ArticleProceedings of the National Academy of Sciences of the United States of America2018
Deep mutational analysis reveals functional trade-offs in the sequences of EGFR autophosphorylation sites.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 49 citations in OpenAlex.
- Substrate-Derived Peptides for Selective Covalent Inhibition of Protein Tyrosine Kinases.ACS chemical biology · 2026Article
- NEK7-induced phosphorylation of EGFR on serine 1070 drives the acquired lenvatinib resistance in hepatocellular carcinoma.Hepatology (Baltimore, Md.) · 2026Article
- Synthetic Substrate Discovery for Hck Kinase via Phage Display.Biochemistry · 2026Article
- Context-dependent peptide recognition shapes tyrosine kinase substrate specificity beyond consensus motifs.bioRxiv : the preprint server for biology · 2026Article
- Substrate-derived peptides for selective covalent inhibition of protein tyrosine kinases.bioRxiv : the preprint server for biology · 2026Article
- Evolution of the MUC1 gene in eutherian mammals as an adaptation responsible for the increasing incidence of cancer in humans.Biochimica et biophysica acta. Reviews on cancer · 2026Review
- Association Between Organophosphate Flame Retardant Exposure and Trouble Sleeping: Integrating Epidemiological Evidence with Mechanistic Insights.International journal of molecular sciences · 2026Article
- Multiplexed assays of variant effect for clinical variant interpretation.Nature reviews. Genetics · 2026Review
- Profiling tyrosine kinase substrate recognition using bacterial peptide display and deep sequencing.bioRxiv : the preprint server for biology · 2025Article
- Accurate affinity models for SH2 domains from peptide binding assays and free-energy regression.Protein science : a publication of the Protein Society · 2025Article
- Synthetic signaling platform uncovers and rewires cellular responses to PD-1 perturbation.bioRxiv : the preprint server for biology · 2025Article
- Construction and validation of an EGFR-related risk signature identifiedTranslational cancer research · 2025Article
- Multiplexed profiling of intracellular protein abundance, activity, interactions and druggability with LABEL-seq.Nature methods · 2024Article
- Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2024Article
- CX3CL1 (Fractalkine)-CX3CR1 Axis in Inflammation-Induced Angiogenesis and Tumorigenesis.International journal of molecular sciences · 2024Review
- Distinct functional constraints driving conservation of the cofilin N-terminal regulatory tail.Nature communications · 2024Article
- Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2.eLife · 2023Article
- Article
- Deep mutational scanning: A versatile tool in systematically mapping genotypes to phenotypes.Frontiers in genetics · 2023Review
- Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Upon activation, the epidermal growth factor receptor (EGFR) phosphorylates tyrosine residues in its cytoplasmic tail, which triggers the binding of Src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains and initiates downstream signaling. The sequences flanking the tyrosine residues (referred to as "phosphosites") must be compatible with phosphorylation by the EGFR kinase domain and the recruitment of adapter proteins, while minimizing phosphorylation that would reduce the fidelity of signal transmission. To understand how phosphosite sequences encode these functions within a small set of residues, we carried out high-throughput mutational analysis of three phosphosite sequences in the EGFR tail. We used bacterial surface display of peptides coupled with deep sequencing to monitor phosphorylation efficiency and the binding of the SH2 and PTB domains of the adapter proteins Grb2 and Shc1, respectively. We found that the sequences of phosphosites in the EGFR tail are restricted to a subset of the range of sequences that can be phosphorylated efficiently by EGFR. Although efficient phosphorylation by EGFR can occur with either acidic or large hydrophobic residues at the -1 position with respect to the tyrosine, hydrophobic residues are generally excluded from this position in tail sequences. The mutational data suggest that this restriction results in weaker binding to adapter proteins but also disfavors phosphorylation by the cytoplasmic tyrosine kinases c-Src and c-Abl. Our results show how EGFR-family phosphosites achieve a trade-off between minimizing off-pathway phosphorylation and maintaining the ability to recruit the diverse complement of effectors required for downstream pathway activation.
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