Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface
Open accessAbstract
Members of the epidermal growth factor receptor family (EGFR/ERBB1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are key targets for inhibition in cancer therapy. Critical for activation is the formation of an asymmetric dimer by the intracellular kinase domains, in which the carboxy-terminal lobe (C lobe) of one kinase domain induces an active conformation in the other. The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 (refs 3–5). Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a ∼25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface. A longer MIG6 peptide that is extended C terminal to segment 1 has increased potency as an inhibitor of the activated EGFR kinase domain, while retaining a critical dependence on segment 1. We show that signalling by EGFR molecules that contain constitutively active kinase domains still requires formation of the asymmetric dimer, underscoring the importance of dimer interface blockage in MIG6-mediated inhibition.
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ERRFI1 blocks EGFR's activity by clamping onto its kinase domain to rapidly decrease EGFR signaling.
“It has been reported that ERRFI1 not only blocks EGFR’s activity by clamping onto its kinase domain to rapidly decrease EGFR signaling [47]”
From Feedback activation of EGFR/wild-type RAS signaling axis limits KRASG12D inhibitor efficacy in KRASG12D-mutated colorectal cancer (2023) · cites this paper as [47]
The passage indexed under Abstract (page not supplied) reports that Mig6 binds the EGFR kinase domain and inhibits EGFR by blocking its activating dimer interface. A cell-based result in the same section reports reduced EGF-induced EGFR autophosphorylation with Mig6. The paper does not establish that Mig6 rapidly decreases signaling; the five-minute EGF treatment in Methods is not a measurement of how quickly inhibition occurs. (LLM, conf=0.84)
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“It has been reported that ERRFI1 not only blocks EGFR’s activity by clamping onto its kinase domain to rapidly decrease EGFR signaling [47], but also directs EGFR to the lysosomes for digestion for a longer-lasting inhibitory effect [48].”
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- Authors
- Zhang, X., Pickin, K. A., Bose, R., Jura, N., Cole, P. A., & Kuriyan, J.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Corresponding author
- Kuriyan, John
- Venue
- Nature
- Published
- 2007-11-29
- Volume
- 450
- Issue
- 7170
- Pages
- 741-744
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3561764
- OpenAlex
- W2046151919
- Semantic Scholar
- 84bdab56e088c2422419e9cd91b3387be8d1ee60
- Cited by
- 357
- References
- 22
- Citations by year
- 2026: 17 · 2025: 8 · 2024: 6 · 2023: 13 · 2022: 13 · 2021: 13 · 2020: 16 · 2019: 10 · 2018: 15 · 2017: 20 · 2016: 33 · 2015: 31 · 2014: 37 · 2013: 18 · 2012: 20
- FWCI
- 10.09
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Susan G. Komen for the Cure
- Susan G. Komen
- National Institutes of Health
- National Cancer Institute (R01CA096504)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- epidermal growth factor receptor, MIG6, ERBB2, HER2, allosteric inhibition, EGFR signaling, constitutively active kinase, product inhibition
- MeSH terms
- Animals, Binding Sites, Chlorocebus aethiops, Humans, Models, Biological, Models, Molecular, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Crystallography, X-Ray, Dimerization, COS Cells, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, ErbB Receptors
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