Role of HSGAGs in Regulation of FGF Signaling Pathway: Insights from Mathematical Modeling

Abstract

Signaling pathways act as relay systems that drive how biological systems respond to specific environmental cues. These cues act as regulators of how cells undergo biological processes like development and normal tissue homeostasis among others. Errors in environmental cues or the ability of cells to respond to such cues leads to erroneous cellular behavior and potentially disease states like cancer. Accordingly, insghts into cell-signaling and processing can be instrumental in design of effective therapies against malignancies. A central paradigm of signaling pathways is that ligands bind to and activate cell-membrane bound receptors, which in turn leads to activation of intracellular cascades. However, to target receptor mediated signaling effectively, it may not be enough to understand the biology of the target receptor in isolation. Interactions with other receptors of the same receptor tyrosine kinase (RTK) family or other families might be critical for understanding the signaling diversity of a particular pathway from the systems perspective. For instance, the role of kinase-dead ErbB3 receptor in the regulation of EGFR and ErbB2 has been critical for a deeper understanding of the ErbB-pathway Along similar lines, heparan sulfate glycosaminoglycans (HSGAGs) have been shown to serve as co-receptors essential for signaling through cell-surface interactions on multiple receptors such as MET and FGFRs. We have recently investigated signaling responses in the FGFR system and found a thus far unappreciated signaling mechanism. We have leveraged a data-driven mechanistic modeling approach to examine the role of FGF2-dependent FGFR signaling driven by FGF2-HSGAG-FGFR1 trimeric complexes. The insights gained from this work can be useful for targeting the FGFR pathway but also to reveal greater insights into the fundamental principles of signaling pathway regulation by HSGAGs in general.