J. Wade Harper
Department of Cell Biology
C2 Building, Room 426
240 Longwood Avenue
Boston, MA 02115
Visit my lab page here.
Ubiquitin and ubiquitin-like (UBL) protein conjugation systems control a vast array of cellular processes, and impact virtually every biological system. In this process, UBLs are activated through an activation and conjugation cascade before attachment to target proteins. Conjugation of ubiquitin itself is best known for its role in protein turnover via the proteasome, but ubiquitin conjugation can also provide regulatory functions in solid-state signaling networks.
Our work seeks to employ systematic genetic and proteomic approaches to elucidate the mechanisms and biology of ubiquitin and UBL protein conjugation systems. Much of our efforts have been devoted to elucidating the components and targets of a superfamily of E3 ubiquitin ligases referred to as cullin-RING ubiquitin ligases. We have explored the roles of these E3s in cell cycle and DNA damage checkpoint control and are currently employing systematic proteomic approaches to identify substrates and biological processes more many poorly understood ubiquitination pathways. We have recently elucidated the network organization of human deubiquitinating enzymes, the human autophagy system, as well as the ERAD system. Current efforts employ proteomics to identify substrates of the Parkin E3 ubiquitin ligase in response to mitochondrial depolarization.
A major emphasis is placed on the development of proteomic tools, methods, and software for quantitative analysis of signaling pathways and ubiquitination. One approach involves the use of multiple Absolute Quantification (mAQUA), which allows the stoichiometry and occupancy of components and modifications within protein complexes to be determined. We are using these approaches to examine the dynamics of multiple signaling pathways.
Christianson JC, Olzmann JA, Shaler TA, Sowa ME, Bennett EJ, Richter CM, Tyler RE, Greenblatt EJ, Harper JW, Kopito RR. (2011) Defining human ERAD networks through an integrative mapping strategy. Nat Cell Biol, 14:93-105.
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.
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 334:674-8.
Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP. (2011) Systematic and quantitative assessment of the
ubiquitin-modified proteome. Mol Cell 44:325-40.
Behrends C, Sowa ME, Gygi SP, Harper JW. (2010) Network organization of the human autophagy system. Nature 466:68-76.
For a complete listing of publications click here.
Last Update: 7/26/2012