Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs

Abstract

Functional selectivity refers to the activation of differential signalling and cellular outputs downstream of the same membrane-bound receptor when activated by two or more different ligands. Functional selectivity has been described and extensively studied for G-protein Coupled Receptors (GPCRs), leading to specific therapeutic options for dysregulated GPCRs functions. However, studies regarding the functional selectivity of Receptor Tyrosine Kinases (RTKs) remain sparse. Here, we will summarize recent data about RTK functional selectivity focusing on how the nature and the amount of RTK ligands and the crosstalk of RTKs with other membrane proteins regulate the specificity of RTK signalling. In addition, we will discuss how structural changes in RTKs upon ligand binding affects selective signalling pathways. Much remains to be known about the integration of different signals affecting RTK signalling specificity to orchestrate long-term cellular outcomes. Recent advancements in omics, specifically quantitative phosphoproteomics, and in systems biology methods to study, model and integrate different types of large-scale omics data have increased our ability to compare several signals affecting RTK functional selectivity in a global, system-wide fashion. We will discuss how such methods facilitate the exploration of important signalling hubs and enable data-driven predictions aiming at improving the efficacy of therapeutics for diseases like cancer, where redundant RTK signalling pathways often compromise treatment efficacy.

Keywords: EGFR; FGFR; cell signalling; functional selectivity; ligand bias; ligand concentration; modelling; receptor tyrosine kinase (RTK).

FIGURE 1

Regulation of functional selectivity. (A) RTKs reside on the plasma membrane and are exposed to several factors in the extracellular environment that modulate their functions. Ligand identity and concentration as well as the crosstalk of RTKs with other molecules regulate RTKs signalling (exemplified by PI3K/AKT, STAT3, MAPK) in space (early, late, recycling endosomes) and time (min vs. hours). RTK signalling specificity in turn determines the functional outcomes of the cell (proliferation, migration, death). P, phosphorylation event. (B) Structural regulation of functional selectivity based on the FGFR2b bound to its two known ligands FGF7 or FGF10 and to HSPGs. Different ligands induce different structural alterations that determine the PTMs and downstream signalling. Receptors can dimerise independent of ligands.