Abstract
Tyrosine kinase receptor (RTK) ligation and dimerization is a key mechanism for translating external cell stimuli into internal signaling events. This process is critical to several key cell and physiological processes, such as in angiogenesis and embryogenesis, among others. While modulating RTK activation is a promising therapeutic target, RTK signaling axes have been shown to involve complicated interactions between ligands and receptors both within and across different protein families. In angiogenesis, for example, several signaling protein families, including vascular endothelial growth factors and platelet-derived growth factors, exhibit significant cross-family interactions that can influence pathway activation. Computational approaches can provide key insight to detangle these signaling pathways but have been limited by the sparse knowledge of these cross-family interactions. Here, we present a framework for studying known and potential non-canonical interactions. We constructed generalized models of RTK ligation and dimerization for systems of two, three and four receptor types and different degrees of cross-family ligation. Across each model, we developed parameter-space maps that fully determine relative pathway activation for any set of ligand-receptor binding constants, ligand concentrations and receptor concentrations. Therefore, our generalized models serve as a powerful reference tool for predicting not only known ligand: Receptor axes but also how unknown interactions could alter signaling dimerization patterns. Accordingly, it will drive the exploration of cross-family interactions and help guide therapeutic developments across processes like cancer and cardiovascular diseases, which depend on RTK-mediated signaling.
Highlights
Tyrosine kinase receptors (RTKs) and their ligands are key to regulating growth, motility and differentiation processes, including: fibroblast growth factors (FGFs), epidermal growth factors (EGFs), vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGFs) [1,2,3,4,5,6]
We explored the impact the introduction of additional of ligand-binding heterodimerizationheterodimerization-partner receptor types had on dimerization patterns by constructing separate partner receptor types had on dimerization patterns by constructing separate models including two, models including two, three andmonomers
We explored the the dimerization patterns from different binding configurations between two ligands and onedimerization patternsresulting resulting from different binding configurations between ligands and dimerization patterns resulting from different binding configurations between two two ligands and oneand two-receptors: (A) two ligands interacting with awith single receptor; (B) two that oneand two-receptors: (A)unique two unique ligands interacting a single receptor; (B)receptors two receptors and two-receptors: (A) two unique ligands interacting with a single receptor; (B) two receptors that each bind a unique ligand, with no cross-interactions—i.e., Ligand that each bind a unique ligand, with no cross-interactions—i.e., Ligand
Summary
Tyrosine kinase receptors (RTKs) and their ligands are key to regulating growth, motility and differentiation processes, including: fibroblast growth factors (FGFs), epidermal growth factors (EGFs), vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGFs) [1,2,3,4,5,6]. RTKs are transmembrane proteins which transduce external signals to internal transduction pathways when an external ligand molecule binds a receptor to induce dimerization [1,7,8]. Different ligands can induce unique receptor conformational changes that are key to allowing downstream signaling activation [9]. RTKs can form dimers with identical or different receptor monomers, each activating unique downstream pathways [10]. One critical process governed by RTK ligand:receptor dynamics [11] is angiogenesis, the process of new blood vessel formation from existing vasculature.
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