Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7

Matteo Boretto; Maarten H Geurts; Shashank Gandhi; Ziliang Ma; Nadzeya Staliarova; Martina Celotti; Sangho Lim; Gui-Wei He; Rosemary Millen; Else Driehuis; Harry Begthel; Lidwien Smabers; Jeanine Roodhart; Johan van Es; Wei Wu; Hans Clevers

doi:10.1073/pnas.2309902121

Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7

Matteo Boretto, Maarten H Geurts, Shashank Gandhi, Ziliang Ma, Nadzeya Staliarova, Martina Celotti, Sangho Lim, Gui-Wei He, Rosemary Millen, Else Driehuis, Harry Begthel, Lidwien Smabers, Jeanine Roodhart, Johan van Es, Wei Wu, Hans Clevers

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

7 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	e2309902121
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	121
Issue number	12
DOIs	https://doi.org/10.1073/pnas.2309902121
Publication status	Published - 19 Mar 2024

Keywords

Humans
F-Box-WD Repeat-Containing Protein 7/genetics
Ubiquitin-Protein Ligases/genetics
Epidermal Growth Factor/genetics
Proteomics
ErbB Receptors/genetics
Neoplasms/drug therapy
F-Box Proteins/genetics

Access to Document

10.1073/pnas.2309902121

Cite this

Boretto, M., Geurts, M. H., Gandhi, S., Ma, Z., Staliarova, N., Celotti, M., Lim, S., He, G.-W., Millen, R., Driehuis, E., Begthel, H., Smabers, L., Roodhart, J., van Es, J., Wu, W., & Clevers, H. (2024). Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7. Proceedings of the National Academy of Sciences of the United States of America, 121(12), e2309902121. https://doi.org/10.1073/pnas.2309902121

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title = "Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7",

abstract = "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.",

keywords = "Humans, F-Box-WD Repeat-Containing Protein 7/genetics, Ubiquitin-Protein Ligases/genetics, Epidermal Growth Factor/genetics, Proteomics, ErbB Receptors/genetics, Neoplasms/drug therapy, F-Box Proteins/genetics",

author = "Matteo Boretto and Geurts, {Maarten H} and Shashank Gandhi and Ziliang Ma and Nadzeya Staliarova and Martina Celotti and Sangho Lim and Gui-Wei He and Rosemary Millen and Else Driehuis and Harry Begthel and Lidwien Smabers and Jeanine Roodhart and {van Es}, Johan and Wei Wu and Hans Clevers",

year = "2024",

month = mar,

day = "19",

doi = "10.1073/pnas.2309902121",

language = "English",

volume = "121",

pages = "e2309902121",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

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Boretto, M, Geurts, MH, Gandhi, S, Ma, Z, Staliarova, N, Celotti, M, Lim, S, He, G-W, Millen, R, Driehuis, E, Begthel, H, Smabers, L, Roodhart, J, van Es, J, Wu, W & Clevers, H 2024, 'Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7', Proceedings of the National Academy of Sciences of the United States of America, vol. 121, no. 12, pp. e2309902121. https://doi.org/10.1073/pnas.2309902121

Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7. / Boretto, Matteo; Geurts, Maarten H; Gandhi, Shashank et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 121, No. 12, 19.03.2024, p. e2309902121.

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

TY - JOUR

T1 - Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7

AU - Boretto, Matteo

AU - Geurts, Maarten H

AU - Gandhi, Shashank

AU - Ma, Ziliang

AU - Staliarova, Nadzeya

AU - Celotti, Martina

AU - Lim, Sangho

AU - He, Gui-Wei

AU - Millen, Rosemary

AU - Driehuis, Else

AU - Begthel, Harry

AU - Smabers, Lidwien

AU - Roodhart, Jeanine

AU - van Es, Johan

AU - Wu, Wei

AU - Clevers, Hans

PY - 2024/3/19

Y1 - 2024/3/19

N2 - 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.

AB - 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.

KW - Humans

KW - F-Box-WD Repeat-Containing Protein 7/genetics

KW - Ubiquitin-Protein Ligases/genetics

KW - Epidermal Growth Factor/genetics

KW - Proteomics

KW - ErbB Receptors/genetics

KW - Neoplasms/drug therapy

KW - F-Box Proteins/genetics

U2 - 10.1073/pnas.2309902121

DO - 10.1073/pnas.2309902121

M3 - Article

C2 - 38483988

SN - 0027-8424

VL - 121

SP - e2309902121

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 12

ER -