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Michael Yaffe


Associate Professor, Biology and Biological Engineering
Ph.D. 1987, Case Western Reserve University
M.D. 1989, Case Western Reserve University

1989-1996 Residency in General Surgery and Fellowship in Trauma, Burns, and Critical Care – University Hospitals of Cleveland and Harvard Medical School
1996-1998 Post-doctoral Fellow, Dept. of Cell Biology, Harvard Medical School

The goal of our research is to understand how protein kinase and lipid signaling pathways are integrated at the systems biology level to control cellular decision processes.  We are particularly interested in two areas directly relevant to human health and disease: (1) signaling pathways and networks that control cell cycle progression and DNA damage responses in cancer and cancer therapy; and (2) signaling pathways and networks that regulate inflammation during infection and sepsis, including cross-talk between inflammation and blood coagulation, and the connection between inflammation and cancer through cytokine feedback loops.

Research Summary

When cells are injured or encounter stressful stimuli such as DNA damage, hypoxia, or bacterial, parasitic, or viral infection, 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 individual 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, 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. Similarly, pathogenic infection, mis-regulation of cytokine feedback loops, and inappropriate activation of the blood clotting cascade, causes dysregulation of cell signaling pathways in neutrophils, causing tissue damage in auto-inflammatory diseases and multiple organ failure in states of overwhelming infection and sepsis.

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.  Current projects in the lab are examining:

(1) How phosphoserine/threonine-binding modules (Polo-box domains, 14-3-3 proteins, BRCT domains, and FHA domains) work together with specific protein kinases to form networks that control DNA damage signaling and cell cycle progression, how these networks are perturbed during tumor progression, and how these networks can be therapeutically targeted to enhance the ability of chemotherapy and radiation to kill tumor cells.

(2) How growth factor signaling pathways cross-talk with DNA damage signaling pathways to control tumor cell responses, and how combination chemotherapy can be intelligently used to re-wire signaling networks in tumor cells for optimal tumor killing.

(3) How MAP kinase pathways, cytokine feedback loops, and DNA damage signaling pathways interact, with a particularly strong focus on the role of the p38MAPK/MAPKAP Kinase-2 pathway in cell cycle control and cytokine signaling. Ongoing work in the lab suggests that this pathway plays a critical role in stress responses through the post-transcriptional control of gene expression by regulating mRNA splicing, stability and translation of cytokines and cell cycle regulatory molecules that are responsible, on one hand for tumor development and resistance to chemotherapy, and on the other hand for pathological inflammation and apoptotic responses seen during sepsis and infection.

(4) How protein kinase pathways work together with lipid signaling molecules, to control the extent to which phagocytic cells either kill pathogens and/or damage host tissues through ROS production by the NADPH oxidase.  Our most recent data suggests a molecular basis through which distinct lipid signaling pathways and molecules converge to control oxidase activity, and implicates pathologic dysregulation of the blood clotting cascade as a significant contributor to inappropriate ROS-mediated inflammation during injury, infection, and sepsis.

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This page last modified on May 19th, 2011