EGFR Signaling Activates Intestinal Stem Cells by Promoting Mitochondrial Biogenesis and β-oxidation

Overview

Journal Curr Biol

Publisher Cell Press

Specialty Biology

Date 2022 Jul 27

PMID 35896119

Authors

Chenge Zhang

Yinhua Jin

Marco Marchetti

Mitchell R Lewis

Omar T Hammouda

Bruce A Edgar

Affiliations

Soon will be listed here.

Abstract

EGFR-RAS-ERK signaling promotes growth and proliferation in many cell types, and genetic hyperactivation of RAS-ERK signaling drives many cancers. Yet, despite intensive study of upstream components in EGFR signal transduction, the identities and functions of downstream effectors in the pathway are poorly understood. In Drosophila intestinal stem cells (ISCs), the transcriptional repressor Capicua (Cic) and its targets, the ETS-type transcriptional activators Pointed (pnt) and Ets21C, are essential downstream effectors of mitogenic EGFR signaling. Here, we show that these factors promote EGFR-dependent metabolic changes that increase ISC mass, mitochondrial growth, and mitochondrial activity. Gene target analysis using RNA and DamID sequencing revealed that Pnt and Ets21C directly upregulate not only DNA replication and cell cycle genes but also genes for oxidative phosphorylation, the TCA cycle, and fatty acid beta-oxidation. Metabolite analysis substantiated these metabolic functions. The mitochondrial transcription factor B2 (mtTFB2), a direct target of Pnt, was required and partially sufficient for EGFR-driven ISC growth, mitochondrial biogenesis, and proliferation. MEK-dependent EGF signaling stimulated mitochondrial biogenesis in human RPE-1 cells, indicating the conservation of these metabolic effects. This work illustrates how EGFR signaling alters metabolism to coordinately activate cell growth and cell division.

Citing Articles

Genomic alterations in the WNT/β-catenin pathway and resistance of colorectal cancer cells to pathway-targeting therapies.

Voutsadakis I Explor Target Antitumor Ther. 2025; 6:1002295.

PMID: 40061138 PMC: 11886378. DOI: 10.37349/etat.2025.1002295.

Alterations in ether phospholipids metabolism activate the conserved UPR-Xbp1- PDIA3/ERp60 signaling to maintain intestinal homeostasis.

Makdissi S, Loudhaief R, George S, Weller T, Salim M, Malick A iScience. 2025; 28(3):111946.

PMID: 40034858 PMC: 11872617. DOI: 10.1016/j.isci.2025.111946.

EGF receptor in organ development, tissue homeostasis and regeneration.

Tito C, Masciarelli S, Colotti G, Fazi F J Biomed Sci. 2025; 32(1):24.

PMID: 39966897 PMC: 11837477. DOI: 10.1186/s12929-025-01119-9.

Theophylline derivatives promote primordial follicle activation via cAMP-PI3K/Akt pathway and ameliorate fertility deficits in naturally aged mice.

Zhang W, Gao L, Zhang X, Weng Y, Du Y, Sun Y Int J Biol Sci. 2024; 20(13):5312-5329.

PMID: 39430241 PMC: 11489179. DOI: 10.7150/ijbs.99936.

Pathways regulating intestinal stem cells and potential therapeutic targets for radiation enteropathy.

Chen S, Guo B, Feng A, Wang X, Zhang S, Miao C Mol Biomed. 2024; 5(1):46.

PMID: 39388072 PMC: 11467144. DOI: 10.1186/s43556-024-00211-0.

References

Mundorf J, Donohoe C, McClure C, Southall T, Uhlirova M . Ets21c Governs Tissue Renewal, Stress Tolerance, and Aging in the Drosophila Intestine. Cell Rep. 2019; 27(10):3019-3033.e5. PMC: 6581828. DOI: 10.1016/j.celrep.2019.05.025. View

Schell J, Wisidagama D, Bensard C, Zhao H, Wei P, Tanner J . Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. Nat Cell Biol. 2017; 19(9):1027-1036. PMC: 6137334. DOI: 10.1038/ncb3593. View

Harden N . New Insights from Drosophila into the Regulation of EGFR Signaling. Methods Mol Biol. 2017; 1652:37-42. DOI: 10.1007/978-1-4939-7219-7_2. View

Dutta D, Xiang J, Edgar B . RNA expression profiling from FACS-isolated cells of the Drosophila intestine. Curr Protoc Stem Cell Biol. 2014; 27:2F.2.1-2F.2.12. DOI: 10.1002/9780470151808.sc02f02s27. View

Jiang H, Grenley M, Bravo M, Blumhagen R, Edgar B . EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila. Cell Stem Cell. 2010; 8(1):84-95. PMC: 3021119. DOI: 10.1016/j.stem.2010.11.026. View

Schweitzer R, Shaharabany M, Seger R, Shilo B . Secreted Spitz triggers the DER signaling pathway and is a limiting component in embryonic ventral ectoderm determination. Genes Dev. 1995; 9(12):1518-29. DOI: 10.1101/gad.9.12.1518. View

Suzuki A, Sekiya S, Gunshima E, Fujii S, Taniguchi H . EGF signaling activates proliferation and blocks apoptosis of mouse and human intestinal stem/progenitor cells in long-term monolayer cell culture. Lab Invest. 2010; 90(10):1425-36. DOI: 10.1038/labinvest.2010.150. View

Morris O, Deng H, Tam C, Jasper H . Warburg-like Metabolic Reprogramming in Aging Intestinal Stem Cells Contributes to Tissue Hyperplasia. Cell Rep. 2020; 33(8):108423. PMC: 8011352. DOI: 10.1016/j.celrep.2020.108423. View

Tamamouna V, Rahman M, Petersson M, Charalambous I, Kux K, Mainor H . Remodelling of oxygen-transporting tracheoles drives intestinal regeneration and tumorigenesis in Drosophila. Nat Cell Biol. 2021; 23(5):497-510. PMC: 8567841. DOI: 10.1038/s41556-021-00674-1. View

10.

Plotnik J, Budka J, Ferris M, Hollenhorst P . ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells. Nucleic Acids Res. 2014; 42(19):11928-40. PMC: 4231772. DOI: 10.1093/nar/gku929. View

11.

Hendrickson S, Scher C . Platelet-derived growth factor-modulated translatable mRNAs. Mol Cell Biol. 1983; 3(8):1478-87. PMC: 369994. DOI: 10.1128/mcb.3.8.1478-1487.1983. View

12.

Ahmad S, Rogers A, Chen M, Dixit R, Adnani L, Frankiw L . Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors. Nat Commun. 2019; 10(1):2000. PMC: 6494820. DOI: 10.1038/s41467-019-09949-6. View

13.

Simon-Carrasco L, Jimenez G, Barbacid M, Drosten M . The Capicua tumor suppressor: a gatekeeper of Ras signaling in development and cancer. Cell Cycle. 2018; 17(6):702-711. PMC: 5969551. DOI: 10.1080/15384101.2018.1450029. View

14.

Yang Y, Ma H, Starchenko A, Huh W, Li W, Hickman F . A Chimeric Egfr Protein Reporter Mouse Reveals Egfr Localization and Trafficking In Vivo. Cell Rep. 2017; 19(6):1257-1267. PMC: 5517093. DOI: 10.1016/j.celrep.2017.04.048. View

15.

Southall T, Gold K, Egger B, Davidson C, Caygill E, Marshall O . Cell-type-specific profiling of gene expression and chromatin binding without cell isolation: assaying RNA Pol II occupancy in neural stem cells. Dev Cell. 2013; 26(1):101-12. PMC: 3714590. DOI: 10.1016/j.devcel.2013.05.020. View

16.

Jin Y, Ha N, Fores M, Xiang J, Glasser C, Maldera J . EGFR/Ras Signaling Controls Drosophila Intestinal Stem Cell Proliferation via Capicua-Regulated Genes. PLoS Genet. 2015; 11(12):e1005634. PMC: 4684324. DOI: 10.1371/journal.pgen.1005634. View

17.

Kulshammer E, Mundorf J, Kilinc M, Frommolt P, Wagle P, Uhlirova M . Interplay among Drosophila transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy. Dis Model Mech. 2015; 8(10):1279-93. PMC: 4610234. DOI: 10.1242/dmm.020719. View

18.

ONeill E, Rebay I, Tjian R, Rubin G . The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway. Cell. 1994; 78(1):137-47. DOI: 10.1016/0092-8674(94)90580-0. View

19.

Rodgers J, King K, Brett J, Cromie M, Charville G, Maguire K . mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature. 2014; 510(7505):393-6. PMC: 4065227. DOI: 10.1038/nature13255. View

20.

Xie Y, Li X, Deng X, Hou Y, OHara K, Urso A . The Ets protein Pointed prevents both premature differentiation and dedifferentiation of Drosophila intermediate neural progenitors. Development. 2016; 143(17):3109-18. PMC: 5047674. DOI: 10.1242/dev.137281. View