Phosphorylation meets nuclear import: a review

Phosphorylation is the most common and pleiotropic modification in biology, which plays a vital role in regulating and finely tuning a multitude of biological pathways. Transport across the nuclear envelope is also an essential cellular function and is intimately linked to many degeneration processes that lead to disease. It is therefore not surprising that phosphorylation of cargos trafficking between the cytoplasm and nucleus is emerging as an important step to regulate nuclear availability, which directly affects gene expression, cell growth and proliferation. However, the literature on phosphorylation of nucleocytoplasmic trafficking cargos is often confusing. Phosphorylation, and its mirror process dephosphorylation, has been shown to have opposite and often contradictory effects on the ability of cargos to be transported across the nuclear envelope. Without a clear connection between attachment of a phosphate moiety and biological response, it is difficult to fully understand and predict how phosphorylation regulates nucleocytoplasmic trafficking. In this review, we will recapitulate clue findings in the field and provide some general rules on how reversible phosphorylation can affect the nuclear-cytoplasmic localization of substrates. This is only now beginning to emerge as a key regulatory step in biology.

[1]  A. Rao,et al.  Calcineurin Binds the Transcription Factor NFAT1 and Reversibly Regulates Its Activity (*) , 1996, The Journal of Biological Chemistry.

[2]  Kevin M. McBride,et al.  Regulated nuclear import of the STAT1 transcription factor by direct binding of importin‐α , 2002, The EMBO journal.

[3]  H. Schlicht,et al.  Analysis of the earliest steps of hepadnavirus replication: genome repair after infectious entry into hepatocytes does not depend on viral polymerase activity , 1993, Journal of virology.

[4]  M. Rexach,et al.  Natively Unfolded Nucleoporins Gate Protein Diffusion across the Nuclear Pore Complex , 2007, Cell.

[5]  P. Najarro,et al.  Vaccinia Virus Blocks Gamma Interferon Signal Transduction: Viral VH1 Phosphatase Reverses Stat1 Activation , 2001, Journal of Virology.

[6]  Daryl J. Thomas,et al.  NFATc3, a Lymphoid-specific NFATc Family Member That Is Calcium-regulated and Exhibits Distinct DNA Binding Specificity (*) , 1995, The Journal of Biological Chemistry.

[7]  E. Nishida,et al.  Two co‐existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimer , 1999, The EMBO journal.

[8]  G. Blobel,et al.  Karyopherins and nuclear import. , 2001, Current opinion in structural biology.

[9]  E. O’Shea,et al.  Regulation of nuclear localization: a key to a door. , 1999, Annual review of cell and developmental biology.

[10]  Bernard Roizman,et al.  Signal transducer and activator of transcription 1 regulates both cytotoxic and prosurvival functions in tumor cells. , 2007, Cancer research.

[11]  B. Neel,et al.  The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. , 2003, Trends in biochemical sciences.

[12]  Yuh Min Chook,et al.  Rules for nuclear localization sequence recognition by karyopherin beta 2. , 2006, Cell.

[13]  G. Cingolani,et al.  Dimeric Quaternary Structure of the Prototypical Dual Specificity Phosphatase VH1* , 2009, Journal of Biological Chemistry.

[14]  G. Feng,et al.  SHP-2 Is a Dual-specificity Phosphatase Involved in Stat1 Dephosphorylation at Both Tyrosine and Serine Residues in Nuclei* , 2002, The Journal of Biological Chemistry.

[15]  A. Krainer,et al.  A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm. , 1998, Genes & development.

[16]  E. Olson,et al.  Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy , 2001, The EMBO journal.

[17]  B. Paschal,et al.  Mechanisms of Receptor‐Mediated Nuclear Import and Nuclear Export , 2005, Traffic.

[18]  A. Helenius,et al.  Nuclear import of hepatitis B virus capsids and release of the viral genome , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  William Arbuthnot Sir Lane,et al.  Isolation of the cyclosporin-sensitive T cell transcription factor NFATp. , 1993, Science.

[20]  J. Manley,et al.  Inactivation of the SR Protein Splicing Factor ASF/SF2 Results in Genomic Instability , 2005, Cell.

[21]  T. Martin,et al.  Nuclear and nucleolar localization of parathyroid hormone‐related protein , 2000, Immunology and cell biology.

[22]  U. Kutay,et al.  Transport between the cell nucleus and the cytoplasm. , 1999, Annual review of cell and developmental biology.

[23]  A. Palmenberg,et al.  A picornavirus protein interacts with Ran-GTPase and disrupts nucleocytoplasmic transport , 2006, Proceedings of the National Academy of Sciences.

[24]  B. Kobe,et al.  Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-alpha. , 2000, Journal of molecular biology.

[25]  R. Weichselbaum,et al.  STAT1 Pathway Mediates Amplification of Metastatic Potential and Resistance to Therapy , 2009, PloS one.

[26]  Andreas Marg,et al.  Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1 , 2004, The Journal of cell biology.

[27]  P. Bork,et al.  A Novel Class of RanGTP Binding Proteins , 1997, The Journal of cell biology.

[28]  Ren-Jye Lin,et al.  Blocking of Interferon-Induced Jak-Stat Signaling by Japanese Encephalitis Virus NS5 through a Protein Tyrosine Phosphatase-Mediated Mechanism , 2006, Journal of Virology.

[29]  M. Lai,et al.  Transportin-SR2 mediates nuclear import of phosphorylated SR proteins , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. A. Crowther,et al.  Three-dimensional structure of hepatitis B virus core particles determined by electron cryomicroscopy , 1994, Cell.

[31]  J. Darnell,et al.  A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. , 1993, Science.

[32]  Ryan E. Mills,et al.  Classical Nuclear Localization Signals: Definition, Function, and Interaction with Importin α* , 2007, Journal of Biological Chemistry.

[33]  L. Kinnunen,et al.  NF-κB Is Transported into the Nucleus by Importin α3 and Importin α4* , 2005, Journal of Biological Chemistry.

[34]  B. Sugden,et al.  A promoter of Epstein-Barr virus that can function during latent infection can be transactivated by EBNA-1, a viral protein required for viral DNA replication during latent infection , 1989, Journal of virology.

[35]  G. Blobel,et al.  Protein export from the nucleus requires the GTPase Ran and GTP hydrolysis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  C. Seeger,et al.  Hepatitis B Virus Biology , 2000, Microbiology and Molecular Biology Reviews.

[37]  T. Martin,et al.  Importin β Recognizes Parathyroid Hormone-related Protein with High Affinity and Mediates Its Nuclear Import in the Absence of Importin α* , 1999, The Journal of Biological Chemistry.

[38]  A. Dickmanns,et al.  Nucleocytoplasmic Shuttling Factors Including Ran and CRM1 Mediate Nuclear Export of NFAT In Vitro , 1998, The Journal of cell biology.

[39]  E. O’Shea,et al.  Phosphorylation regulates association of the transcription factor Pho4 with its import receptor Pse1/Kap121. , 1998, Genes & development.

[40]  D. Jans,et al.  Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles. , 2003, Vitamins and hormones.

[41]  E. Krebs,et al.  Conversion of phosphorylase b to phosphorylase a in muscle extracts. , 1955, The Journal of biological chemistry.

[42]  Y. Tesfaigzi,et al.  How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer? , 2009, Cell cycle.

[43]  P. A. Friedman,et al.  Parathyroid hormone‐related protein and its receptors: nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets , 2001, British journal of pharmacology.

[44]  J. Pouysségur,et al.  The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition , 2007, Oncogene.

[45]  B. Kobe,et al.  Role of flanking sequences and phosphorylation in the recognition of the simian-virus-40 large T-antigen nuclear localization sequences by importin-alpha. , 2003, The Biochemical journal.

[46]  M. Stewart Molecular mechanism of the nuclear protein import cycle , 2007, Nature Reviews Molecular Cell Biology.

[47]  U. Vinkemeier,et al.  Molecular basis for the recognition of phosphorylated STAT1 by importin alpha5. , 2010, Journal of molecular biology.

[48]  B. Lanske,et al.  Role of Parathyroid Hormone‐Related Protein in Skeletal Development , 1996, Annals of the New York Academy of Sciences.

[49]  A. Helenius,et al.  Phosphorylation-dependent Binding of Hepatitis B Virus Core Particles to the Nuclear Pore Complex , 1999, The Journal of cell biology.

[50]  J. Manley,et al.  New Talents for an Old Acquaintance: the SR Protein Splicing Factor ASF/SF2 Functions in the Maintenance of Genome Stability , 2005, Cell cycle.

[51]  B. Lemon,et al.  The dual-specificity phosphatase encoded by vaccinia virus, VH1, is essential for viral transcription in vivo and in vitro , 1995, Journal of virology.

[52]  W. Greene,et al.  Shaping the nuclear action of NF-kappaB. , 2004, Nature reviews. Molecular cell biology.

[53]  E. Nishida,et al.  Activation of a C-terminal Transcriptional Activation Domain of ERK5 by Autophosphorylation* , 2007, Journal of Biological Chemistry.

[54]  B. Chain,et al.  Dengue virus NS5 inhibits interferon-alpha signaling by blocking signal transducer and activator of transcription 2 phosphorylation. , 2009, The Journal of infectious diseases.

[55]  J. Mercer,et al.  Investigation of Structural and Functional Motifs within the Vaccinia Virus A14 Phosphoprotein, an Essential Component of the Virion Membrane , 2003, Journal of Virology.

[56]  S. Chawla,et al.  Differential Effects of Ca2+ and cAMP on Transcription Mediated by MEF2D and cAMP-response Element-binding Protein in Hippocampal Neurons* , 2006, Journal of Biological Chemistry.

[57]  R. Seger,et al.  Identification and characterization of a general nuclear translocation signal in signaling proteins. , 2008, Molecular cell.

[58]  A. Hodel,et al.  Regulation of Nuclear Import by Phosphorylation Adjacent to Nuclear Localization Signals* , 2004, Journal of Biological Chemistry.

[59]  H. Dyson,et al.  Structural basis for recruitment of CBP/p300 coactivators by STAT1 and STAT2 transactivation domains , 2009, The EMBO journal.

[60]  S. Eckhardt,et al.  Hepatitis B virus core antigen has two nuclear localization sequences in the arginine-rich carboxyl terminus , 1991, Journal of virology.

[61]  B Hamilton,et al.  Nuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity. , 1998, Genes & development.

[62]  D. Goldfarb,et al.  Evolution of the Metazoan-Specific Importin α Gene Family , 2009, Journal of Molecular Evolution.

[63]  U. Vinkemeier,et al.  Nucleocytoplasmic translocation of Stat1 is regulated by a leucine-rich export signal in the coiled-coil domain. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[64]  J. Whittle,et al.  The nuclear pore complex has entered the atomic age. , 2009, Structure.

[65]  E. Nishida,et al.  Regulation of Nuclear Translocation of Extracellular Signal-Regulated Kinase 5 by Active Nuclear Import and Export Mechanisms , 2006, Molecular and Cellular Biology.

[66]  M. Bloom,et al.  Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist , 2005, Journal of Virology.

[67]  U. Vinkemeier,et al.  Nucleocytoplasmic shuttling of STAT transcription factors. , 2004, European journal of biochemistry.

[68]  Gustav Ammerer,et al.  Acute glucose starvation activates the nuclear localization signal of a stress‐specific yeast transcription factor , 2002, The EMBO journal.

[69]  Philip R. Cohen,et al.  Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer , 2008, Oncogene.

[70]  C. Xiao,et al.  The Protein Kinase CK2 Site (Ser111/112) Enhances Recognition of the Simian Virus 40 Large T-antigen Nuclear Localization Sequence by Importin* , 1997, The Journal of Biological Chemistry.

[71]  T. Maniatis,et al.  An amino acid sequence motif sufficient for subnuclear localization of an arginine/serine-rich splicing factor. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[72]  Jiahuai Han,et al.  BMK1/ERK5 regulates serum‐induced early gene expression through transcription factor MEF2C , 1997, The EMBO journal.

[73]  R. Weichselbaum,et al.  Ad.Egr-TNF and local ionizing radiation suppress metastases by interferon-beta-dependent activation of antigen-specific CD8+ T cells. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[74]  I. Macara,et al.  Requirement of guanosine triphosphate-bound ran for signal-mediated nuclear protein export. , 1997, Science.

[75]  C. Hill Nucleocytoplasmic shuttling of Smad proteins , 2009, Cell Research.

[76]  R. Weichselbaum,et al.  STAT1-dependent expression of energy metabolic pathways links tumour growth and radioresistance to the Warburg effect , 2009, BMC medicine.

[77]  R. Peters Translocation Through the Nuclear Pore Complex: Selectivity and Speed by Reduction‐of‐Dimensionality , 2005, Traffic.

[78]  Richard S. Rogers,et al.  SUMO Modification of STAT1 and Its Role in PIAS-mediated Inhibition of Gene Activation* , 2003, Journal of Biological Chemistry.

[79]  J. ten Hoeve,et al.  Identification of a Nuclear Stat1 Protein Tyrosine Phosphatase , 2002, Molecular and Cellular Biology.

[80]  D. Goldfarb,et al.  Importin α: A multipurpose nuclear-transport receptor , 2004 .

[81]  B. Pogo,et al.  POXVIRUS INFECTION AND APOPTOSIS , 2004, International reviews of immunology.

[82]  G. Cingolani,et al.  Synergy of Silent and Hot Spot Mutations in Importin β Reveals a Dynamic Mechanism for Recognition of a Nuclear Localization Signal* , 2003, The Journal of Biological Chemistry.

[83]  A. Harel,et al.  Importin beta: conducting a much larger cellular symphony. , 2004, Molecular cell.

[84]  I. Mansuy Calcineurin in memory and bidirectional plasticity. , 2003, Biochemical and biophysical research communications.

[85]  J. Darnell,et al.  Crystal Structure of a Tyrosine Phosphorylated STAT-1 Dimer Bound to DNA , 1998, Cell.

[86]  Bernard Roizman,et al.  STAT1 is overexpressed in tumors selected for radioresistance and confers protection from radiation in transduced sensitive cells. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[87]  J. Darnell,et al.  Structural bases of unphosphorylated STAT1 association and receptor binding. , 2005, Molecular cell.

[88]  K. Weis The Nuclear Pore Complex: Oily Spaghetti or Gummy Bear? , 2007, Cell.

[89]  L. Pemberton,et al.  Karyopherins: from nuclear-transport mediators to nuclear-function regulators. , 2004, Trends in cell biology.

[90]  Fan Wang,et al.  Neurotrophins and Netrins Require Calcineurin/NFAT Signaling to Stimulate Outgrowth of Embryonic Axons , 2003, Cell.

[91]  M. Lai,et al.  A Human Importin-β Family Protein, Transportin-SR2, Interacts with the Phosphorylated RS Domain of SR Proteins* , 2000, The Journal of Biological Chemistry.

[92]  S. Shoelson,et al.  Crystal Structure of the Tyrosine Phosphatase SHP-2 , 1998, Cell.

[93]  G. Cingolani,et al.  The Importin β Binding Domain Modulates the Avidity of Importin β for the Nuclear Pore Complex* , 2010, The Journal of Biological Chemistry.

[94]  T. Hunter,et al.  Protein kinases and phosphatases: The Yin and Yang of protein phosphorylation and signaling , 1995, Cell.

[95]  T. Curran,et al.  The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun , 1993, Nature.

[96]  F. Bischoff,et al.  The importin β/importin 7 heterodimer is a functional nuclear import receptor for histone H1 , 1999, The EMBO journal.

[97]  J. Darnell,et al.  Structure of the amino-terminal protein interaction domain of STAT-4. , 1998, Science.

[98]  U. Vinkemeier,et al.  Constitutive and IFN-gamma-induced nuclear import of STAT1 proceed through independent pathways. , 2002, The EMBO journal.

[99]  Aurelia Cassany,et al.  Reconstitution of nuclear import in permeabilized cells. , 2009, Methods in molecular biology.

[100]  Y. Chook,et al.  Rules for Nuclear Localization Sequence Recognition by Karyopherinβ2 , 2006, Cell.

[101]  L. Trinkle-Mulcahy,et al.  Emerging roles of nuclear protein phosphatases , 2007, Nature Reviews Molecular Cell Biology.

[102]  L. Gerace,et al.  Phosphorylation of the Nuclear Transport Machinery Down-regulates Nuclear Protein Import in Vitro * , 2000, The Journal of Biological Chemistry.

[103]  J. Qian,et al.  Understanding protein phosphorylation on a systems level. , 2010, Briefings in functional genomics.

[104]  M. Khanna,et al.  Tyrosine Phosphorylation of A17 during Vaccinia Virus Infection: Involvement of the H1 Phosphatase and the F10 Kinase , 1999, Journal of Virology.

[105]  R. Aebersold,et al.  Expression of a tyrosine phosphorylated, DNA binding Stat3β dimer in bacteria , 1998, FEBS letters.

[106]  N. Daigle,et al.  Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit , 2007, Nature Structural &Molecular Biology.

[107]  Shuang Huang,et al.  Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor , 1998, Nature.

[108]  J. Hauber,et al.  Multiple Importins Function as Nuclear Transport Receptors for the Rev Protein of Human Immunodeficiency Virus Type 1* , 2006, Journal of Biological Chemistry.

[109]  G. Cingolani,et al.  Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta. , 2002, Molecular cell.

[110]  R. Seger,et al.  MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation , 2004, Journal of Cell Science.

[111]  Warren S. Alexander,et al.  Suppressors of cytokine signalling (SOCS) in the immune system , 2002, Nature Reviews Immunology.

[112]  G R Stark,et al.  Formation of STAT1-STAT2 Heterodimers and Their Role in the Activation of IRF-1 Gene Transcription by Interferon- (*) , 1996, The Journal of Biological Chemistry.

[113]  Roderick Y. H. Lim,et al.  Biology and biophysics of the nuclear pore complex and its components. , 2008, International review of cell and molecular biology.

[114]  G. Blobel,et al.  SUMO-1 Modification and Its Role in Targeting the Ran GTPase-activating Protein, RanGAP1, to the Nuclear Pore Complex , 1998, The Journal of cell biology.

[115]  R. Seger,et al.  Protein-protein interactions in the regulation of the extracellular signal-regulated kinase , 2005, Molecular biotechnology.

[116]  M. Ohtsubo,et al.  The RCC1 protein, a regulator for the onset of chromosome condensation locates in the nucleus and binds to DNA , 1989, The Journal of cell biology.

[117]  Elizabeth J. Tran,et al.  Dynamic Nuclear Pore Complexes: Life on the Edge , 2006, Cell.

[118]  M. Niepel,et al.  The nuclear pore complex: bridging nuclear transport and gene regulation , 2010, Nature Reviews Molecular Cell Biology.

[119]  J. Ou,et al.  Phosphorylation and nuclear localization of the hepatitis B virus core protein: significance of serine in the three repeated SPRRR motifs , 1995, Journal of virology.

[120]  H. Braak,et al.  Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease. , 2002, Brain research. Molecular brain research.

[121]  E. Fischer,et al.  COOH-terminal sequence motifs target the T cell protein tyrosine phosphatase to the ER and nucleus , 1995, The Journal of cell biology.

[122]  A. Beck‐Sickinger,et al.  Cell Communication and Signaling , 2009 .

[123]  G. Garin,et al.  BMK1/ERK5 Is a Novel Regulator of Angiogenesis by Destabilizing Hypoxia Inducible Factor 1&agr; , 2005, Circulation research.

[124]  T. Martin,et al.  Phosphorylation at the Cyclin-dependent Kinases Site (Thr85) of Parathyroid Hormone-related Protein Negatively Regulates Its Nuclear Localization* , 1999, The Journal of Biological Chemistry.

[125]  B. Sugden,et al.  EBNA-1, a Bifunctional Transcriptional Activator , 2003, Molecular and Cellular Biology.

[126]  Yigong Shi Serine/Threonine Phosphatases: Mechanism through Structure , 2009, Cell.

[127]  E. Nishida,et al.  Activation of the Protein Kinase ERK5/BMK1 by Receptor Tyrosine Kinases , 1999, The Journal of Biological Chemistry.

[128]  J. Redondo,et al.  c-Jun N-terminal Kinase (JNK) Positively Regulates NFATc2 Transactivation through Phosphorylation within the N-terminal Regulatory Domain* , 2005, Journal of Biological Chemistry.

[129]  Ursula Klingmüller,et al.  Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals , 1995, Cell.

[130]  M. Cobb,et al.  Identification of Novel Point Mutations in ERK2 That Selectively Disrupt Binding to MEK1* , 2002, The Journal of Biological Chemistry.

[131]  C. Xiao,et al.  SV40 Large Tumor Antigen Nuclear Import Is Regulated by the Double-stranded DNA-dependent Protein Kinase Site (Serine 120) Flanking the Nuclear Localization Sequence* , 1997, The Journal of Biological Chemistry.

[132]  P. Wingfield,et al.  Localization of the C terminus of the assembly domain of hepatitis B virus capsid protein: implications for morphogenesis and organization of encapsidated RNA. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[133]  A. Palmenberg,et al.  Leader-Induced Phosphorylation of Nucleoporins Correlates with Nuclear Trafficking Inhibition by Cardioviruses , 2008, Journal of Virology.

[134]  L. Kinnunen,et al.  Arginine/Lysine-rich Nuclear Localization Signals Mediate Interactions between Dimeric STATs and Importin α5* , 2002, The Journal of Biological Chemistry.

[135]  L. Breeden,et al.  Cell cycle-regulated phosphorylation of Swi6 controls its nuclear localization. , 1995, Molecular biology of the cell.

[136]  J. Darnell STATs and gene regulation. , 1997, Science.

[137]  W. Fantl,et al.  Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK , 1998, Current Biology.

[138]  H. Masai,et al.  Nuclear Import of Epstein-Barr Virus Nuclear Antigen 1 Mediated by NPI-1 (Importin α5) Is Up- and Down-Regulated by Phosphorylation of the Nuclear Localization Signal for Which Lys379 and Arg380 Are Essential , 2006, Journal of Virology.

[139]  M. Kann,et al.  Nucleoporin 153 Arrests the Nuclear Import of Hepatitis B Virus Capsids in the Nuclear Basket , 2010, PLoS pathogens.

[140]  J. Orloff,et al.  Defining the roles of parathyroid hormone-related protein in normal physiology. , 1996, Physiological reviews.

[141]  G. Blobel,et al.  Two distinct classes of Ran-binding sites on the nucleoporin Nup-358. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[142]  S. Zhou,et al.  RNA- and DNA-binding activities in hepatitis B virus capsid protein: a model for their roles in viral replication , 1992, Journal of virology.

[143]  D. Botstein,et al.  Genomic expression programs in the response of yeast cells to environmental changes. , 2000, Molecular biology of the cell.

[144]  E. Goldsmith,et al.  Phosphorylation of the MAP Kinase ERK2 Promotes Its Homodimerization and Nuclear Translocation , 1998, Cell.

[145]  M. Tremblay,et al.  Nuclear localization and cell cycle regulation of a murine protein tyrosine phosphatase , 1994, Molecular and cellular biology.

[146]  T. Hirano,et al.  Extracellular signal‐dependent nuclear import of Stat1 is mediated by nuclear pore‐targeting complex formation with NPI‐1, but not Rch1 , 1997, The EMBO journal.

[147]  U. Vinkemeier,et al.  Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations , 2008, Proceedings of the National Academy of Sciences.

[148]  M. D'Angelo,et al.  Structure, dynamics and function of nuclear pore complexes. , 2008, Trends in cell biology.

[149]  H. Ruis,et al.  Stress signaling in yeast , 1995, BioEssays : news and reviews in molecular, cellular and developmental biology.

[150]  Xiang-Dong Fu,et al.  SR proteins and related factors in alternative splicing. , 2007, Advances in experimental medicine and biology.

[151]  L. Kinnunen,et al.  Importin α Nuclear Localization Signal Binding Sites for STAT1, STAT2, and Influenza A Virus Nucleoprotein* , 2003, Journal of Biological Chemistry.

[152]  E. Queralt,et al.  Cell Cycle Activation of the Swi6p Transcription Factor Is Linked to Nucleocytoplasmic Shuttling , 2003, Molecular and Cellular Biology.

[153]  Y. Oshima The phosphatase system in Saccharomyces cerevisiae. , 1997, Genes & genetic systems.

[154]  C. Xiao,et al.  A Consensus cAMP-dependent Protein Kinase (PK-A) Site in Place of the CcN Motif Casein Kinase II Site of Simian Virus 40 Large T-antigen Confers PK-A-mediated Regulation of Nuclear Import (*) , 1996, The Journal of Biological Chemistry.

[155]  E. Nishida,et al.  A conserved docking motif in MAP kinases common to substrates, activators and regulators , 2000, Nature Cell Biology.

[156]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[157]  R. Tapping,et al.  MEKK3 Directly Regulates MEK5 Activity as Part of the Big Mitogen-activated Protein Kinase 1 (BMK1) Signaling Pathway* , 1999, The Journal of Biological Chemistry.

[158]  B. Lanske,et al.  Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death , 1995, Molecular and cellular biology.

[159]  L. Kinnunen,et al.  NF-{kappa}B is transported into the nucleus by importin {alpha}3 and importin {alpha}4. , 2005, The Journal of biological chemistry.

[160]  L. J. Terry,et al.  Flexible Gates: Dynamic Topologies and Functions for FG Nucleoporins in Nucleocytoplasmic Transport , 2009, Eukaryotic Cell.

[161]  D. Goldfarb,et al.  Importin alpha: a multipurpose nuclear-transport receptor. , 2004, Trends in cell biology.

[162]  A. Ullrich,et al.  The Unique C-terminal Tail of the Mitogen-activated Protein Kinase ERK5 Regulates Its Activation and Nuclear Shuttling* , 2005, Journal of Biological Chemistry.

[163]  Emmitt R. Jolly,et al.  Regulation of PHO4 Nuclear Localization by the PHO80-PHO85 Cyclin-CDK Complex , 1996, Science.

[164]  T. Pawson,et al.  Post-translational modifications in signal integration , 2010, Nature Structural &Molecular Biology.

[165]  M. Fornerod,et al.  The nucleoporin Nup153 is required for nuclear pore basket formation, nuclear pore complex anchoring and import of a subset of nuclear proteins , 2001, The EMBO journal.

[166]  I. Lödige,et al.  Constitutive and IFN‐γ‐induced nuclear import of STAT1 proceed through independent pathways , 2002 .

[167]  E. O’Shea,et al.  Roles of phosphorylation sites in regulating activity of the transcription factor Pho4. , 1999, Science.

[168]  W. Greene,et al.  Shaping the nuclear action of NF-κB , 2004, Nature Reviews Molecular Cell Biology.