Michael Yaffe, Ph.D.
Department of Biology
Howard S. and Linda Stern Associate Professor of Biology
Center for Cancer Research and Division of Biological Engineering
B.S. Materials Science and Engineering, Cornell 1981
Ph.D. Biophysical Chemistry, Case Western Reserve 1987
Resident and Fellow in General Surgery/Critical Care Medicine, Harvard, 1989-1996
Fellow, Division of Signal Transduction, Harvard 1996
Instructor in Medicine and Suregry, Harvard Medical School 1998
Assistant Professor, Dept. of Biology, MIT 2000
Associate Professor, Dept. of Biology, MIT 2003
Research in the Yaffe lab is targeted at understanding the regulation of signaling pathways that control the cell cycle. In particular, we study how modifications of proteins are involved in transmitting environmental signals to the cell cycle machinery. Our technology uses the basic principles of biochemistry to identify all members of a particular signaling pathway and place them in a systems level network.
Research in Computational and Systems Biology
Kinases, the primary enzyme involved in signal transduction, modify proteins by recognizing particular linear sequence motifs in proteins, and covalently modifying them by attaching a phosphate group to serine, threonine, or tyrosine residues within the protein. These enzymes are the largest single enzyme family in the human genome, and it is thought that at least 30% of all proteins are modified by phosphorylation. These modifications play a particularly significant role controlling the cell cycle and the response of cells of DNA damage, primarily by phosphorylation-dependent formation of multi-protein signaling complexes.
Our lab uses oriented peptide library technology to identify the motifs that are recognized and phosphorylated by protein kinases involved in cell cycle control. Many of these motifs are conserved in proteins from yeast to humans. How do these evolutionarily conserved phosphorylation motifs fit into the complex network of signaling pathways that regulate the cell cycle? To address this, we have developed a proteomics approach to identify phosphoserine/phosphothreonine-binding domains that specifically recognize the phosphorylated sequences produced by the action of these protein kinases. By binding to specific phosphorylated sequences on proteins, these binding domains orchestrate the formation of signaling complexes that, in turn, control the cell cycle. Our proteomic approach utilizes libraries of phosphorylated peptides that mimic the sequence produced by a protein kinase. These phosphopeptides libraries are then used to fish out? binding domains from the cell, and map them onto signaling pathways in a system-wide manner. In addition, this approach allows us to rapidly identify targets for anti-cancer drug design.
A new mechanism for the breast cancer gene BRCA1.
Using our proteomic peptide library approach, we have identified a new functional domain involved in the development of breast cancer. The BRCA1 breast cancer gene contains a tandem pair of BRCT domains that function together a unit to bind to specific phosphorylated proteins involved in detection and repair of DNA damage. Eighty percent of women who inherit mutant forms of the BRCA1 protein develop breast cancer and 65% develop ovarian cancer. Many of these mutations eliminate the phosphopeptides-binding function of the tandem BRCT domains, preventing propogation of the DNA damage signal. The result is that DNA damage is not repaired before the onset of the next cell cycle, causing the accumulation of additional mutations, and ultimately causing cancer. Absence of BRCA1 activity is detrimental to healthy cells. However, disruption of the tandem BRCT domains of BRCA1 that our lab has identified may allow tumor cells to be more susceptible to anti-cancer drugs.
- Elia AE, Cantley LC, Yaffe MB. Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates. Science 2003 299:1228-31.
- Elia AEH, Rellos P, Haire LF, Chao JW, Ivins FJ, Hoepker K, Mohammad D, Cantley LC, Smerdon SJ and Yaffe MB. The molecular basis of phosphodependent substrate targeting and regulation of Plks by the Polo- Box domain. Cell 2003 115(1):83-95.
- Yaffe MB, Leparc GG, Lai J, Obata T, Volinia S, and Cantley LC. A motif-based profile scanning approach for genome-wide prediction of signaling pathways. Nat Biotechnol 2001 19:348-53.
- Yaffe MB, Smerdon SJ. PhosphoSerine/ Threonine Binding Domains. You Can`t pSERious? Structure 2001 9:R33-8.
- Manke IA, Lowery DM, Nguyen A and Yaffe MB. BRCT repeats as phosphopeptide binding modules involved in protein targeting. Science 2003 302:636-9.
Last Updated: April 16, 2008