(557d) Direct and Indirect Regulation of Growth Factor Binding and Signaling by Proteoglycan Binding Competitors

Mammalian cells are constantly receiving signals that they must respond to properly to contribute to the function of their resident tissue and organism. This information transfer is mediated by a large number of extracellular growth factors, cytokines and hormones through interactions with specific cell surface receptors. In addition to binding to receptors on the surface of cells, many of these signaling molecules bind to other macromolecules on cells and within the extracellular matrix. In particular, many factors bind to heparan sulfate proteoglycans (HSPGs) through interactions with the complex heparan sulfate chains. Heparan sulfates are linear polysaccharides made up of variably modified disaccharide units that can present a wide range of protein binding sites. In this way, HSPGs might function as higher order selectivity elements that allow cells to interpret how to respond to the simultaneous presence of a large number of signaling proteins.

In this study we have established a base model to begin to consider the relative influence of heparin-binding growth factors on the activity of one another based on their ability to compete for HSPG binding. We investigated interactions of two prototypical heparin-binding growth factors, fibroblast growth factor-2 (FGF-2) and heparin binding epidermal growth factor-like growth factor (HB-EGF), which signal through distinct receptors. We coupled computational model results with experimental data to reveal a range of potential influences that these growth factors can have on the receptor binding and signaling of each other. Our findings indicate that the presence of heparin-binding proteins can impact binding and signaling of both other heparin-binding and non-binding proteins via changes in the network of interactions. In this presentation, key parameters for the system are discussed as well as how changes in the network structure can have significant ramifications for how ?disturbances? in the system impact binding and, ultimately, cell signaling. It will be critical to continue to expand our analysis to include the influence of other interacting factors in order to begin to establish a unifying framework for understanding and predicting how cells translate complex signals into effective biological responses. These studies may ultimately provide insight toward the development of new approaches to regulate cell function through the administration of bio-active proteins such as growth factors.