Kinetic and Spatial
Analysis of Intracellular Signal Transduction Networks
Jason Haugh
Department of Chemical and Biomolecular
Engineering
An ongoing challenge in
mammalian cell biology is to bridge the gaps in our understanding of processes
at the molecular, cellular, and tissue levels.
Central to the hierarchy of biological complexity is the field of signal transduction, which deals with
the biochemical mechanisms and pathways by which cells respond to external
stimuli, such as soluble growth factors/cytokines, immobilized ligands such as those found in extracellular
matrix or the surfaces of other cells, and mechanical forces. Intracellular signaling processes control the
growth, survival, and migration of cells in normal physiological contexts, and
defects in signaling form the molecular basis for cancer, immune system
disorders, and other diseases. Using a
quantitative approach that combines biochemical measurements, live-cell fluorescence
microscopy, and mathematical modeling, we seek to characterize signal
transduction networks through analysis of their kinetics and spatial patterns
in cells. Based on analysis of
experimental data and informed where appropriate by knowledge of protein domain
structure, mechanistic models are developed that may be embedded (in
coarse-grained form) in mathematical representations of cell population
dynamics, with the goal of evaluating hypotheses regarding the concerted
responses of cells in tissues.
As an example of this
approach, our efforts to characterize signal transduction mediated by cell
surface receptors for platelet-derived growth factor (PDGF), a soluble factor
that accelerates dermal wound healing by directing the migration and
proliferation of dermal fibroblasts, will be described in two parts. In the first part of the talk, I will
describe spatial modeling and subcellular
characterization of the signaling mechanism by which fibroblasts sense PDGF
gradients, which in turn has led us to analyze tissue-scale models of wound invasion
driven by such gradients. The second
part of the talk will cover the elucidation and kinetic characterization of the
so-called crosstalk interactions
between two canonical signaling pathways strongly activated by PDGF receptors (Ras/Erk and PI 3-kinase), which has moved us towards
predictive modeling at the level of signal transduction networks.