5213
Kutay U, Güttinger S (2005) Leucine-rich nuclear-export signals: born to be weak. Trends Cell Biol 15:121–124
Kuwano Y, Kim HH, Abdelmohsen K, Pullmann R Jr, Martindale JL, Yang X, Gorospe M (2008) MKP-1 mRNA stabilization and translational control by RNA-binding proteins HuR and NF90. Mol Cell Biol 28:4562–4575
Lee MH, Hook B, Pan G, Kershner AM, Merritt C, Seydoux G, Thomson JA, Wickens M, Kimble J (2007) Conserved regulation of MAP kinase expression by PUF RNA-binding proteins. PLoS Genet 3:e233. doi:10.1371/journal.pgen.0030233
Ma Y, Kuno T, Kita A, Asayama Y, Sugiura R (2006) Rho2 is a target of the farnesyltransferase Cpp1 and acts upstream of Pmk1 mitogen-activated protein kinase signaling in fission yeast. Mol Biol Cell 17:5028–5037
Major AT, Whiley PA, Loveland KL (2011) Expression of nucleocytoplasmic transport machinery: clues to regulation of spermatogenic development. Biochim Biophys Acta 1813:1668–1688
Marti F, Krause A, Post NH, Lyddane C, Dupont B, Sadelain M, King PD (2001) Negative-feedback regulation of CD28 costimulation by a novel mitogen-activated protein kinase phosphatase, MKP6. J Immunol 166:197–206
Muda M, Boschert U, Dickinson R, Martinou JC, Martinou I, Camps M, Schlegel W, Arkinstall S (1996a) MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. J Biol Chem 271:4319–4326
Muda M, Theodosiou A, Rodrigues N, Boschert U, Camps M, Gillieron C, Davies K, Ashworth A, Arkinstall S (1996b) The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. J Biol Chem 271:27205–27208
Muda M, Boschert U, Smith A, Antonsson B, Gillieron C, Chabert C, Camps M, Martinou I, Ashworth A, Arkinstall S (1997) Molecular cloning and functional characterization of a novel mitogen-activated protein kinase phosphatase, MKP-4. J Biol Chem 272:5141–5151
Murphy R, Watkins JL, Wente SR (1996) GLE2, a Saccharomyces cerevisiae homologue of the Schizosaccharomyces pombe export factor RAE1, is required for nuclear pore complex structure and function. Mol Biol Cell 7:1921–1937
Pieper D, Schirmer S, Prechtel AT, Kehlenbach RH, Hauber J, Chemnitz J (2011) Functional characterization of the HuR:CD83 mRNA interaction. PLoS One 6:e23290. doi:10.1371/journal.pone.0023290
Pollard VW, Michael WM, Nakielny S, Siomi MC, Wang F, Dreyfuss G (1996) A novel receptor-mediated nuclear protein import pathway. Cell 86:985–994
Polledo JM, Cervini G, Romaniuk MA, Cassola A (2016) Interactions between RNA-binding proteins and P32 homologues in trypanosomes and human cells. Curr Genet 62:203–212
Pritchard CE, Fornerod M, Kasper LH, van Deursen JM (1999) RAE1 is a shuttling mRNA export factor that binds to a GLEBS-like NUP98 motif at the nuclear pore complex through multiple domains. J Cell Biol 145:237–254
Rahmouni S, Cerignoli F, Alonso A, Tsutji T, Henkens R, Zhu C, Louis-dit-Sully C, Moutschen M, Jiang W, Mustelin T (2006) Loss of the VHR dual-specific phosphatase causes cell-cycle arrest and senescence. Nat Cell Biol 8:524–531
Rebane A, Aab A, Steitz JA (2004) Transportins 1 and 2 are redundant nuclear import factors for hnRNP A and HuR. RNA 10:590–599
Santos-Rosa H, Moreno H, Simos G, Segref A, Fahrenkrog B, Panté N, Hurt E (1998) Nuclear mRNA export requires complex formation between Mex67p and Mtr2p at the nuclear pores. Mol Cell Biol 18:6826–6838
Sarto-Jackson I, Tomaska L (2016) How to bake a brain: yeast as a model neuron. Curr Genet 62:347–370
Satoh R, Morita T, Takada H, Kita A, Ishiwata S, Boi A, Hagihara K, Taga A, Matsumura Y, Tohda H, Sugiura R (2009) Role of the RNA-binding protein Nrd1 and Pmk1 mitogen-activated protein kinase in the regulation of myosin mRNA stability in fission yeast. Mol Biol Cell 20:2473–2485
Satoh R, Hagihara K, Matsuura K, Manse Y, Kita A, Kunoh T, Masuko T, Moriyama M, Moriyama H, Tanabe G, Muraoka O, Sugiura R (2017a) Identification of ACA-28, a 1’-acetoxychavicol acetate analogue compound, as a novel modulator of ERK MAPK signaling, which preferentially kills human melanoma cells. Genes Cells 22:608–618
Satoh R, Matsumura Y, Tanaka A, Takada M, Ito Y, Hagihara K, Inari M, Kita A, Fukao A, Fujiwara T, Hirai S, Tani T, Sugiura R (2017b) Spatial regulation of the KH domain RNA-binding protein Rnc1 mediated by a Crm1-independent nuclear export system in Schizosaccharomyces pombe. Mol Microbiol 104:428–448
Seger R, Krebs EG (1995) The MAPK signaling cascade. FASEB J 9:726–735
Segref A, Sharma K, Doye V, Hellwig A, Huber J, Lührmann R, Hurt E (1997) Mex67p, a novel factor for nuclear mRNA export, binds to both poly(A)+ RNA and nuclear pores. EMBO J 16:3256–3271
Siomi H, Dreyfuss G (1995) A nuclear localization domain in the hnRNP A1 protein. J Cell Biol 129:551–560
Sugiura R, Toda T, Shuntoh H, Yanagida M, Kuno T (1998) pmp1 +, a suppressor of calcineurin deficiency, encodes a novel MAP kinase phosphatase in fission yeast. EMBO J 17:140–148
Sugiura R, Toda T, Dhut S, Shuntoh H, Kuno T (1999) The MAPK kinase Pek1 acts as a phosphorylation-dependent molecular switch. Nature 399:479–483
Sugiura R, Sio SO, Shuntoh H, Kuno T (2002) Calcineurin phosphatase in signal transduction: lessons from fission yeast. Genes Cells 7:619–627
Sugiura R, Kita A, Shimizu Y, Shuntoh H, Sio SO, Kuno T (2003) Feedback regulation of MAPK signalling by an RNA-binding protein. Nature 424:961–965
Takada H, Nishimura M, Asayama Y, Mannse Y, Ishiwata S, Kita A, Doi A, Nishida A, Kai N, Moriuchi S, Tohda H, Giga-Hama Y, Kuno T, Sugiura R (2007) Atf1 is a target of the mitogen-activated protein kinase Pmk1 and regulates cell integrity in fission yeast. Mol Biol Cell 18:4794–4802
Theodosiou A, Smith A, Gillieron C, Arkinstall S, Ashworth A (1999) MKP5, a new member of the MAP kinase phosphatase family, which selectively dephosphorylates stress-activated kinases. Oncogene 18:6981–6988
Toda T, Dhut S, Superti-Furga G, Gotoh Y, Nishida E, Sugiura R, Kuno T (1996) The fission yeast pmk1 + gene encodes a novel mitogen-activated protein kinase homolog which regulates cell integrity and functions coordinately with the protein kinase C pathway. Mol Cell Biol 16:6752–6764
Togashi N, Yamashita A, Sato M, Yamamoto M (2014) Functional significance of nuclear export and mRNA binding of meiotic regulator Spo5 in fission yeast. BMC Microbiol 14. doi: 10.1186/1471-2180-14-188
Truant R, Kang Y, Cullen BR (1999) The human tap nuclear RNA export factor contains a novel transportin-dependent nuclear localization signal that lacks nuclear export signal function. J Biol Chem 274:32167–32171
Wickramasinghe VO, Laskey RA (2015) Control of mammalian gene expression by selective mRNA export. Nat Rev Mol Cell Biol 16:431–442
Yoon JH, Love DC, Guhathakurta A, Hanover JA, Dhar R (2000) Mex67p of Schizosaccharomyces pombe interacts with Rae1p in mediating mRNA export. Mol Cell Biol 20:8767–8782
Acknowledgements
We would like to thank William Figoni for critical reading of the manuscript. We also would like to express our gratitude to members of the Laboratory of Molecular Pharmacogenomics for their support. This study was supported by a Grant-in-Aid for Japan Society for the Promotion of Science (JSPS) Fellows (22∙5817) (to R. Satoh), and Scientific Research on Innovative Areas ‘RNA regulation’ (20112006) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (to R. Sugiura). This study was also supported by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2014–2018 (S1411037).
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by M. Kupiec.
Rights and permissions
About this article
Cite this article
Satoh, R., Hagihara, K. & Sugiura, R. Rae1-mediated nuclear export of Rnc1 is an important determinant in controlling MAPK signaling. Curr Genet 64, 103–108 (2018). https://doi.org/10.1007/s00294-017-0732-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00294-017-0732-5