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RESEARCH PAPER
Pseudosubstrate regulation of the SCF-TrCP ubiquitin ligase by hnRNP-U
Matti
Davis,1
Ada
Hatzubai,1
Jens S.
Andersen,2
Etti
Ben-Shushan,1
Gregory Zvi
Fisher,1
Avraham
Yaron,1
Asne
Bauskin,3
Frank
Mercurio,4
Matthias
Mann,2 and
Yinon
Ben-Neriah1,5
1 The Lautenberg Center for Immunology, The Hebrew
University-Hadassah Medical School, Jerusalem 91120, Israel;
2 Protein Interaction Laboratory, University of Southern
Denmark, DK-5230 Odense M, Denmark; 3 Centre for Immunology,
St. Vincent's Hospital and University of New South Wales, Sydney 2010, Australia; 4 Signal Research Division, Celgene Corp., San
Diego, California 92121, USA
-TrCP/E3RS (E3RS) is the F-box protein that functions as the
receptor subunit of the SCF-TrCP ubiquitin ligase (E3).
Surprisingly, although its two recognizedsubstrates, IB and
-catenin, are present in the cytoplasm,we have found that E3RS is
located predominantly in the nucleus.Here we report the isolation of
the major E3RS-associated protein,hnRNP-U, an abundant nuclear
phosphoprotein. This protein occupiesE3RS in a specific and
stoichiometric manner, stabilizes the E3component, and is likely
responsible for its nuclear localization.hnRNP-U binding was abolished
by competition with a pIB peptide,or by a specific point
mutation in the E3RS WD region, indicatingan E3-substrate-type
interaction. However, unlike pIB, whichis targeted by
SCF-TrCP for degradation, the E3-bound hnRNP-U is stable
and is, therefore,a pseudosubstrate. Consequently, hnRNP-U engages a
highly neddylatedactive SCF-TrCP, which dissociates in
the presence of a high-affinity substrate,resulting in ubiquitination
of the latter. Our study points toa novel regulatory mechanism, which
secures the localization,stability, substrate binding threshold, and
efficacy of a specificprotein-ubiquitinligase.
The mRNA-stabilizing Factor HuR Protein Is Targeted by {beta}-TrCP Protein for Degradation in Response to Glycolysis Inhibition.
P.-C. Chu, H.-C. Chuang, S. K. Kulp, and C.-S. Chen (2012)
J. Biol. Chem.
287, 43639-43650
|Abstract »|Full Text »|PDF »
Enhancement of NEIL1 Protein-initiated Oxidized DNA Base Excision Repair by Heterogeneous Nuclear Ribonucleoprotein U (hnRNP-U) via Direct Interaction.
M. L. Hegde, S. Banerjee, P. M. Hegde, L. J. Bellot, T. K. Hazra, I. Boldogh, and S. Mitra (2012)
J. Biol. Chem.
287, 34202-34211
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Nuclear to Cytoplasmic Translocation of Heterogeneous Nuclear Ribonucleoprotein U Enhances TLR-Induced Proinflammatory Cytokine Production by Stabilizing mRNAs in Macrophages.
W. Zhao, L. Wang, M. Zhang, P. Wang, J. Qi, L. Zhang, and C. Gao (2012)
J. Immunol.
188, 3179-3187
|Abstract »|Full Text »|PDF »
Mislocalization of the E3 Ligase, {beta}-Transducin Repeat-containing Protein 1 ({beta}-TrCP1), in Glioblastoma Uncouples Negative Feedback between the Pleckstrin Homology Domain Leucine-rich Repeat Protein Phosphatase 1 (PHLPP1) and Akt.
N. A. Warfel, M. Niederst, M. W. Stevens, P. M. Brennan, M. C. Frame, and A. C. Newton (2011)
J. Biol. Chem.
286, 19777-19788
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Nucleolar Targeting of the Fbw7 Ubiquitin Ligase by a Pseudosubstrate and Glycogen Synthase Kinase 3.
M. Welcker, E. A. Larimore, L. Frappier, and B. E. Clurman (2011)
Mol. Cell. Biol.
31, 1214-1224
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Ubiquitination and Degradation of the Inhibitors of NF-{kappa}B.
N. Kanarek, N. London, O. Schueler-Furman, and Y. Ben-Neriah (2010)
Cold Spring Harb Perspect Biol
2, a000166
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Novel Roles of Hakai in Cell Proliferation and Oncogenesis.
A. Figueroa, H. Kotani, Y. Toda, K. Mazan-Mamczarz, E.-C. Mueller, A. Otto, L. Disch, M. Norman, R. M. Ramdasi, M. Keshtgar, et al. (2009)
Mol. Biol. Cell
20, 3533-3542
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Molecular characterization of Mybbp1a as a co-repressor on the Period2 promoter.
Y. Hara, Y. Onishi, K. Oishi, K. Miyazaki, A. Fukamizu, and N. Ishida (2009)
Nucleic Acids Res.
37, 1115-1126
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The Role of {beta}-TrCP1 and {beta}-TrCP2 in Circadian Rhythm Generation by Mediating Degradation of Clock Protein PER2.
K. Ohsaki, K. Oishi, Y. Kozono, K. Nakayama, K. I. Nakayama, and N. Ishida (2008)
J. Biochem.
144, 609-618
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Glucocorticoid-Induced Degradation of Glycogen Synthase Kinase-3 Protein Is Triggered by Serum- and Glucocorticoid-Induced Protein Kinase and Akt Signaling and Controls {beta}-Catenin Dynamics and Tight Junction Formation in Mammary Epithelial Tumor Cells.
K. L. Failor, Y. Desyatnikov, L. A. Finger, and G. L. Firestone (2007)
Mol. Endocrinol.
21, 2403-2415
|Abstract »|Full Text »|PDF »
The Ubiquitin Ligase SCF(betaTrCP) Regulates the Degradation of the Growth Hormone Receptor.
P. van Kerkhof, J. Putters, and G. J. Strous (2007)
J. Biol. Chem.
282, 20475-20483
|Abstract »|Full Text »|PDF »
Molecular profile of mouse stromal mesenchymal stem cells.
S. Chateauvieux, J.-L. Ichante, B. Delorme, V. Frouin, G. Pietu, A. Langonne, N. Gallay, L. Sensebe, M. T. Martin, K. A. Moore, et al. (2007)
Physiol Genomics
29, 128-138
|Abstract »|Full Text »|PDF »
RASSF1C, an Isoform of the Tumor Suppressor RASSF1A, Promotes the Accumulation of {beta}-Catenin by Interacting with {beta}TrCP.
E. Estrabaud, I. Lassot, G. Blot, E. Le Rouzic, V. Tanchou, E. Quemeneur, L. Daviet, F. Margottin-Goguet, and R. Benarous (2007)
Cancer Res.
67, 1054-1061
|Abstract »|Full Text »|PDF »
Prophase I arrest and progression to metaphase I in mouse oocytes are controlled by Emi1-dependent regulation of APCCdh1.
P. Marangos, E. W. Verschuren, R. Chen, P. K. Jackson, and J. Carroll (2007)
J. Cell Biol.
176, 65-75
|Abstract »|Full Text »|PDF »
Myeloid Leukemia Factor 1 Associates with a Novel Heterogeneous Nuclear Ribonucleoprotein U-like Molecule.
L. N. Winteringham, R. Endersby, S. Kobelke, R. K. McCulloch, J. H. Williams, J. Stillitano, S. M. Cornwall, E. Ingley, and S. P. Klinken (2006)
J. Biol. Chem.
281, 38791-38800
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Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor.
J. J. Miller, M. K. Summers, D. V. Hansen, M. V. Nachury, N. L. Lehman, A. Loktev, and P. K. Jackson (2006)
Genes & Dev.
20, 2410-2420
|Abstract »|Full Text »|PDF »
The COP9 signalosome regulates the Neurospora circadian clock by controlling the stability of the SCFFWD-1 complex.
Increased Expression of the E3-Ubiquitin Ligase Receptor Subunit {beta}TRCP1 Relates to Constitutive Nuclear Factor-{kappa}B Activation and Chemoresistance in Pancreatic Carcinoma Cells.
S. Muerkoster, A. Arlt, B. Sipos, M. Witt, M. Grossmann, G. Kloppel, H. Kalthoff, U. R. Folsch, and H. Schafer (2005)
Cancer Res.
65, 1316-1324
|Abstract »|Full Text »|PDF »
Role of Oxidative Modifications in Atherosclerosis.
Associations Among {beta}-TrCP, an E3 Ubiquitin Ligase Receptor, {beta}-Catenin, and NF-{kappa}B in Colorectal Cancer.
A. Ougolkov, B. Zhang, K. Yamashita, V. Bilim, M. Mai, S. Y. Fuchs, and T. Minamoto (2004)
J Natl Cancer Inst
96, 1161-1170
|Abstract »|Full Text »|PDF »
Heterogeneous Nuclear Ribonuclear Protein U Associates with YAP and Regulates Its Co-activation of Bax Transcription.
M. Howell, C. Borchers, and S. L. Milgram (2004)
J. Biol. Chem.
279, 26300-26306
|Abstract »|Full Text »|PDF »
Transient and Selective NF-{kappa}B p65 Serine 536 Phosphorylation Induced by T Cell Costimulation Is Mediated by I{kappa}B Kinase {beta} and Controls the Kinetics of p65 Nuclear Import.
I. Mattioli, A. Sebald, C. Bucher, R.-P. Charles, H. Nakano, T. Doi, M. Kracht, and M. L. Schmitz (2004)
J. Immunol.
172, 6336-6344
|Abstract »|Full Text »|PDF »
Negative Regulation of Prolactin Receptor Stability and Signaling Mediated by SCF{beta}-TrCP E3 Ubiquitin Ligase.
Y. Li, K. G. Suresh Kumar, W. Tang, V. S. Spiegelman, and S. Y. Fuchs (2004)
Mol. Cell. Biol.
24, 4038-4048
|Abstract »|Full Text »|PDF »
Stability of Homologue of Slimb F-box Protein Is Regulated by Availability of Its Substrate.
Y. Li, S. Gazdoiu, Z.-Q. Pan, and S. Y. Fuchs (2004)
J. Biol. Chem.
279, 11074-11080
|Abstract »|Full Text »|PDF »
The Amino-terminal Portion of the F-box Protein Met30p Mediates Its Nuclear Import and Assimilation into an SCF Complex.
L. E. Brunson, C. Dixon, L. Kozubowski, and N. Mathias (2004)
J. Biol. Chem.
279, 6674-6682
|Abstract »|Full Text »|PDF »
HIV-1 Vpu Sequesters {beta}-Transducin Repeat-containing Protein ({beta}TrCP) in the Cytoplasm and Provokes the Accumulation of {beta}-Catenin and Other SCF{beta}TrCP Substrates.
C. Besnard-Guerin, N. Belaidouni, I. Lassot, E. Segeral, A. Jobart, C. Marchal, and R. Benarous (2004)
J. Biol. Chem.
279, 788-795
|Abstract »|Full Text »|PDF »
The Role of {beta}-Transducin Repeat-Containing Protein ({beta}-TrCP) in the Regulation of NF-{kappa}B in Vascular Smooth Muscle Cells.
X. Wang, N. Adhikari, Q. Li, Z. Guan, and J. L. Hall (2004)
Arterioscler Thromb Vasc Biol
24, 85-90
|Abstract »|Full Text »|PDF »
Interaction of Epstein-Barr Virus Latent Membrane Protein 1 with SCFHOS/{beta}-TrCP E3 Ubiquitin Ligase Regulates Extent of NF-{kappa}B Activation.
W. Tang, O. A. Pavlish, V. S. Spiegelman, A. A. Parkhitko, and S. Y. Fuchs (2003)
J. Biol. Chem.
278, 48942-48949
|Abstract »|Full Text »|PDF »
Exploring the functional complexity of cellular proteins by protein knockout.
Structural and Transcriptional Analysis of the Self-Incompatibility Locus of Almond: Identification of a Pollen-Expressed F-Box Gene with Haplotype-Specific Polymorphism.
K. Ushijima, H. Sassa, A. M. Dandekar, T. M. Gradziel, R. Tao, and H. Hirano (2003)
PLANT CELL
15, 771-781
|Abstract »|Full Text »|PDF »
-TrCP ubiquitin ligase by hnRNP-U
-TrCP/E3RS (E3RS) is the F-box protein that functions as the
receptor subunit of the SCF
-TrCP ubiquitin ligase (E3).
Surprisingly, although its two recognized substrates, I
B
and
