David H. Koch Professor of Science
Professor of Biology and Biological Engineering
Director, MIT Center for Precision Cancer Medicine
Director, KI Clinical Investigator Program
KI Research Areas of Focus:
Signaling and Systems Biology
"The goal of our research is to understand how signaling pathways are integrated at the molecular and systems level to control cellular responses. We are particularly interested in: (1) signaling pathways and networks that control cell cycle progression and DNA damage responses in cancer and cancer therapy; and (2) cross-talk between inflammation, cytokine signaling and cancer. Much of our work focuses on how modular protein domains and kinases work together to build molecular signaling circuits. The work is multi-disciplinary and encompasses biochemistry, biophysics, structural and cell biology, engineering, and computation/bioinformatics-based methods."
Dr. Yaffe is the David H. Koch Professor of Biology and Biological Engineering at MIT and Attending Surgeon at the Beth Israel Deaconess Medical Center, Harvard Medical School. He is also a founder of Consensus Pharmaceuticals and Merrimack Pharmaceuticals. Dr. Yaffe co-founded The DNA Repair Company in 2004 and serves as Chairman of Scientific Advisory Board at the company. He also serves as Member of Scientific Advisory Board of Merrimack Pharmaceuticals, Inc. and Boston Biomedical Research Institute, Inc. He completed a residency in General Surgery, a Fellowship in Surgical Critical Care, Burns and Trauma at Harvard Medical School, and post-doctoral training in Signal Transduction with Lew Cantley in Cell Biology at Harvard. He received his B.S. degree in Materials Science and Engineering at Cornell University, and his M.D. in 1989 and Ph.D. degree in 1987 from Case Western Reserve University in Biophysical Chemistry.
When cells encounter stress or injury such DNA damage, they activate complex signaling networks that regulate their ability to recover, repair the damage, and return to a homeostatic equilibrium. These networks must integrate a wide variety of signals from inside and outside the cell, transduced through protein kinase and lipid signaling pathways, to ultimately control cell cycle arrest or progression, coordinately regulate specific patterns of gene expression and/or initiate programmed cell death. Mutations in, or dysfunction of, protein kinase signaling pathways that normally respond to DNA damage, for example, play critical roles in tumor development and progression, while intentional targeting of these pathways can enhance the ability of commonly used DNA damaging chemotherapy and radiation to cure cancer.
DNA damage signaling pathways are intimately interconnected with pathways involved in cell growth, RNA processing and cytokine signaling, but how these pathways are integrated together at the systems level is poorly understood. Similarly, cells and tissues subjected to other types of injuries and/or infection by pathogens activate many of the same pathways involved in the DNA damage response. Inappropriate activity of these pathways cause auto-inflammatory tissue damage and multiple organ failure in states of overwhelming infection and sepsis as a result of mis-regulation of cytokine feedback loops, dysfunction of the blood clotting cascade, and uncontrolled activity of neutrophils, macophages and lymphocytes.
How are the signals from individual pathways integrated at the molecular level to control the phenotypic response of cells to infection, stress and DNA damage? What are the key pathways and molecules that are involved in these cellular events, and how are their activities and their interactions regulated by protein phosphorylation? How can these pathways be therapeutically manipulated using combination chemotherapies to re-wire tumor cells for optimal killing, or to limit cytokine-mediated inflammation and death? Our lab uses a broad range of technologies to decode how these cell signaling pathways are “wired” into functional networks through proteomic methods, high- and medium-throughput signaling assays, RNAi-based screens using high-content imaging, and computational/bioinformatics approaches, together with more traditional techniques from cell biology, physical biochemistry, structural biology and mouse genetics. We also have a long history of inventing new chemical, biochemical, and computational methods to study signaling, including peptide library-based screens and motif-based bioinformatics tools for building signaling networks in silico. Current projects in the lab are examining:
Alexander J, Lim D, Joughin BA, Hegemann B, Hutchins JR, Ehrenberger T, Ivins F, Sessa F, Hudecz O, Nigg EA, Fry AM, Musacchio A, Stukenberg PT, Mechtler K, Peters JM, Smerdon SJ, Yaffe MB. Spatial exclusivity combined with positive and negative selection of phosphorylation motifs is the basis for context-dependent mitotic signaling. Science Signal. 2011 4:ra42
Reinhardt HC, Hasskamp P, Schmedding I, Morandell S, van Vugt MA, Wang X, Linding R, Ong SE, Weaver D, Carr SA, Yaffe MB. DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. Molecular Cell 2010 40:34-49.
van Vugt MA, Gardino AK, Linding R, Ostheimer GJ, Reinhardt HC, Ong SE, Tan CS, Miao H, Keezer SM, Li J, Pawson T, Lewis TA, Carr SA, Smerdon SJ, Brummelkamp TR, Yaffe MB. A mitotic phosphorylation feedback network connects Cdk1, Plk1, 53BP1, and Chk2 to inactivate the G(2)/M DNA damage checkpoint. PLoS Biol. 2010 8:e1000287.
Macůrek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB, Medema RH. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature 2008 455:119-23.
Janes KA, Reinhardt HC, Yaffe MB. Cytokine-induced signaling networks prioritize dynamic range over signal strength. Cell 2008 135:343-54.
Wilker EW, van Vugt MA, Artim SA, Huang PH, Petersen CP, Reinhardt HC, Feng Y, Sharp PA, Sonenberg N, White FM, Yaffe MB. 14-3-3 sigma controls mitotic translation to facilitate cytokinesis. Nature. 2007 446:329-32.
Janes KA, Albeck JG, Gaudet S, Sorger PK, Lauffenburger DA, Yaffe MB. A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis. Science. 2005 310:1646-53.
Manke IA, Lowery DM, Nguyen A and Yaffe MB. BRCT repeats as phosphopeptide binding modules involved in protein targeting. Science 2003 302:636-639.
Elia AE, Cantley LC, Yaffe MB. Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates. Science 2003 299:1228-31.