A threshold model for receptor tyrosine kinase signaling specificity and cell fate determination

Abstract

Upon ligand engagement, the single-pass transmembrane receptor tyrosine kinases (RTKs) dimerize to transmit qualitatively and quantitatively different intracellular signals that alter the transcriptional landscape and thereby determine the cellular response. The molecular mechanisms underlying these fundamental events are not well understood. Considering recent insights into the structural biology of fibroblast growth factor signaling, we propose a threshold model for RTK signaling specificity in which quantitative differences in the strength/longevity of ligand-induced receptor dimers on the cell surface lead to quantitative differences in the phosphorylation of activation loop (A-loop) tyrosines as well as qualitative differences in the phosphorylation of tyrosines mediating substrate recruitment. In this model, quantitative differences on A-loop tyrosine phosphorylation result in gradations in kinase activation, leading to the generation of intracellular signals of varying amplitude/duration. In contrast, qualitative differences in the pattern of tyrosine phosphorylation on the receptor result in the recruitment/activation of distinct substrates/intracellular pathways. Commensurate with both the dynamics of the intracellular signal and the types of intracellular pathways activated, unique transcriptional signatures are established. Our model provides a framework for engineering clinically useful ligands that can tune receptor dimerization stability so as to bias the cellular transcriptome to achieve a desired cellular output.

Kinetics of cytokine receptor trafficking determine signaling and functional selectivity

“…These data suggest that non-detectable short-lived IL-6/gp130 complexes can partially engage signaling, but fail to trigger a full response, evoking a kinetic-proof reading model. A kinetic-proof reading model has been previously proposed for other ligand-receptor systems, including the T cell receptor system (TCR) (McKeithan, 1995) and more recently Receptor Tyrosine Kinases (RTKs) (Zinkle and Mohammadi, 2018). In these two systems, changes on ligand-receptor complex half-life induce phosphorylation of different Tyr pools in the receptors ICDs, ultimately recruiting and activating different signaling effectors (Acuto et al, 2008;Lemmon and Schlessinger, 2010).…”

Engineering Cell‐Surface Receptors with DNA Nanotechnology for Cell Manipulation

“…However, the biophysical consequences for the downstream pathways and cell behavior modes remain unclear. Previous work has revealed that the dose and the geometry of the ligands, the distinct receptor expression profiles on cell surfaces, the time‐dependent effects and frequency of ligand–receptor interaction, and receptor oligomerization status act in concert to perform complex signal processing for different cell fates . In the bone morphogenetic protein (BMP) signaling pathway, for example, more than 30 different ligands interact with only seven different receptors.…”

“…However,t he biophysicalc onsequencesf or the downstream pathways and cell behavior modesr emain unclear.P revious work has revealed that the dose and the geometry of the ligands, the distinct receptor expression profileso nc ell surfaces, the time-dependent effects and frequency of ligand-receptor interaction, and receptor oligomerization statusa ct in concert to perform complex signal processing for different cell fates. [2,7] In the bone morphogenetic protein (BMP) signaling pathway,f or example, more than 30 different ligands interact with only seven different receptors. When exposed to combinations of different BMP ligands, cells use their repertoire of BMP receptorst op erceive mixed ligand milieus and to orchestrate both homodimerization and heterodimerization of different receptors, with conversion into specific signaling output patterns, leadingt od istinct cell fate decisions.…”

“…Modern cell biology research has revealed deep insights into the mechanisms of receptor activation and their downstream cell signaling propagation . Mounting evidence supports the conjecture that the cell‐surface receptor assembly and its stability, duration, and spatial organization play pivotal roles in cell signaling regulation and cellular decision making …”

“…[6] Mounting evidences upportst he conjecture that the cell-surface receptor assembly and its stability,d uration, and spatial organizationp lay pivotalr oles in cell signaling regulation and cellular decision making. [7] Twod istinct approaches to achievingp recise control over receptors have been developed. The synthetic biology approach involves the manipulation of receptor functions through the introduction of artificially modified receptors into cells with the aid of genetic engineering.…”