The Harper Lab
Harvard Medical School
Department of Cell Biology
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. A central focus of the lab is cullin-RING E3 ubiquitin ligases and deubiquitinating enzymes which remove ubiquitin from various target proteins. In addition, we have recently employed proteomics to study the global architecture of the autophagy system, which is an alternative pathway for regulating bulk protein turnover and to maintain cell viability in the absence of sufficient nutrients. We are employing various proteomic strategies to elucidate the ubiquitinome - the array of proteins that are modified by ubiquitin in response to various signaling pathways.
Protein homeostasis through the ubiquitin and autophagy
systems - links to cell cycle control and cancer
Tan MJ, White EA, Sowa ME, Harper JW, Aster JC, Howley PM. Cutaneous β-human papillomavirus E6 proteins bind Mastermind-like coactivators and repress Notch signaling. Proc Natl Acad Sci U S A. 2012 Apr 30. [Epub ahead of print] PubMed
Popovic D, Akutsu M, Noval I, Harper JW, Behrends C, Dikic I. (2012) Rab GAPs in Autophagy: regulation of endocytic and autophagy pathways by direct binding to human ATG8 modifiers. Mol Cell Biol, 32(9):1733-1744.
White EA, Sowa ME, Tan MJ, Jeudy S, Hayes SD, Santha S, Münger K, Harper JW, Howley PM. (2012) Systematic identification of interactions between host cell proteins and E7 oncoproteins from diverse human papillomaviruses. Proc Natl Acad Sci USA. 109:E260-7.
Christianson JC, Olzmann JA, Shaler TA, Sowa ME, Bennett EJ, Richter CM, Tyler RE, Greenblatt EJ, Harper JW and Kopito RR. (2011) Defining human ERAD networks through an integrative mapping strategy. Nature Cell Biology, 14, 93-105.
Scott DC, Monda JK, Bennett EJ, Harper JW, Schulman BA. (2011) N-Terminal Acetylation Acts as an Avidity Enhancer Within an Interconnected Multiprotein Complex.
Science, 334:674-678.
Gao D, Inuzuka H, Tan MK, Fukushima H, Locasale JW, Liu P, Wan L, Zhai B, Chin YR, Shaik S, Lyssiotis CA, Gygi SP, Toker A, Cantley LC, Asara JM, Harper JW*, Wei W*. (2011) mTOR Drives Its Own Activation via SCF(βTrCP)-Dependent Degradation of the mTOR Inhibitor DEPTOR. Mol Cell 44:290-303.
Raman M, Havens CG, Walter JC, Harper JW. (2011) A Genome-wide Screen Identifies p97 as an Essential Regulator of DNA Damage-Dependent CDT1 Destruction. Mol Cell 44:72-84.
Kim W, Bennett EJ, Huttlin EL, Guo A., Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW*, and Gygi SP*. (2010) Systematic and quantitative analysis of the ubiquitin modified proteome. Molecular Cell, 44:325-340.
Lee PC, Sowa SE, Gygi SP, Harper JW . (2011) Alternative Ubiquitin Activation/Conjugation Cascades Interact with N-End Rule Ubiquitin Ligases to Control Degradation of RGS Proteins. Molecular Cell 43:392-405.
Tan M-K M, Lim H-J, Harper JW. (2011) SCFFBXO22
regulates histone H3 lysine 9 and 36 methylation
levels by targeting histone demethylase KDM4A
for ubiquitin-mediated proteasomal degradation.
Mol. Cell. Biol. 31:3687-3699.
Bennett, EJ and Harper, JW. (2011) Simply quantifying ubiquitin complexity. Nature Methods 8, 630-631. (News and Views)
Harper, JW, and King RW. (2011) Stuck in the middle: Drugging the ubiquitin system at the E2 step. Cell, 145:1007-1009. (Preview).
Behrends C, Harper JW. (2011) Constructing and decoding unconventional ubiquitin chains. Nat Struct Mol Biol. 18:520-528.
Litterman N, Ikeuchi Y, Gallardo G, O'Connell BC, Sowa ME, Gygi SP, Harper JW, Bonni A. (2011) An OBSL1-Cul7 Ubiquitin Ligase Signaling Mechanism Regulates Golgi Morphology and Dendrite Patterning. PLoS Biol. 9:e1001060.
Bennett, E.J., Ruch, J., Gygi, SP, and Harper, JW. (2010) Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 143:951-965.
O'Connell BC, Adamson B, Lydeard JR, Sowa ME, Ciccia A, Bredemeyer AL, Schlabach M, Gygi SP, Elledge SJ, Harper JW. (2010) A Genome-wide Camptothecin Sensitivity Screen Identifies a Mammalian MMS22L-NFKBIL2 Complex Required for Genomic Stability. Mol Cell. 40:645-657.
Behrends, C, Sowa ME, Gygi SP, and Harper JW. (2010) Network organization of the human autophagy system. Nature 466, 68-77.
Sowa, M.E., Bennett, E.J., Gygi, S.P., and Harper, J.W. (2009) Defining the Human Deubiquitinating Enzyme Interaction Landscape. Cell, 138:389-403.
Svendsen, J., Smogorzewska, A.,Sowa, M.E., O’Connell, B.O., Gygi, S.P., Elledge, S.J., and Harper, J.W. (2009) Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell, 138:63-77.
Ciccia, A, Bredemeyer, AL, Sowa, ME, Terret, M-E, Jallepalli, PV, Harper, JW, and Elledge, SJ. (2009) The SIOD disorder protein SMARCAL1 is an RPA-interacting protein involved in replication fork restart. Genes and Development, 23:2415-2425.
Svendsen JM, Harper JW. (2010) GEN1/Yen1 and the SLX4 complex: solutions to the problem of Holliday junction resolution. Genes Dev. 24:521-536.
Sarraf SA, Harper JW. (2010) Telomeric TuRF1 wars. Developmental Cell 18:167-168.
Raman M, Harper JW. (2009) Cell biology: Stairway to the proteasome. Nature 462:585-586.
Zhuang M, Calabrese MF, Liu J, Waddell MB, Nourse A, Hammel M, Miller DJ, Walden H, Duda DM, Seyedin SN, Hoggard T, Harper JW, White KP, Schulman BA. (2009) Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Molecular Cell. 36:39-50.
Bennett EJ, Harper JW. (2010) Ubiquitin gets CARDed. Cell 141:220-222.
Recent/Upcoming Publications
To aid in our proteomic studies, we have developed a 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 and 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.
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