Jason Haugh, Massachusetts Institute of Technology
Most of the proximal intracellular targets of signaling proteins activated by transmembrane receptors are membrane lipids or membrane-tethered proteins, suggesting that the regulation of cellular location is probably as important as the modification of protein structure induced by tyrosine phosphorylation. We feel that spatiotemporal considerations in signal transduction present fertile ground for mathematical modeling efforts, and we have focused on compartmentalization of signaling initiated by receptor tyrosine kinases (RTKs) as a well understood system. The underlying principles, however, are easily extended to receptors involved in the activation and proliferation of lymphocytes. Two theoretical aspects of receptor compartmentation are presented, dealing with signaling in two versus three dimensions and the potential separation of signaling activities incurred by receptor internalization. We have also designed experimental protocols based on model predictions that indicate that signaling mediated by the prototypical RTK epidermal growth factor receptor is spatially regulated. The data also suggests complexities not predicted by our first generation model, providing an impetus for future work in signaling theory.
This work was done jointly with Douglas Lauffenburger.