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SnapShot: Nuclear Transport Elizabeth J. Tran, Timothy A. Bolger, and Susan R. Wente Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA S. cerevisiae Metazoan Transport Karyopherins Karyopherins Complex & Other & Other Category Receptors Cargo(s) Essential Receptors Cargo(s) I Kap95 Kap60 adaptor Yes Importin-b1 Importin-a adaptor for cNLS proteins for cNLS proteins, Snurportin adaptor for U snRNPs II Kap95 — Yes Importin-b1 SREBP-2, HIV Rev and TAT, Cyclin B Kap104 Nab2, Hrp1 t.s. Transportin or PY-NLS-containing (mRNA-binding Transportin 2 proteins, mRNA- proteins) binding proteins, histones, ribosomal proteins Kap123 SRP proteins, No Importin 4 histones, ribosomal histones, ribo- protein S3a, somal proteins Transition Protein 2 Kap111/Mtr10 Npl3 (mRNA- t.s. Transportin SR1 SR proteins, HuR binding protein), or SR2 tRNAs Kap121/Pse1 ribosomal Yes Importin 5/ histones, ribosomal proteins, Yra1, Importin-b3/ proteins Import Spo12, Ste12, RanBP5 Yap1, Pho4, histones Kap119/Nmd5 ribosomal pro- No Importin 7 GR, ribosomal pro- teins, histones, teins, Smad, ERK Hog1, Crz1, Dst1 Kap108/Sxm1 Lhp1, ribosomal No Importin 8 SRP19, Smad proteins Kap114 TBP, histones, No Importin 9 histones, ribosomal Nap1, Sua7 proteins Kap122/Pdr6 Toa1 and Toa2, No — — TFIIA Kap120 Rpf1 No — — — — — Importin 11 UbcM2, rpL12 Ntf2 Ran/Gsp1 (GDP- Yes NTF2 Ran (GDP-bound bound form) form) III Kap142/Msn5 Replication pro- No — — tein A (import), Pho4, Crz1, Export Cdh1 (export) — — — Importin 13 UBC9, Y14 (import), Import/ eIFIA (export) IV Crm1/Xpo1 Leucine-rich NES Yes CRM1/ Leucine-rich NES sequences Exportin 1 sequences Kap109/Cse1 Kap60/Srp1 Yes CAS Importin-a family members Kap127/Los1 tRNAs No Exportin-t tRNAs — — — Exportin 4 eIF5A — — — Exportin 5 pre-miRNA — — — Exportin 6 Profilin, actin — — — RanBP16/ p50-RhoGAP Exportin 7 V Crm1/Xpo1 Nmd3 adaptor Yes CRM1/ NMD3 adaptor Export for 60S ribosomal Exportin 1 for 60S ribosomal subunit subunit Mex67-Mtr2 60S via 5S rRNA Yes — — Arx1 60S ribosomal No — — subunit Crm1/Xpo1 Ltv1 putative Yes CRM1/ 40S ribosomal adaptor for Exportin 1 subunit 40S ribosomal subunit VI Mex67-Mtr2 Npl3, Yra1, and Yes TAP/NXF1-p15/ REF/Aly adaptor for Hpr1 adaptors NXT1 mRNA for mRNA 420 Cell 131, October 19, 2007 ©2007 Elsevier Inc. DOI 10.1016/j.cell.2007.10.015 See online version for legend, references, and abbreviations.. SnapShot: Nuclear Transport Elizabeth J. Tran, Timothy A. Bolger, and Susan R. Wente Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Exchange of macromolecules between the nucleus and the cytoplasm occurs through nuclear pore complexes (NPCs), large proteinaceous structures embedded within the nuclear envelope. Small molecules (<30 kDa) can passively diffuse through NPCs. Nuclear transport receptors are required to facilitate import and export of large molecules (>30 kDa). This includes the karyopherin-b (Kapb) receptor family wherein each associates directly with the NPC and has cargo binding controlled by the asymmetric distribution of Ran-GTP and the Ran cycle (see Figure). Nuclear localization of the Ran guanine-nucleotide exchange factor (Ran-GEF, Prp20 in S. cerevisiae) via chromatin association maintains high concentrations of Ran-GTP in the nucleus. Conversely, Ran-GDP predominates in the cytoplasm through the com- bined action of cytoplasmically localized Ran-Binding Protein 1 (RanBP1, Yrb1 in S. cerevisiae) and Ran GTPase–Activating Protein (Ran-GAP, Rna1 in S. cerevisiae). During import, Kapb receptors interact with cytoplasmic cargos and traverse the NPC. In the nucleus, Ran-GTP binds to the importing Kapb and triggers cargo release. Conversely, during export, Ran-GTP stabilizes the association of Kapb receptors with nuclear cargo. Hydrolysis of GTP to GDP at the cytoplasmic NPC face promotes disassembly of the export receptor-cargo complex. Transport receptors are categorized based on transport direction, the use of cargo adaptors, and transport of spe- cialized cargo such as Ran-GDP, ribosomes, and/or mRNA. (I) Import receptor complexes with adaptors: Kap60-Kap95 (importin-a-importin-b in metazoa) is the prototypical import receptor. Cargo with a classical nuclear local- ization signal (cNLS) is recognized by the adaptor Kap60, which binds the receptor Kap95. Whereas yeast has only one importin-a, metazoans have several importin-a homologs (not shown). (II) Import receptors that bind cargo directly: Many Kapbs, including Kap104, can bind directly to their cargo. (III) Bidirectional transport receptors: The receptor Msn5 has the striking capacity to function in both import and export. (IV) Export receptor complexes: The first identified export receptor, Crm1, recognizes leucine-rich nuclear export sequences (NES) in cargo proteins. (V) Export of ribosomal subunits: Large cargos, such as ribosomal subunits, require multiple receptors for transport. Export of the assembled 60S subunit requires Crm1 (with the adaptor Nmd3) and, in S. cerevisiae, the Mex67-Mtr2 heterodimer as well as Arx1. Export of the 40S subunit also requires Crm1 and possibly an adap- tor, Ltv1. (VI) Export of mRNA: Export of most mRNA is Ran independent and, instead, requires the nonkaryopherin Mex67-Mtr2 (TAP/NXF1 and p15/NXT1 in metazoans, re- spectively). Mex67-Mtr2 binds mRNA thorough association with mRNA-binding proteins, or some metazoan mRNAs can recruit TAP/NXF1 by directly binding a specific RNA element, the CTE (not shown). CTEs are also present in some viral RNAs. Directionality of mRNA export is determined by the ATPase Dbp5, whose activation is controlled by spatially restricted inositol hexakisphosphate (IP6)-bound Gle1. Consensus Sequences cNLS: PKKKRKV (monopartite) or KRX(10–12)KRRK (bipartite); PY-NLS: ϕ(G/S/A)ϕϕX(5–10)(R/H/K)X(2–5)PY (hPY-NLS) or basic-enriched(5–8)X(2–7) (R/H/K)X(2–5)PY (bPY-NLS), ϕ denotes hydrophobic residue; NES: (L/V)X(2–3)(ψ/F)X(2–3)LXψ, ψ denotes large aliphatic residue (I, V, L, M). Abbreviations NLS, nuclear localization signal; NES, nuclear export signal; t.s., temperature sensitive; U snRNP, uridine-rich small nuclear ribonucleoprotein complex; SR, serine/ar- ginine-rich; TBP, TATA-binding protein; SRP, signal recognition particle; hnRNP, heterogeneous nuclear ribonucleoprotein. REFERENCES Bradatsch, B., Katahira, J., Kowalinski, E., Bange, G., Yao, W., Sekimoto, T., Baumgartel, V., Boese, G., Bassler, J., Wild, K., et al. (2007). Arx1 functions as an unortho- dox nuclear export receptor for the 60S preribosomal subunit. Mol. Cell 27, 767–779. Caesar, S., Greiner, M., and Schlenstedt, G. (2006). Kap120 functions as a nuclear import receptor for ribosome assembly factor Rpf1 in yeast. Mol. Cell. Biol. 26, 3170–3180. Culjkovic, B., Topisirovic, I., Skrabanek, L., Ruiz-Gutierrez, M., and Borden, K.L. (2006). eIF4E is a central node of an RNA regulon that governs cellular proliferation. J. Cell Biol. 175, 415–426. Fried, H., and Kutay, U. (2003). 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    Multiple Roles of Phosphoinositide-Specific Phospholipase C Isozymes

    BMB reports Mini Review Multiple roles of phosphoinositide-specific phospholipase C isozymes Pann-Ghill Suh1,*, Jae-Il Park1, Lucia Manzoli2, Lucio Cocco2, Joanna C. Peak3, Matilda Katan3, Kiyoko Fukami4, Tohru Kataoka5, Sanguk Yun1 & Sung Ho Ryu1 1Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Korea, 2Cellular Signaling Laboratory, Department of Anatomical Sciences, University of Bologna, Via Irnerio, 48 I-40126, Bologna, Italy, 3Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK, 4Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, 192-0392 Tokyo, Japan, 5Division of Molecular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan Phosphoinositide-specific phospholipase C is an effector mole- cellular calcium release (1-3; Fig. 1a). cule in the signal transduction process. It generates two sec- The first evidence of PLC activity was suggested by Hokin et ond messengers, inositol-1,4,5-trisphosphate and diacylglycer- al. in 1953 who reported specific hydrolysis of phospholipids ol from phosphatidylinositol 4,5-bisphosphate. Currently, thir- in pigeon’s pancreas slices after cholinergic stimulation (4). teen mammal PLC isozymes have been identified, and they are The authors showed that the enhanced turnover of phosphor- divided into six groups: PLC-β, -γ, -δ, -ε, -ζ and -η. Sequence ylinositol groups of phosphatidylinositol occurred in cells as a analysis studies demonstrated that each isozyme has more response to a variety of stimuli. In 1983, Streb et al.
  • Small Gtpase Ran and Ran-Binding Proteins

    Small Gtpase Ran and Ran-Binding Proteins

    BioMol Concepts, Vol. 3 (2012), pp. 307–318 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/bmc-2011-0068 Review Small GTPase Ran and Ran-binding proteins Masahiro Nagai 1 and Yoshihiro Yoneda 1 – 3, * highly abundant and strongly conserved GTPase encoding ∼ 1 Biomolecular Dynamics Laboratory , Department a 25 kDa protein primarily located in the nucleus (2) . On of Frontier Biosciences, Graduate School of Frontier the one hand, as revealed by a substantial body of work, Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Ran has been found to have widespread functions since Osaka 565-0871 , Japan its initial discovery. Like other small GTPases, Ran func- 2 Department of Biochemistry , Graduate School of Medicine, tions as a molecular switch by binding to either GTP or Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871 , GDP. However, Ran possesses only weak GTPase activ- Japan ity, and several well-known ‘ Ran-binding proteins ’ aid in 3 Japan Science and Technology Agency , Core Research for the regulation of the GTPase cycle. Among such partner Evolutional Science and Technology, Osaka University, 1-3 molecules, RCC1 was originally identifi ed as a regulator of Yamada-oka, Suita, Osaka 565-0871 , Japan mitosis in tsBN2, a temperature-sensitive hamster cell line (3) ; RCC1 mediates the conversion of RanGDP to RanGTP * Corresponding author in the nucleus and is mainly associated with chromatin (4) e-mail: [email protected] through its interactions with histones H2A and H2B (5) . On the other hand, the GTP hydrolysis of Ran is stimulated by the Ran GTPase-activating protein (RanGAP) (6) , in con- Abstract junction with Ran-binding protein 1 (RanBP1) and/or the large nucleoporin Ran-binding protein 2 (RanBP2, also Like many other small GTPases, Ran functions in eukaryotic known as Nup358).