دورية أكاديمية
Integrin α6β4 Promotes Autocrine Epidermal Growth Factor Receptor (EGFR) Signaling to Stimulate Migration and Invasion toward Hepatocyte Growth Factor (HGF).
| العنوان: | Integrin α6β4 Promotes Autocrine Epidermal Growth Factor Receptor (EGFR) Signaling to Stimulate Migration and Invasion toward Hepatocyte Growth Factor (HGF). |
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| المؤلفون: | Carpenter BL; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40506-0509; Departments of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40506-0509., Chen M; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40506-0509; Departments of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40506-0509., Knifley T; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40506-0509., Davis KA; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40506-0509., Harrison SMW; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40506-0509., Stewart RL; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40506-0509; Departments of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky 40506-0509., O'Connor KL; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40506-0509; Departments of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40506-0509. Electronic address: kloconnor@uky.edu. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2015 Nov 06; Vol. 290 (45), pp. 27228-27238. Date of Electronic Publication: 2015 Sep 17. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | ErbB Receptors/*metabolism , Hepatocyte Growth Factor/*metabolism , Integrin alpha6beta4/*metabolism, Amphiregulin ; Cell Line, Tumor ; Cell Movement ; EGF Family of Proteins/genetics ; EGF Family of Proteins/metabolism ; Epiregulin/genetics ; Epiregulin/metabolism ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/genetics ; Gene Knockdown Techniques ; Humans ; Integrin alpha6beta4/genetics ; Matrix Metalloproteinase 1/genetics ; Matrix Metalloproteinase 1/metabolism ; Models, Biological ; Neoplasm Invasiveness ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; Signal Transduction ; Tumor Microenvironment ; Up-Regulation |
| مستخلص: | Integrin α6β4 is up-regulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion by altering the transcriptome. In this study, we found that integrin α6β4 up-regulates several genes in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (AREG), epiregulin (EREG), and ectodomain cleavage protease MMP1, which is mediated by promoter demethylation and NFAT5. The correlation of these genes with integrin α6β4 was confirmed in The Cancer Genome Atlas Pancreatic Cancer Database. Based on previous observations that integrin α6β4 cooperates with c-Met in pancreatic cancers, we examined the impact of EGFR signaling on hepatocyte growth factor (HGF)-stimulated migration and invasion. We found that AREG and EREG were required for autocrine EGFR signaling, as knocking down either ligand inhibited HGF-mediated migration and invasion. We further determined that HGF induced secretion of AREG, which is dependent on integrin-growth factor signaling pathways, including MAPK, PI3K, and PKC. Moreover, matrix metalloproteinase activity and integrin α6β4 signaling were required for AREG secretion. Blocking EGFR signaling with EGFR-specific antibodies or an EGFR tyrosine kinase inhibitor hindered HGF-stimulated pancreatic carcinoma cell chemotaxis and invasive growth in three-dimensional culture. Finally, we found that EGFR was phosphorylated in response to HGF stimulation that is dependent on EGFR kinase activity; however, c-Met phosphorylation in response to HGF was unaffected by EGFR signaling. Taken together, these data illustrate that integrin α6β4 stimulates invasion by promoting autocrine EGFR signaling through transcriptional up-regulation of key EGFR family members and by facilitating HGF-stimulated EGFR ligand secretion. These signaling events, in turn, promote pancreatic carcinoma migration and invasion. (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.) |
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| معلومات مُعتمدة: | R01 CA109136 United States CA NCI NIH HHS; T32 CA160003 United States CA NCI NIH HHS; T32 CA165990 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: pancreatic cancer; protein secretion; receptor protein-tyrosine kinase; receptor protein-tyrosine kinases; receptor regulation; receptor tyrosine kinase; signal transduction |
| المشرفين على المادة: | 0 (AREG protein, human) 0 (Amphiregulin) 0 (EGF Family of Proteins) 0 (EREG protein, human) 0 (Epiregulin) 0 (HGF protein, human) 0 (Integrin alpha6beta4) 0 (RNA, Messenger) 0 (RNA, Neoplasm) 67256-21-7 (Hepatocyte Growth Factor) EC 2.7.10.1 (EGFR protein, human) EC 2.7.10.1 (ErbB Receptors) EC 3.4.24.7 (MMP1 protein, human) EC 3.4.24.7 (Matrix Metalloproteinase 1) |
| تواريخ الأحداث: | Date Created: 20150919 Date Completed: 20160422 Latest Revision: 20210306 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC4646402 |
| DOI: | 10.1074/jbc.M115.686873 |
| PMID: | 26381405 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1083-351X |
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| DOI: | 10.1074/jbc.M115.686873 |