Photo of Wade Harper,  PhD

Wade Harper, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-6590
Fax: (617) 432-6591


wade_harper@hms.harvard.edu

Wade Harper, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • Bert and Natalie Vallee Professor of Molecular Path, Cell Biology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

DF/HCC ASSOCIATIONS

  • Member, Center Scientific Council

Research Abstract

Ubiquitin: from Signaling to Disease

Cullin-RING Ubiquitin Ligases and Cell Signaling

Protein Interaction Networks and Quantitative Proteomics

Macro and Selective Autophagy

Mitochondrial Quality Control and Parkinson’s Disease

Protein turnover through the ubiquitin system is a central means by which the abundance of regulatory proteins are controlled. Many such proteins are involved in signal transduction cascades linked with cell proliferation, checkpoints, and cancer. This lab employs proteomic and genetic approaches to uncover key signaling systems, ubiquitin ligases, and regulatory circuits that control various biological pathways. Broad research areas are outlined on the RESEARCH link above.

In addition to the ubiquitin system, the lab is also exploring the mechanisms underlying large-scale proteome homeostasis, including the autophagy system and mitochondrial quality control in diseases such as Parkinson’s Disease. For example, the PARKIN protein, found mutated in familial early on-set forms of Parkinson’s Disease is a ubiquitin ligase that controls the degradation of damaged mitochondria via the process of autophagy (referred to as mitophagy). Our work in this area is focused on the use of proteomic approaches to identify targets of the PARKIN ubiquitin ligase and how PARKIN activates the mitophagy process (Sarraf et al., Nature, 2013). We have also now extended our mitochondrial work towards understanding how mitochondrial networks are established and how these complexes are deregulated in mitochondrial disease. Our first publication in this area recently appeared in Molecular and Cellular Biology (Guarani et a., MCB, 2014), where we identified a novel component of the assembly apparatus for Complex I of the electron transport chain.

To aid in our proteomic studies, we have developed several proteomic tools and methods that facilitate quantitative studies of signaling pathways and protein modifications such as phosphorylation and ubiquitylation. A key system is our proteomics platform called CompPASS (Comparative Proteomics Analysis Software Suite) (Sowa et al., Cell, 2009). CompPASS is designed to help facilitate the identification of high confidence candidate interacting proteins from IP-MS/MS data. The CompPASS website contains all of the data from the Cell paper describing the deubiquitinating enzyme interactome, the autophagy interactome (Nature, 2010), and ERAD interactome (Nature Cell Biology, 2011), as well as tools for navigating this data, and a CompPASS tutorial. This software can be accessed by clicking on the CompPASS icon (below). We have used this approach to examine the interaction partners of hundreds of proteins involved in signal transduction and disease. Recently, we have developed a new method called Parallel Adaptor Capture proteomics to identify substrates of cullin-RING ligases, and have applied it to the entire SCF-FBXL family of E3s, identifying numerous candidate substrates (Tan et al., Molecular Cell, 2013).

We have recently reported in Nature the use of quantitative proteomics to systematically identify autophagosome-enriched proteins, with a major goal of identifying new cargo and cargo receptors. Among the novel autophagosomally enriched proteins was NCOA4, a cytoplasmic protein that we demonstrated to localize to autophagosomal vesicles in response to activation of autophagy. Unbiased identification of NCOA4-associated proteins revealed ferritin heavy and light chains, components of an iron-filled cage structure that protects cells from reactive iron species but is degraded via autophagy to release iron through an unknown mechanism. We found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin leads to decreased bioavailable intracellular iron. Their work identifies NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy) critical for iron homeostasis and provides a resource for further dissection of autophagosomal cargo-receptor connectivity.

In addition, with the Gygi Lab we have developed diGLY proteomics as an approach for identification of ubiquitylation sites in proteins in a dynamic and quantitative manner (Kim et al., Molecular Cell 2011). This system can be used to characterize the ubiquitin modified proteome and to identify sites of ubiquitylation by specific ubiquitin ligases.

Finally, we are involved in the development of multiple quantitative approaches for measuring the effects of cellular perturbations on signaling networks and post-translational modifications. One approach is called Absolute Quantification (AQUA) which employs heavily labeled reference peptides to quantify individual proteins in complexes. We have used this approach to examine the dynamics of the CRL system (Bennett et al., Cell, 2010).

Publications

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  • Izhar L, Adamson B, Ciccia A, Lewis J, Pontano-Vaites L, Leng Y, Liang AC, Westbrook TF, Harper JW, Elledge SJ. A Systematic Analysis of Factors Localized to Damaged Chromatin Reveals PARP-Dependent Recruitment of Transcription Factors. Cell Rep 2015; 11:1486-500. PubMed
  • Galligan JT, Martinez-Noël G, Arndt V, Hayes S, Chittenden TW, Harper JW, Howley PM. Proteomic analysis and identification of cellular interactors of the giant ubiquitin ligase HERC2. J Proteome Res 2015; 14:953-66. PubMed
  • Guarani V, McNeill EM, Paulo JA, Huttlin EL, Fröhlich F, Gygi SP, Van Vactor D, Harper JW. QIL1 is a novel mitochondrial protein required for MICOS complex stability and cristae morphology. Elife 2015. PubMed
  • Ciccia A, Huang JW, Izhar L, Sowa ME, Harper JW, Elledge SJ. Treacher Collins syndrome TCOF1 protein cooperates with NBS1 in the DNA damage response. Proc Natl Acad Sci U S A 2014; 111:18631-6. PubMed
  • Li N, Fassl A, Chick J, Inuzuka H, Li X, Mansour MR, Liu L, Wang H, King B, Shaik S, Gutierrez A, Ordureau A, Otto T, Kreslavsky T, Baitsch L, Bury L, Meyer CA, Ke N, Mulry KA, Kluk MJ, Roy M, Kim S, Zhang X, Geng Y, Zagozdzon A, Jenkinson S, Gale RE, Linch DC, Zhao JJ, Mullighan CG, Harper JW, Aster JC, Aifantis I, von Boehmer H, Gygi SP, Wei W, Look AT, Sicinski P. Cyclin C is a haploinsufficient tumour suppressor. Nat Cell Biol 2014; 16:1080-91. PubMed
  • Conwell SE, White AE, Harper JW, Knipe DM. Identification of TRIM27 as a Novel Degradation Target of Herpes Simplex Virus 1 ICP0. J Virol 2014. PubMed
  • Ordureau A, Sarraf SA, Duda DM, Heo JM, Jedrychowski MP, Sviderskiy VO, Olszewski JL, Koerber JT, Xie T, Beausoleil SA, Wells JA, Gygi SP, Schulman BA, Harper JW. Quantitative Proteomics Reveal a Feedforward Mechanism for Mitochondrial PARKIN Translocation and Ubiquitin Chain Synthesis. Mol Cell 2014. PubMed
  • Ikeuchi Y, Dadakhujaev S, Chandhoke AS, Huynh MA, Oldenborg A, Ikeuchi M, Deng L, Bennett EJ, Harper JW, Bonni A, Bonni S. TIF1粒 protein regulates epithelial-mesenchymal transition by operating as a small ubiquitin-like modifier (SUMO) E3 ligase for the transcriptional regulator SnoN1. J Biol Chem 2014; 289:25067-78. PubMed
  • Fischer ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, Nagel J, Serluca F, Acker V, Lingaraju GM, Tichkule RB, Schebesta M, Forrester WC, Schirle M, Hassiepen U, Ottl J, Hild M, Beckwith RE, Harper JW, Jenkins JL, Thomä NH. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 2014; 512:49-53. PubMed
  • Ordureau A, Harper JW. Cell biology: balancing act. Nature 2014; 510:347-8. PubMed
  • Scott DC, Sviderskiy VO, Monda JK, Lydeard JR, Cho SE, Harper JW, Schulman BA. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell 2014; 157:1671-84. PubMed
  • Mancias JD, Wang X, Gygi SP, Harper JW, Kimmelman AC. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 2014. PubMed
  • Mejia LA, Litterman N, Ikeuchi Y, de la Torre-Ubieta L, Bennett EJ, Zhang C, Harper JW, Bonni A. A novel Hap1-Tsc1 interaction regulates neuronal mTORC1 signaling and morphogenesis in the brain. J Neurosci 2013; 33:18015-21. PubMed
  • Mosammaparast N, Kim H, Laurent B, Zhao Y, Lim HJ, Majid MC, Dango S, Luo Y, Hempel K, Sowa ME, Gygi SP, Steen H, Harper JW, Yankner B, Shi Y. The histone demethylase LSD1/KDM1A promotes the DNA damage response. J Cell Biol 2013; 203:457-70. PubMed
  • Tan MK, Lim HJ, Bennett EJ, Shi Y, Harper JW. Parallel SCF adaptor capture proteomics reveals a role for SCFFBXL17 in NRF2 activation via BACH1 repressor turnover. Mol Cell 2013; 52:9-24. PubMed
  • Lee PC, Dodart JC, Aron L, Finley LW, Bronson RT, Haigis MC, Yankner BA, Harper JW. Altered Social Behavior and Neuronal Development in Mice Lacking the Uba6-Use1 Ubiquitin Transfer System. Mol Cell 2013. PubMed
  • White EA, Kramer RE, Tan MJ, Hayes SD, Harper JW, Howley PM. Comprehensive analysis of host cellular interactions with human papillomavirus e6 proteins identifies new e6 binding partners and reflects viral diversity. J Virol 2012; 86:13174-86. PubMed
  • Martínez-Noël G, Galligan JT, Sowa ME, Arndt V, Overton TM, Harper JW, Howley PM. Identification and proteomic analysis of distinct UBE3A/E6AP protein complexes. Mol Cell Biol 2012; 32:3095-106. PubMed
  • Tan MJ, White EA, Sowa ME, Harper JW, Aster JC, Howley PM. Cutaneous 硫-human papillomavirus E6 proteins bind Mastermind-like coactivators and repress Notch signaling. Proc Natl Acad Sci U S A 2012; 109:E1473-80. PubMed
  • O'Connell BC, Adamson B, Lydeard JR, Sowa ME, Ciccia A, Bredemeyer AL, Schlabach M, Gygi SP, Elledge SJ, Harper JW. A genome-wide camptothecin sensitivity screen identifies a mammalian MMS22L-NFKBIL2 complex required for genomic stability. Mol Cell 2010; 40:645-57. PubMed
  • Gao D, Wan L, Inuzuka H, Berg AH, Tseng A, Zhai B, Shaik S, Bennett E, Tron AE, Gasser JA, Lau A, Gygi SP, Harper JW, DeCaprio JA, Toker A, Wei W. Rictor forms a complex with Cullin-1 to promote SGK1 ubiquitination and destruction. Mol Cell 2010; 39:797-808. PubMed
  • Inuzuka H, Tseng A, Gao D, Zhai B, Zhang Q, Shaik S, Wan L, Ang XL, Mock C, Yin H, Stommel JM, Gygi S, Lahav G, Asara J, Xiao ZX, Kaelin WG, Harper JW, Wei W. Phosphorylation by casein kinase I promotes the turnover of the Mdm2 oncoprotein via the SCF(beta-TRCP) ubiquitin ligase. Cancer Cell 2010; 18:147-59. PubMed
  • Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiácovo MP, Elledge SJ. A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol Cell 2010; 39:36-47. PubMed
  • Song EJ, Werner SL, Neubauer J, Stegmeier F, Aspden J, Rio D, Harper JW, Elledge SJ, Kirschner MW, Rape M. The Prp19 complex and the Usp4Sart3 deubiquitinating enzyme control reversible ubiquitination at the spliceosome. Genes Dev 2010; 24:1434-47. PubMed
  • Powell ML, Smith JA, Sowa ME, Harper JW, Iftner T, Stubenrauch F, Howley PM. NCoR1 Mediates Papillomavirus E8;E2C Transcriptional Repression. J Virol 2010; 84:4451-60. PubMed
  • Smith JA, White EA, Sowa ME, Powell ML, Ottinger M, Harper JW, Howley PM. Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression. Proc Natl Acad Sci U S A 2010; 107:3752-7. PubMed
  • Ciccia A, Bredemeyer AL, Sowa ME, Terret ME, Jallepalli PV, Harper JW, Elledge SJ. The SIOD disorder protein SMARCAL1 is an RPA-interacting protein involved in replication fork restart. Genes Dev 2009; 23:2415-25. PubMed
  • Zheng G, Schweiger MR, Martinez-Noel G, Zheng L, Smith JA, Harper JW, Howley PM. Brd4 regulation of papillomavirus protein E2 stability. J Virol 2009; 83:8683-92. PubMed
  • Sowa ME, Bennett EJ, Gygi SP, Harper JW. Defining the human deubiquitinating enzyme interaction landscape. Cell 2009; 138:389-403. PubMed
  • Svendsen JM, Smogorzewska A, Sowa ME, O'Connell BC, Gygi SP, Elledge SJ, Harper JW. Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell 2009; 138:63-77. PubMed
  • Xu L, Sowa ME, Chen J, Li X, Gygi SP, Harper JW. An FTS/Hook/p107(FHIP) complex interacts with and promotes endosomal clustering by the homotypic vacuolar protein sorting complex. Mol Biol Cell 2008; 19:5059-71. PubMed
  • Jin J, Ang XL, Ye X, Livingstone M, Harper JW. Differential roles for checkpoint kinases in DNA damage-dependent degradation of the Cdc25A protein phosphatase. J Biol Chem 2008; 283:19322-8. PubMed
  • Kato N, Sakata T, Breton G, Le Roch KG, Nagle A, Andersen C, Bursulaya B, Henson K, Johnson J, Kumar KA, Marr F, Mason D, McNamara C, Plouffe D, Ramachandran V, Spooner M, Tuntland T, Zhou Y, Peters EC, Chatterjee A, Schultz PG, Ward GE, Gray N, Harper J, Winzeler EA. Gene expression signatures and small-molecule compounds link a protein kinase to Plasmodium falciparum motility. Nat Chem Biol 2008; 4:347-56. PubMed
  • Westbrook TF, Hu G, Ang XL, Mulligan P, Pavlova NN, Liang A, Leng Y, Maehr R, Shi Y, Harper JW, Elledge SJ. SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 2008; 452:370-4. PubMed
  • Schlabach MR, Luo J, Solimini NL, Hu G, Xu Q, Li MZ, Zhao Z, Smogorzewska A, Sowa ME, Ang XL, Westbrook TF, Liang AC, Chang K, Hackett JA, Harper JW, Hannon GJ, Elledge SJ. Cancer proliferation gene discovery through functional genomics. Science 2008; 319:620-4. PubMed
  • Bennett EJ, Harper JW. DNA damage: ubiquitin marks the spot. Nat Struct Mol Biol 2008; 15:20-2. PubMed
  • Harper JW, Elledge SJ. The DNA damage response: ten years after. Mol Cell 2007; 28:739-45. PubMed
  • Ghule PN, Becker KA, Harper JW, Lian JB, Stein JL, van Wijnen AJ, Stein GS. Cell cycle dependent phosphorylation and subnuclear organization of the histone gene regulator p220(NPAT) in human embryonic stem cells. J Cell Physiol 2007; 213:9-17. PubMed
  • Huh K, Zhou X, Hayakawa H, Cho JY, Libermann TA, Jin J, Wade Harper J, Munger K. Human papillomavirus type 16 e7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor. J Virol 2007; 81:9737-47. PubMed
  • Jin J, Li X, Gygi SP, Harper JW. Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Nature 2007; 447:1135-8. PubMed
  • Draviam VM, Stegmeier F, Nalepa G, Sowa ME, Chen J, Liang A, Hannon GJ, Sorger PK, Harper JW, Elledge SJ. A functional genomic screen identifies a role for TAO1 kinase in spindle-checkpoint signalling. Nat Cell Biol 2007; 9:556-64. PubMed
  • Stegmeier F, Rape M, Draviam VM, Nalepa G, Sowa ME, Ang XL, McDonald ER, Li MZ, Hannon GJ, Sorger PK, Kirschner MW, Harper JW, Elledge SJ. Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. Nature 2007; 446:876-81. PubMed
  • Harper JW, Schulman BA. Structural complexity in ubiquitin recognition. Cell 2006; 124:1133-6. PubMed
  • Lee TH, Perrem K, Harper JW, Lu KP, Zhou XZ. The F-box protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance. J Biol Chem 2005; 281:759-68. PubMed
  • Shirogane T, Jin J, Ang XL, Harper JW. SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein. J Biol Chem 2005; 280:26863-72. PubMed
  • Miele A, Braastad CD, Holmes WF, Mitra P, Medina R, Xie R, Zaidi SK, Ye X, Wei Y, Harper JW, van Wijnen AJ, Stein JL, Stein GS. HiNF-P directly links the cyclin E/CDK2/p220NPAT pathway to histone H4 gene regulation at the G1/S phase cell cycle transition. Mol Cell Biol 2005; 25:6140-53. PubMed
  • Wei W, Jin J, Schlisio S, Harper JW, Kaelin WG. The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell 2005; 8:25-33. PubMed
  • Sundqvist A, Bengoechea-Alonso MT, Ye X, Lukiyanchuk V, Jin J, Harper JW, Ericsson J. Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7). Cell Metab 2005; 1:379-91. PubMed
  • Ye X, Nalepa G, Welcker M, Kessler BM, Spooner E, Qin J, Elledge SJ, Clurman BE, Harper JW. Recognition of phosphodegron motifs in human cyclin E by the SCF(Fbw7) ubiquitin ligase. J Biol Chem 2004; 279:50110-9. PubMed
  • Jin J, Cardozo T, Lovering RC, Elledge SJ, Pagano M, Harper JW. Systematic analysis and nomenclature of mammalian F-box proteins. Genes Dev 2004; 18:2573-80. PubMed
  • Cullinan SB, Gordan JD, Jin J, Harper JW, Diehl JA. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Mol Cell Biol 2004; 24:8477-86. PubMed
  • Nalepa G, Harper JW. Visualization of a highly organized intranuclear network of filaments in living mammalian cells. Cell Motil Cytoskeleton 2004; 59:94-108. PubMed
  • Ang XL, Harper JW. Interwoven ubiquitination oscillators and control of cell cycle transitions. Sci STKE 2004; 2004:pe31. PubMed
  • Harper JW. Neddylating the guardian; Mdm2 catalyzed conjugation of Nedd8 to p53. Cell 2004; 118:2-4. PubMed
  • Welcker M, Orian A, Jin J, Grim JA, Harper JW, Eisenman RN, Clurman BE. The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation. Proc Natl Acad Sci U S A 2004; 101:9085-90. PubMed
  • Tetzlaff MT, Yu W, Li M, Zhang P, Finegold M, Mahon K, Harper JW, Schwartz RJ, Elledge SJ. Inaugural Article, From The Cover: Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein. Proc Natl Acad Sci U S A 2004; 101:3338-3345. PubMed
  • Rodriguez M, Li SS, Harper JW, Songyang Z. An oriented peptide array library (OPAL) strategy to study protein-protein interactions. J Biol Chem 2003; 279:8802-7. PubMed
  • Tetzlaff MT, Bai C, Finegold M, Wilson J, Harper JW, Mahon KA, Elledge SJ. Cyclin F disruption compromises placental development and affects normal cell cycle execution. Mol Cell Biol 2004; 24:2487-98. PubMed
  • Wang W, Ungermannova D, Jin J, Harper JW, Liu X. Negative regulation of SCFSkp2 ubiquitin ligase by TGF-beta signaling. Oncogene 2003; 23:1064-75. PubMed
  • Li S, Armstrong CM, Bertin N, Ge H, Milstein S, Boxem M, Vidalain PO, Han JD, Chesneau A, Hao T, Goldberg DS, Li N, Martinez M, Rual JF, Lamesch P, Xu L, Tewari M, Wong SL, Zhang LV, Berriz GF, Jacotot L, Vaglio P, Reboul J, Hirozane-Kishikawa T, Li Q, Gabel HW, Elewa A, Baumgartner B, Rose DJ, Yu H, Bosak S, Sequerra R, Fraser A, Mango SE, Saxton WM, Strome S, Van Den Heuvel S, Piano F, Vandenhaute J, Sardet C, Gerstein M, Doucette-Stamm L, Gunsalus KC, Harper JW, Cusick ME, Roth FP, Hill DE, Vidal M. A map of the interactome network of the metazoan C. elegans. Science 2004; 303:540-3. PubMed
  • Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ, Harper JW. SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev 2003; 17:3062-74. PubMed
  • Ye X, Wei Y, Nalepa G, Harper JW. The cyclin E/Cdk2 substrate p220(NPAT) is required for S-phase entry, histone gene expression, and Cajal body maintenance in human somatic cells. Mol Cell Biol 2003; 23:8586-600. PubMed
  • Mitra P, Xie RL, Medina R, Hovhannisyan H, Zaidi SK, Wei Y, Harper JW, Stein JL, van Wijnen AJ, Stein GS. Identification of HiNF-P, a key activator of cell cycle-controlled histone H4 genes at the onset of S phase. Mol Cell Biol 2003; 23:8110-23. PubMed
  • Xu L, Wei Y, Reboul J, Vaglio P, Shin TH, Vidal M, Elledge SJ, Harper JW. BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature 2003; 425:316-21. PubMed
  • Wu G, Xu G, Schulman BA, Jeffrey PD, Harper JW, Pavletich NP. Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase. Mol Cell 2003; 11:1445-56. PubMed
  • Jin J, Harper JW. A license to kill: transcriptional activation and enhanced turnover of Myc by the SCF(kp2) ubiquitin ligase. Cancer Cell 2003; 3:517-8. PubMed
  • Wei Y, Jin J, Harper JW. The cyclin E/Cdk2 substrate and Cajal body component p220(NPAT) activates histone transcription through a novel LisH-like domain. Mol Cell Biol 2003; 23:3669-80. PubMed
  • Baumgartner B, Harper JW. Deafening cycle. Nat Cell Biol 2003; 5:385-7. PubMed
  • Wang Y, Shirogane T, Liu D, Harper JW, Elledge SJ. Exit from exit: resetting the cell cycle through Amn1 inhibition of G protein signaling. Cell 2003; 112:697-709. PubMed
  • Passmore LA, McCormack EA, Au SW, Paul A, Willison KR, Harper JW, Barford D. Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition. EMBO J 2003; 22:786-96. PubMed
  • Yang G, Ayala G, De Marzo A, Tian W, Frolov A, Wheeler TM, Thompson TC, Harper JW. Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival. Clin Cancer Res 2002; 8:3419-26. PubMed
  • Nelson DM, Ye X, Hall C, Santos H, Ma T, Kao GD, Yen TJ, Harper JW, Adams PD. Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin/cdk2 activity. Mol Cell Biol 2002; 22:7459-72. PubMed
  • Harper JW, Burton JL, Solomon MJ. The anaphase-promoting complex: it's not just for mitosis any more. Genes Dev 2002; 16:2179-206. PubMed
  • Nalepa G, Harper JW. Efp: a ring of independence? Nat Med 2002; 8:661-2. PubMed
  • Jin J, Harper JW. RING finger specificity in SCF-driven protein destruction. Dev Cell 2002; 2:685-7. PubMed
  • Zheng N, Schulman BA, Song L, Miller JJ, Jeffrey PD, Wang P, Chu C, Koepp DM, Elledge SJ, Pagano M, Conaway RC, Conaway JW, Harper JW, Pavletich NP. Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 2002; 416:703-9. PubMed
  • Leng X, Noble M, Adams PD, Qin J, Harper JW. Reversal of growth suppression by p107 via direct phosphorylation by cyclin D1/cyclin-dependent kinase 4. Mol Cell Biol 2002; 22:2242-54. PubMed
  • Harper JW. A phosphorylation-driven ubiquitination switch for cell-cycle control. Trends Cell Biol 2002; 12:104-7. PubMed
  • Au SW, Leng X, Harper JW, Barford D. Implications for the ubiquitination reaction of the anaphase-promoting complex from the crystal structure of the Doc1/Apc10 subunit. J Mol Biol 2002; 316:955-68. PubMed
  • Koepp DM, Schaefer LK, Ye X, Keyomarsi K, Chu C, Harper JW, Elledge SJ. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 2001; 294:173-7. PubMed
  • Harper JW, Adams PD. Cyclin-dependent kinases. Chem Rev 2001; 101:2511-26. PubMed
  • Harper JW. Protein destruction: adapting roles for Cks proteins. Curr Biol 2001; 11:R431-5. PubMed
  • Ye X, Zhu C, Harper JW. A premature-termination mutation in the Mus musculus cyclin-dependent kinase 3 gene. Proc Natl Acad Sci U S A 2001; 98:1682-6. PubMed
  • Goldberg AL, Elledge SJ, Harper JW. The cellular chamber of doom. Sci Am 2001; 284:68-73. PubMed
  • Schulman BA, Carrano AC, Jeffrey PD, Bowen Z, Kinnucan ER, Finnin MS, Elledge SJ, Harper JW, Pagano M, Pavletich NP. Insights into SCF ubiquitin ligases from the structure of the Skp1-Skp2 complex. Nature 2000; 408:381-6. PubMed
  • Ma T, Van Tine BA, Wei Y, Garrett MD, Nelson D, Adams PD, Wang J, Qin J, Chow LT, Harper JW. Cell cycle-regulated phosphorylation of p220(NPAT) by cyclin E/Cdk2 in Cajal bodies promotes histone gene transcription. Genes Dev 2000; 14:2298-313. PubMed
  • Stepanova L, Finegold M, DeMayo F, Schmidt EV, Harper JW. The oncoprotein kinase chaperone CDC37 functions as an oncogene in mice and collaborates with both c-myc and cyclin D1 in transformation of multiple tissues. Mol Cell Biol 2000; 20:4462-73. PubMed
  • Stepanova L, Yang G, DeMayo F, Wheeler TM, Finegold M, Thompson TC, Harper JW. Induction of human Cdc37 in prostate cancer correlates with the ability of targeted Cdc37 expression to promote prostatic hyperplasia. Oncogene 2000; 19:2186-93. PubMed
  • Lin BY, Ma T, Liu JS, Kuo SR, Jin G, Broker TR, Harper JW, Chow LT. HeLa cells are phenotypically limiting in cyclin E/CDK2 for efficient human papillomavirus DNA replication. J Biol Chem 2000; 275:6167-74. PubMed
  • Shapiro GI, Harper JW. Anticancer drug targets: cell cycle and checkpoint control. J Clin Invest 1999; 104:1645-53. PubMed
  • Winston JT, Chu C, Harper JW. Culprits in the degradation of cyclin E apprehended. Genes Dev 1999; 13:2751-7. PubMed
  • Winston JT, Koepp DM, Zhu C, Elledge SJ, Harper JW. A family of mammalian F-box proteins. Curr Biol 1999; 9:1180-2. PubMed
  • Wang Y, Penfold S, Tang X, Hattori N, Riley P, Harper JW, Cross JC, Tyers M. Deletion of the Cul1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E. Curr Biol 1999; 9:1191-4. PubMed
  • Erdamar S, Yang G, Harper JW, Lu X, Kattan MW, Thompson TC, Wheeler TM. Levels of expression of p27KIP1 protein in human prostate and prostate cancer: an immunohistochemical analysis. Mod Pathol 1999; 12:751-5. PubMed
  • Kitagawa K, Skowyra D, Elledge SJ, Harper JW, Hieter P. SGT1 encodes an essential component of the yeast kinetochore assembly pathway and a novel subunit of the SCF ubiquitin ligase complex. Mol Cell 1999; 4:21-33. PubMed
  • Koepp DM, Harper JW, Elledge SJ. How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell 1999; 97:431-4. PubMed
  • Harper JW, Elledge SJ. Skipping into the E2F1-destruction pathway. Nat Cell Biol 1999; 1:E5-7. PubMed
  • Skowyra D, Koepp DM, Kamura T, Conrad MN, Conaway RC, Conaway JW, Elledge SJ, Harper JW. Reconstitution of G1 cyclin ubiquitination with complexes containing SCFGrr1 and Rbx1. Science 1999; 284:662-5. PubMed
  • Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, Kaelin WG, Elledge SJ, Conaway RC, Harper JW, Conaway JW. Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 1999; 284:657-61. PubMed
  • Winston JT, Strack P, Beer-Romero P, Chu CY, Elledge SJ, Harper JW. The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev 1999; 13:270-83. PubMed
  • Adams PD, Li X, Sellers WR, Baker KB, Leng X, Harper JW, Taya Y, Kaelin WG. Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes. Mol Cell Biol 1999; 19:1068-80. PubMed
  • Ma T, Zou N, Lin BY, Chow LT, Harper JW. Interaction between cyclin-dependent kinases and human papillomavirus replication-initiation protein E1 is required for efficient viral replication. Proc Natl Acad Sci U S A 1999; 96:382-7. PubMed
  • Zhang P, Wong C, Liu D, Finegold M, Harper JW, Elledge SJ. p21(CIP1) and p57(KIP2) control muscle differentiation at the myogenin step. Genes Dev 1999; 13:213-24. PubMed
  • Zhang P, Wong C, DePinho RA, Harper JW, Elledge SJ. Cooperation between the Cdk inhibitors p27(KIP1) and p57(KIP2) in the control of tissue growth and development. Genes Dev 1998; 12:3162-7. PubMed
  • Callahan MA, Handley MA, Lee YH, Talbot KJ, Harper JW, Panganiban AT. Functional interaction of human immunodeficiency virus type 1 Vpu and Gag with a novel member of the tetratricopeptide repeat protein family. J Virol 1998; 72:8461. PubMed
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