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Early Phosposite Dynamics in T Cell Receptor Signaling

Event Type
Bioengineering Seminar
2240 DCL
Feb 25, 2013   12:00 pm  
Dr. William S. Hlavacek, Los Alamos National Laboratory
Originating Calendar
MechSE Events
Proteins generally comprise multiple functional components or sites. These sites, which are responsible for protein-protein interactions and their effects, can undergo various state transitions, including phosphorylation and dephosphorylation. Understanding the dynamics of these state transitions is key to understanding cellular information processing and decision-making. Site dynamics can be captured in rule-based models, which correspond to traditional models for chemical kinetics but are specified differently and involve different assumptions. A rule-based modeling approach is advantageous when interactions are modular. In this talk, Dr. Hlavacek will briefly review the principles and advantages of rule-based modeling and then discuss a study in which rule-based modeling was used to obtain insights into T cell receptor (TCR) signaling, specifically to interpret mass spectrometry (MS)-based temporal phosphoproteomic data that characterize some of the earliest events in TCR signaling. The model and data together indicate that T cells use bang-bang control - fast activation followed by fast inhibition- to respond to TCR/CD28 co-stimulation through at least two distinct mechanisms. One mechanism involves positive feedback loops engaged and then counteracted by regulated phosphatase activity; the other, a transient shortcut pathway to WASP activation.
Dr. Hlavacek received a Ph.D. in chemical engineering from the University of Michigan, where he worked with Michael A. Savageau on theoretical studies of the design principles of gene circuits. He did postdoctoral work in Los Alamos with Alan S. Perelson, working with HIV dynamics in lymphoid tissue, and he worked with Byron Goldstein on cell signaling. In 2000, he joined the Theoretical Division in Los Alamos as a Technical Staff Member.
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