Photo of Wade Harper,  PhD

Wade Harper, PhD

Harvard Medical School

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

Wade Harper, PhD

Harvard Medical School


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



  • 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).


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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