ArticleThe Journal of biological chemistry2008
Smad4-dependent TGF-beta signaling suppresses RON receptor tyrosine kinase-dependent motility and invasion of pancreatic cancer cells.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
35 citing papers in PubMed, 51 citations in OpenAlex.
- MSP-RON signaling in liver pathobiology and as an emerging therapeutic target: a review of the current evidence.Cell communication and signaling : CCS · 2025Review
- Small-molecule agents for cancer immunotherapy.Acta pharmaceutica Sinica. B · 2024Review
- Molecular mechanism(s) of regulation(s) of c-MET/HGF signaling in head and neck cancer.Molecular cancer · 2022Review
- CMTM8 as an LPA1-associated partner mediates lysophosphatidic acid-induced pancreatic cancer metastasis.Annals of translational medicine · 2021Article
- RON Mediates Tumor-Promoting Effects in Endometrial Adenocarcinoma.BioMed research international · 2021Article
- Therapeutic efficacy of a novel humanized antibody-drug conjugate recognizing plexin-semaphorin-integrin domain in the RON receptor for targeted cancer therapy.Journal for immunotherapy of cancer · 2019Article
- Therapeutic efficacy, pharmacokinetic profiles, and toxicological activities of humanized antibody-drug conjugate Zt/g4-MMAE targeting RON receptor tyrosine kinase for cancer therapy.Journal for immunotherapy of cancer · 2019Article
- Aberrant RON and MET Co-overexpression as Novel Prognostic Biomarkers of Shortened Patient Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Pancreatic Cancer.Frontiers in oncology · 2019Article
- Automatic cell fusion via optically-induced dielectrophoresis and optically-induced locally-enhanced electric field on a microfluidic chip.Biomicrofluidics · 2018Article
- Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities.Molecular cancer · 2018Review
- Therapeutic Considerations for Ron Receptor Expression in Prostate Cancer.EMS cancer science journal · 2018Article
- The Role of Platelet-Derived ADP and ATP in Promoting Pancreatic Cancer Cell Survival and Gemcitabine Resistance.Cancers · 2017Article
- miR‑196a‑5p modulates gastric cancer stem cell characteristics by targeting Smad4.International journal of oncology · 2017Article
- Prognostic value of loss of heterozygosity and sub-cellular localization of SMAD4 varies with tumor stage in colorectal cancer.Oncotarget · 2017Article
- Effects of PTCs on nonsense-mediated mRNA decay are dependent on PTC location.Oncology letters · 2017Article
- Cadherin-11 Is a Cell Surface Marker Up-Regulated in Activated Pancreatic Stellate Cells and Is Involved in Pancreatic Cancer Cell Migration.The American journal of pathology · 2017Article
- Crosstalk between RON and androgen receptor signaling in the development of castration resistant prostate cancer.Oncotarget · 2016Article
- Insights Into SMAD4 Loss in Pancreatic Cancer From Inducible Restoration of TGF-β Signaling.Molecular endocrinology (Baltimore, Md.) · 2015Article
- The involvement of insulin-like growth factor 2 binding protein 3 (IMP3) in pancreatic cancer cell migration, invasion, and adhesion.BMC cancer · 2015Article
- Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets.Oncotarget · 2015Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Transforming growth factorbeta (TGF-beta) signals through Smad-dependent and Smad-independent pathways. However, Smad signaling is altered by allelic deletion or intragenic mutation of the Smad4 gene in more than half of pancreatic ductal adenocarcinomas. We show here that loss of Smad4-dependent signaling leads to aberrant expression of RON, a phosphotyrosine kinase receptor, and that signaling by RON cooperates with Smad4-independent TGF-beta signaling to promote cell motility and invasion. Restoring Smad4 expression in a pancreatic ductal adenocarcinoma cell line that is deficient in Smad4 repressed RON expression. Conversely, small interference RNA knock down of Smad4 or blocking TGF-beta signaling with a TGF-beta type I receptor kinase inhibitor in Smad4-intact cell lines induced RON expression. TGF-beta-induced motility and invasion were inhibited in cells that express Smad4 and that have low levels of RON compared with isogenically matched cells that were deficient in Smad4. Furthermore, knocking down RON expression in Smad4-deficient cells suppressed TGF-beta-mediated motility and invasion. We further determined that Smad4-dependent signaling regulated RON expression at the transcriptional level by real-time reverse transcription PCR and RON promoter luciferase reporter assays. Functional inactivation by site-directed mutations of two Smad binding sites on the RON promoter inhibited TGF-beta-mediated repression of RON promoter activity. These studies indicate that loss of Smad4 contributes to aberrant RON expression and that cross-talk of Smad4-independent TGF-beta signaling and the RON pathway promotes an invasive phenotype.
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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.