ArticleThe Journal of biological chemistry2015
Integrin α6β4 Promotes Autocrine Epidermal Growth Factor Receptor (EGFR) Signaling to Stimulate Migration and Invasion toward Hepatocyte Growth Factor (HGF).
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 31 citations in OpenAlex.
- Beyond DNA damage: 3D tumor models and the integrin mechanobiology of radioresistance.Journal of experimental & clinical cancer research : CR · 2026Review
- Targeting EGFR Endocytosis and Signaling for Cancer Drug Delivery and Cancer Treatment.Cancers · 2026Review
- circFOXP1 Promotes Pancreatic Ductal Adenocarcinoma Progression Through Regulating EREG/MAPK/ERK Axis.Journal of cellular and molecular medicine · 2026Article
- Amphiregulin in Fibrotic Diseases and Cancer.International journal of molecular sciences · 2025Review
- HCMV US2 co-opts TRC8 to degrade the endoplasmic reticulum-resident protein LMAN2L.The Journal of general virology · 2024Article
- Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer.Theranostics · 2023Article
- Integrin α6β4 signals through DNA damage response pathway to sensitize breast cancer cells to cisplatin.Frontiers in oncology · 2022Article
- Signatures of Dermal Fibroblasts from RDEB Pediatric Patients.International journal of molecular sciences · 2021Article
- Article
- A signature of 18 immune-related gene pairs to predict the prognosis of pancreatic cancer patients.Immunity, inflammation and disease · 2020Article
- The role of PDIA3 in myogenesis during muscle regeneration.Experimental & molecular medicine · 2020Article
- Identification of Prognostic Immune-Related Genes in Pancreatic Adenocarcinoma and Establishment of a Prognostic Nomogram: A Bioinformatic Study.BioMed research international · 2020Article
- TMEM16A controls EGF-induced calcium signaling implicated in pancreatic cancer prognosis.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Combination of Selected MET and EGFR Inhibitors Decreases Melanoma Cells' Invasive Abilities.Frontiers in pharmacology · 2019Article
- Non-genomic Actions of Thyroid Hormones Regulate the Growth and Angiogenesis of T Cell Lymphomas.Frontiers in endocrinology · 2019Review
- Article
- Integrin α6β4 Upregulates Amphiregulin and Epiregulin through Base Excision Repair-Mediated DNA Demethylation and Promotes Genome-wide DNA Hypomethylation.Scientific reports · 2017Article
- Beyond adhesion: emerging roles for integrins in control of the tumor microenvironment.F1000Research · 2017Review
- Integrins in the Spotlight of Cancer.International journal of molecular sciences · 2016Review
- MET-activating Residues in the B-repeat of the Listeria monocytogenes Invasion Protein InlB.The Journal of biological chemistry · 2016Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.