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

Typically, binding on monomeric ligand to monomeric receptors leads to Michaelis-Menten type activation of intracellular signaling cascades. Specifically, as the concentration of extracellular ligand increases from low to high, larger fraction of receptor gets activated until the ligandconcentration becomes high enough such that receptor activation is saturated. Receptor activation initiates a cascade of enzymatic reactions that lead to phosphorylation of effector molecules like ERK and AKT amongst others. Thus, saturable activation of receptor by ligand leads to saturable activation of effector molecules. Accordingly, one would expect that cellular responses to signaling pathway activation also follow Michaelis-Menten type kinetics. This is indeed the case for signaling pathways like ErbB and IGFR at physiological ligand concentrations.

Interestingly, some cells respond to FGF signaling in an atypical fashion. Instead of following Michaelis-Menten type reaction kinetics and responding in a saturable fashion, cells respond in a biphasic manner. Specifically, from low to intermediate concentrations of FGF-ligands, cellular response increases but then decreases from intermediate to high concentrations of FGF-ligand.