However, the molecular mechanisms responsible for biased signaling are unresolved due to a lack of insight into the phosphorylation patterns of full-length EGFR.

These results reveal how ligand-regulated receptor dimerization dynamics and adaptor protein concentrations play critical roles in EGFR signaling.Дifferential epidermal growth factor receptor (EGFR) phosphorylation is thought to couple receptor activation to distinct signaling pathways. The predictions were confirmed in studies of cell lines with different expression levels of signaling partners, and in experiments comparing low- and high-affinity ligands and oncogenic EGFR mutants. The model predicted that variations in phosphorylation are dependent on the abundances of signaling partners, while phosphorylation levels are dependent on dimer lifetimes. To understand this heterogeneity, we developed a mathematical model. We found distinct populations of receptors as soon as 1 min after ligand stimulation, indicating early diversification of function. We found that EGFR is predominantly phosphorylated at multiple sites, yet phosphorylation at specific tyrosines is variable and only a subset of receptors share phosphorylation at the same site, even with saturating ligand concentrations. We extended a single-molecule pull-down technique previously used to study protein-protein interactions to allow for robust measurement of receptor phosphorylation. Differential epidermal growth factor receptor (EGFR) phosphorylation is thought to couple receptor activation to distinct signaling pathways.

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