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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Enterotoxigenic Bacteroides fragilis (ETBF) secretes Bacteroides fragilis toxin (BFT), a metalloprotease that disrupts intestinal epithelial integrity and activates pro-inflammatory signaling. Although E-cadherin cleavage is a well-established response to BFT, the involvement of other membrane receptors in BFT-induced signaling remains poorly defined. In this study, we examined whether HER2 undergoes proteolytic processing following BFT exposure and whether HER2 contributes to BFT-induced ERK activation. In HT29\/c1 and MCF-7 epithelial cells, BFT induced the loss of full-length 185 kDa HER2 and the generation of a membrane-tethered ~95 kDa fragment. This truncated HER2 underwent \u03b3-secretase-dependent intramembrane processing and subsequent proteasomal degradation. Knockdown of MMP-7 or ADAM10 did not prevent HER2 cleavage, indicating that neither protease is required for this process. In addition, BFT-induced ERK phosphorylation was observed in HER2-expressing cells but was abolished in HER2-deficient HT29\/c1 clones, whereas E-cadherin cleavage and IL-8 secretion remained detectable. These findings identify HER2 as a previously unrecognized target of BFT-induced proteolytic remodeling and support a contribution of HER2 to BFT-induced ERK activation.<\/jats:p>","DOI":"10.3390\/ijms27198497","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:36:07Z","timestamp":1790166967000},"page":"8497","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bacteroides fragilis Toxin Induces Extracellular Domain Cleavage of HER2 in Intestinal Epithelial Cells"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5430-8383","authenticated-orcid":false,"given":"Sang-Hyeon","family":"Yoo","sequence":"first","affiliation":[{"name":"Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University, Wonju 26493, Republic of 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USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5357-4476","authenticated-orcid":false,"given":"Ju-Eun","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University, Wonju 26493, Republic of Korea"},{"name":"Medical Device Business Division, ECO DM LAB Co., Ltd., Cheongju 28121, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3278-0710","authenticated-orcid":false,"given":"Jiyun","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University, Wonju 26493, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-6490","authenticated-orcid":false,"given":"Young Woo","family":"Eom","sequence":"additional","affiliation":[{"name":"Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5130-2728","authenticated-orcid":false,"given":"Ki-Jong","family":"Rhee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University, Wonju 26493, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1093\/cid\/ciu787","article-title":"The Bacteroides fragilis toxin gene is prevalent in the colon mucosa of colorectal cancer patients","volume":"60","author":"Boleij","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zamani, S., Taslimi, R., Sarabi, A., Jasemi, S., Sechi, L.A., and Feizabadi, M.M. (2020). Enterotoxigenic Bacteroides fragilis: A possible etiological candidate for bacterially-induced colorectal precancerous and cancerous lesions. Front. Cell Infect. Microbiol., 9.","DOI":"10.3389\/fcimb.2019.00449"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2185028","DOI":"10.1080\/19490976.2023.2185028","article-title":"Intestinal bacteria and colorectal cancer: Etiology and treatment","volume":"15","author":"Dougherty","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4166","DOI":"10.1172\/JCI72334","article-title":"Bacteroides fragilis subverts mucosal biology: From symbiont to colon carcinogenesis","volume":"124","author":"Sears","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.anaerobe.2005.11.001","article-title":"The distribution of the bft alleles among enterotoxigenic Bacteroides fragilis strains from stool specimens and extraintestinal sites","volume":"12","author":"Toprak","year":"2006","journal-title":"Anaerobe"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Guo, Y., Ouyang, Z., He, W., Zhang, J., Qin, Q., Jiao, M., Muyldermans, S., Zheng, F., and Wen, Y. (2023). Screening and epitope characterization of diagnostic nanobody against total and activated Bacteroides fragilis toxin. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1065274"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"14979","DOI":"10.1073\/pnas.95.25.14979","article-title":"Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin","volume":"95","author":"Wu","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1242\/jcs.03455","article-title":"Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and \u03b3-secretase-dependent E-cadherin cleavage","volume":"120","author":"Wu","year":"2007","journal-title":"J. Cell Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"37","DOI":"10.15324\/kjcls.2023.55.1.37","article-title":"Bacteroides fragilis toxin induces cleavage and proteasome degradation of E-cadherin in human breast cancer cell lines BT-474 and MCF7","volume":"55","author":"Kang","year":"2023","journal-title":"Korean J. Clin. Lab. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/s41586-026-10375-0","article-title":"A pro-carcinogenic bacterial toxin binds claudin-4 to cleave E-cadherin","volume":"654","author":"White","year":"2026","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5832","DOI":"10.1128\/IAI.72.10.5832-5839.2004","article-title":"Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 through mitogen-activated protein kinases and a tyrosine kinase-regulated nuclear factor-\u03baB pathway","volume":"72","author":"Wu","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lee, C.-G., Hwang, S., Gwon, S.-Y., Park, C., Jo, M., Hong, J.-E., and Rhee, K.-J. (2022). Bacteroides fragilis toxin induces intestinal epithelial cell secretion of interleukin-8 by the E-cadherin\/\u03b2-catenin\/NF-\u03baB dependent pathway. Biomedicines, 10.","DOI":"10.3390\/biomedicines10040827"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/nature01392","article-title":"Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab","volume":"421","author":"Cho","year":"2003","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.18632\/oncotarget.2713","article-title":"Molecular architecture of the ErbB2 extracellular domain homodimer","volume":"6","author":"Hu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Cheng, X. (2024). A comprehensive review of HER2 in cancer biology and therapeutics. Genes, 15.","DOI":"10.20944\/preprints202406.0515.v1"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Scerri, J., Scerri, C., Sch\u00e4fer-Ruoff, F., Fink, S., Templin, M., and Grech, G. (2022). PKC-mediated phosphorylation and activation of the MEK\/ERK pathway as a mechanism of acquired trastuzumab resistance in HER2-positive breast cancer. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1010092"},{"key":"ref_17","first-page":"54","article-title":"Effects of HER2 overexpression on cell signaling networks governing proliferation and migration","volume":"2","author":"Kumar","year":"2006","journal-title":"Mol. Syst. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Siddiqa, A., Long, L.M., Li, L., Marciniak, R.A., and Kazhdan, I. (2008). Expression of HER-2 in MCF-7 breast cancer cells modulates anti-apoptotic proteins Survivin and Bcl-2 via the extracellular signal-related kinase (ERK) and phosphoinositide-3 kinase (PI3K) signalling pathways. BMC Cancer, 8.","DOI":"10.1186\/1471-2407-8-129"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1093\/jnci\/djk134","article-title":"Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer","volume":"99","author":"Scaltriti","year":"2007","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41388-018-0465-z","article-title":"Gamma-secretase-dependent signaling of receptor tyrosine kinases","volume":"38","author":"Merilahti","year":"2019","journal-title":"Oncogene"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ctrv.2011.03.008","article-title":"HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer","volume":"38","author":"Gauchez","year":"2012","journal-title":"Cancer Treat. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1002\/cncr.31125","article-title":"Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3","volume":"124","author":"Ross","year":"2018","journal-title":"Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.1007\/s12094-025-03887-0","article-title":"HER2-targeted therapy in colorectal cancer: A comprehensive review","volume":"27","author":"Benli","year":"2025","journal-title":"Clin. Transl. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e149","DOI":"10.14694\/EdBook_AM.2015.35.e149","article-title":"Overcoming resistance to anti-EGFR therapy in colorectal cancer","volume":"35","author":"Dienstmann","year":"2015","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1016\/S0002-9440(10)64318-0","article-title":"Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium","volume":"162","author":"McGuire","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/ncb2298","article-title":"Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling","volume":"13","author":"Solanas","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9182","DOI":"10.1073\/pnas.0500918102","article-title":"ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation","volume":"102","author":"Maretzky","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","first-page":"3289","article-title":"Matrilysin mediates extracellular cleavage of E-cadherin from prostate cancer cells: A key mechanism in hepatocyte growth factor\/scatter factor-induced cell-cell dissociation and in vitro invasion","volume":"7","author":"Davies","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"657","DOI":"10.4161\/cbt.5.6.2708","article-title":"Identification of ADAM10 as a major source of HER2 ectodomain sheddase activity in HER2 overexpressing breast cancer cells","volume":"5","author":"Liu","year":"2006","journal-title":"Cancer Biol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cell.2006.07.037","article-title":"Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain","volume":"127","author":"Sardi","year":"2006","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1126\/science.1065412","article-title":"\u03b3-Secretase cleavage and nuclear localization of ErbB-4 receptor tyrosine kinase","volume":"294","author":"Ni","year":"2001","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hachmeister, M., Bobowski, K.D., Hogl, S., Dislich, B., Fukumori, A., Eggert, C., Mack, B., Kremling, H., Sarrach, S., and Coscia, F. (2013). Regulated intramembrane proteolysis and degradation of murine epithelial cell adhesion molecule mEpCAM. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071836"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"213","DOI":"10.4110\/in.2013.13.5.213","article-title":"Bacteroides fragilis toxin induces IL-8 secretion in HT29\/C1 cells through disruption of E-cadherin junctions","volume":"13","author":"Hwang","year":"2013","journal-title":"Immune Netw."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4417","DOI":"10.1111\/cas.14676","article-title":"beta2-AR activation promotes cleavage and nuclear translocation of Her2 and metastatic potential of cancer cells","volume":"111","author":"Liu","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"25302","DOI":"10.1074\/jbc.M109.001982","article-title":"HER2 carboxyl-terminal fragments regulate cell migration and cortactin phosphorylation","volume":"284","author":"Pedersen","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3234","DOI":"10.1038\/sj.emboj.7601191","article-title":"Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation","volume":"25","author":"Anido","year":"2006","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/S1097-2765(03)00048-0","article-title":"The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors","volume":"11","author":"Garrett","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1111\/j.1365-2362.2006.01676.x","article-title":"Modulation of HER2 expression by ferulic acid on human breast cancer MCF7 cells","volume":"36","author":"Chang","year":"2006","journal-title":"Eur. J. Clin. Invest."},{"key":"ref_39","first-page":"811","article-title":"Detection of an elevated HER2 expression in MCF-7 breast cancer cells overexpressing estrogen receptor \u03b21","volume":"19","author":"Lattrich","year":"2008","journal-title":"Oncol. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1093\/procel\/pwae005","article-title":"Microbiota enterotoxigenic Bacteroides fragilis-secreted BFT-1 promotes breast cancer cell stemness and chemoresistance through its functional receptor NOD1","volume":"15","author":"Ma","year":"2024","journal-title":"Protein Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8497\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:38:39Z","timestamp":1790167119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8497"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":40,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198497"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198497","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]}}}