Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Schumacher, Michael A.; Hsieh, Jonathan J.; Liu, Cambrian Y.; Appel, Keren; Waddell, Amanda; Almohazey, Dana; Katada, Kay; Bernard, Jessica K.; Bucar, Edie B; Gadeock, Safina; Maselli, Kathryn M.; Washington, Mary Kay; Grikscheit, Tracy C.; Warburton, David; Rosen, Michael J.; Frey, Mark R.

doi:10.1038/s41467-021-21113-7

Cited by 37 publications

(42 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…With respect to colorectal cancer (CRC), we demonstrated, for the first time, upregulation of SPRY2 in CRC [13] and inflammatory bowel disease (IBD) [14] along with an oncogenic role of SPRY2 in CRC [15]. More recently, increased expression of SPRY2 in IBD was also confirmed by other investigators [16].…”

Section: Introductionsupporting

confidence: 61%

“…In addition, SPRY2 might serve as a potential biomarker with respect to anti-EGFR treatment response in colon cancers [54]. Furthermore, another recent study found that SPRY2 was increased in colon epithelial cells in patients with ulcerative colitis and Crohn's disease [16]. More importantly, they revealed the underlying mechanism using a SPRY2 KO mice model and found that in response to acute colitis, deletion/suppression of SPRY2 played a protective role in maintaining the integrity of the colon epithelium against inflammation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic DNA Modifications Upregulate SPRY2 in Human Colorectal Cancers

Stuckel

Zeng

Lyu

et al. 2021

Cells

View full text Add to dashboard Cite

Conventional wisdom is that Sprouty2 (SPRY2), a suppressor of Receptor Tyrosine Kinase (RTK) signaling, functions as a tumor suppressor and is downregulated in many solid tumors. We reported, for the first time, that increased expression of SPRY2 augments cancer phenotype and Epithelial-Mesenchymal-Transition (EMT) in colorectal cancer (CRC). In this report, we assessed epigenetic DNA modifications that regulate SPRY2 expression in CRC. A total of 4 loci within SPRY2 were evaluated for 5mC using Combined Bisulfite Restriction Analysis (COBRA). Previously sequenced 5hmC nano-hmC seal data within SPRY2 promoter and gene body were evaluated in CRC. Combined bioinformatics analyses of SPRY2 CRC transcripts by RNA-seq/microarray and 450K methyl-array data archived in The Cancer Genome Atlas (TCGA) and GEO database were performed. SPRY2 protein in CRC tumors and cells was measured by Western blotting. Increased SPRY2 mRNA was observed across several CRC datasets and increased protein expression was observed among CRC patient samples. For the first time, SPRY2 hypomethylation was identified in adenocarcinomas in the promoter and gene body. We also revealed, for the first time, increases of 5hmC deposition in the promoter region of SPRY2 in CRC. SPRY2 promoter hypomethylation and increased 5hmC may play an influential role in upregulating SPRY2 in CRC.

show abstract

Section: Introductionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Epigenetic DNA Modifications Upregulate SPRY2 in Human Colorectal Cancers

Stuckel

Zeng

Lyu

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…ILC2 attracts and activates T H 2 cells by producing the type 2 cytokines IL-4, IL-5, and IL-13 [7,34]. As a result, effector cytokines such as IL-13 promote tissue remodeling by modulating crypt stemness and stimulating goblet cell (GC) and tuft cell hyperplasia in order to facilitate pathogen clearance [34][35][36].…”

Section: Type 2 Innate Lymphoid Cells (Ilc2) In Ibdmentioning

confidence: 99%

“…The failure to regulate the IL-33-tuft cell axis may be associated with SPRY2 (Sprouty2, an intracellular signaling regulator). SPRY2 expression has been shown to be enhanced in both CD and UC patients, resulting in tuft cells and GC inhibition [ 35 ]. Collectively, different studies showing both pathogenic and protective roles of IL-33 suggest that IL-33 may be a double-edged sword.…”

Section: Epithelium-derived Type 2 Immunity Associated Cytokinesmentioning

confidence: 99%

Type 2 immunity in intestinal homeostasis and inflammatory bowel disease

Luo

Villablanca

2021

Biochemical Society Transactions

View full text Add to dashboard Cite

Type 2 immune responses commonly emerge during allergic reactions or infections with helminth parasites. Most of the cytokines associated with type 2 immune responses are IL-4, IL-5, and IL13, which are mainly produced by T helper 2 cells (TH2), eosinophils, basophils, mast cells, and group 2 innate lymphoid cells (ILC2s). Over the course of evolution, humans have developed type 2 immune responses to fight infections and to protect tissues from the potential collateral damage caused by inflammation. For example, worm parasites induce potent type 2 immune responses, which are needed to simultaneously clear the pathogen and to promote tissue repair following injury. Due to the strong type 2 immune responses induced by helminths, which can promote tissue repair in the damaged epithelium, their use has been suggested as a possible treatment for inflammatory bowel disease (IBD); however, the role of type 2 immune responses in the initiation and progression of IBD is not fully understood. In this review, we discuss the molecular and cellular mechanisms that regulate type 2 immune responses during intestinal homeostasis, and we briefly discuss the scarce evidence linking type 2 immune responses with the aetiology of IBD.

show abstract

“…In response to enteric parasites that colonize the small intestine, increased IL-13 production by immune cells induced stem cells to differentiate to the tuft and goblet cell types via IL-4Rα signaling in the small intestine [6,9,33], but not in the colon [6]. Interestingly, differentiation of colonic tuft cells was found to be ATOH-1 dependent [13,30,34] and colonic tuft cell hyperplasia is recorded in response to changes in the microbiome and during acute inflammation [25,35]. Such variation in the regulation of differentiation hints at the probability that small intestinal and colonic ETCs may perform different functions [30].…”

Section: Tuft Cell Lineage Subtypes and Basic Biologymentioning

confidence: 99%

Enteric Tuft Cells in Host-Parasite Interactions

Rajeev

Sosnowski

et al. 2021

Pathogens

View full text Add to dashboard Cite

Enteric tuft cells are chemosensory epithelial cells gaining attention in the field of host-parasite interactions. Expressing a repertoire of chemosensing receptors and mediators, these cells have the potential to detect lumen-dwelling helminth and protozoan parasites and coordinate epithelial, immune, and neuronal cell defenses against them. This review highlights the versatility of enteric tuft cells and sub-types thereof, showcasing nuances of tuft cell responses to different parasites, with a focus on helminths reflecting the current state of the field. The role of enteric tuft cells in irritable bowel syndrome, inflammatory bowel disease and intestinal viral infection is assessed in the context of concomitant infection with parasites. Finally, the review presents pertinent questions germane to understanding the enteric tuft cell and its role in enteric parasitic infections. There is much to be done to fully elucidate the response of this intriguing cell type to parasitic-infection and there is negligible data on the biology of the human enteric tuft cell—a glaring gap in knowledge that must be filled.

show abstract

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

Cited by 37 publications

References 79 publications

Epigenetic DNA Modifications Upregulate SPRY2 in Human Colorectal Cancers

Epigenetic DNA Modifications Upregulate SPRY2 in Human Colorectal Cancers

Type 2 immunity in intestinal homeostasis and inflammatory bowel disease

Enteric Tuft Cells in Host-Parasite Interactions

Contact Info

Product

Resources

About