 |
Center for Nonlinear Studies |
Transforming growth factor-β (TGF-β) is a prominent signaling pathway crucial for regulating diverse aspects of cellular homeostasis. The physiological responses to TGF-β stimulation are diverse and vary amongst different cell types and environmental conditions. The principal molecular components of TGF-ß signaling have been identified yet this knowledge is insufficient to fully account for the known biology. Understanding TGF-β signaling complexity will require adopting a system view of cell function in which the discovery of new molecules and connections is combined with studies of system dynamics. Our research has been focused on understanding the quantitative basis for how TGF-β signals are transduced into both canonical Smad and non-canonical Smad-independent pathway kinetics. Using a combined experimental and modeling approach, we analyzed how cells read TGF-β concentration with high precision to produce different biological responses and demonstrated that the duration and amplitude of cellular response depend on ligand dose. TGF-β ligand depletion can be the principal determinant of the Smad signal duration and account for long term ultrasensitive response to TGF-β signaling. At the cellular level, TGF-ß stimulates collective migration of epithelial sheets of keratinocyte through spatially constrained activation of MAPK. How TGF-ß modulates MAPK signaling networks to regulate coordinated and individual cell migration in epithelial sheets will be discussed.
Host: Bill Hlavacek wish@lanl.gov