دورية أكاديمية
Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7.
| العنوان: | Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7. |
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| المؤلفون: | Boretto M; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands., Geurts MH; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands., Gandhi S; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands.; Department of Molecular and Cellular Biology, Miller Institute for Basic Research in Science, University of California, Berkeley, CA 94720., Ma Z; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore.; Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore.; Department of Biomolecular Mass Spectrometry and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, the Netherlands., Staliarova N; Department of Biomolecular Mass Spectrometry and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, the Netherlands., Celotti M; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands., Lim S; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands., He GW; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands., Millen R; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands., Driehuis E; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands., Begthel H; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands., Smabers L; Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands., Roodhart J; Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands., van Es J; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands., Wu W; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore.; Department of Pharmacy, National University of Singapore, Singapore 117543, Singapore.; Department of Biomolecular Mass Spectrometry and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, the Netherlands., Clevers H; Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Mar 19; Vol. 121 (12), pp. e2309902121. Date of Electronic Publication: 2024 Mar 14. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Neoplasms*/drug therapy , Neoplasms*/genetics , Neoplasms*/metabolism , F-Box Proteins*/genetics, Humans ; F-Box-WD Repeat-Containing Protein 7/genetics ; F-Box-WD Repeat-Containing Protein 7/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Epidermal Growth Factor/genetics ; Epidermal Growth Factor/pharmacology ; Epidermal Growth Factor/metabolism ; Proteomics ; ErbB Receptors/genetics ; ErbB Receptors/metabolism |
| مستخلص: | FBXW7 is an E3 ubiquitin ligase that targets proteins for proteasome-mediated degradation and is mutated in various cancer types. Here, we use CRISPR base editors to introduce different FBXW7 hotspot mutations in human colon organoids. Functionally, FBXW7 mutation reduces EGF dependency of organoid growth by ~10,000-fold. Combined transcriptomic and proteomic analyses revealed increased EGFR protein stability in FBXW7 mutants. Two distinct phosphodegron motifs reside in the cytoplasmic tail of EGFR. Mutations in these phosphodegron motifs occur in human cancer. CRISPR-mediated disruption of the phosphodegron motif at T693 reduced EGFR degradation and EGF growth factor dependency. FBXW7 mutant organoids showed reduced sensitivity to EGFR-MAPK inhibitors. These observations were further strengthened in CRC-derived organoid lines and validated in a cohort of patients treated with panitumumab. Our data imply that FBXW7 mutations reduce EGF dependency by disabling EGFR turnover. Competing Interests: Competing interests statement:H.C. is inventor of several patents related to organoid technology, is cofounder of Xilis Inc. and is currently employee of Roche, Basel (CH) Switzerland. His full disclosure is given at https://www.uu.nl/staff/JCClevers/. |
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| معلومات مُعتمدة: | ALTF 769-2019 European Molecular Biology Organization (EMBO) |
| فهرسة مساهمة: | Keywords: EGFR; FBXW7; colorectal cancer; organoids |
| المشرفين على المادة: | 0 (F-Box-WD Repeat-Containing Protein 7) EC 2.3.2.27 (Ubiquitin-Protein Ligases) 62229-50-9 (Epidermal Growth Factor) EC 2.7.10.1 (ErbB Receptors) 0 (F-Box Proteins) 0 (FBXW7 protein, human) EC 2.7.10.1 (EGFR protein, human) |
| تواريخ الأحداث: | Date Created: 20240314 Date Completed: 20240318 Latest Revision: 20240327 |
| رمز التحديث: | 20240327 |
| مُعرف محوري في PubMed: | PMC10962967 |
| DOI: | 10.1073/pnas.2309902121 |
| PMID: | 38483988 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.2309902121 |