ArticleProceedings of the National Academy of Sciences of the United States of America2012
Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 84 citations in OpenAlex.
- TERT drives liver tumorigenesis beyond telomere elongation.Life science alliance · 2026Article
- The role of HNF4α in adenocarcinoma.Biochemical Society transactions · 2026Review
- HNF4α-HKDC1 axis orchestrates a metabolic rewiring to promote migration and metastasis in advanced gastric cancer.Cell death & disease · 2026Article
- Blocking TRIM47-mediated HNF4Acta pharmaceutica Sinica. B · 2026Article
- HNF4A P2 isoform alleviates kidney fibrosis by inhibiting dedifferentiation of proximal tubular cells through JAG1/NOTCH signaling.Cellular & molecular biology letters · 2026Article
- The Wnt/β-catenin-P2-HNF4α feedback loop facilitates colorectal tumorigenesis and malignancy.Journal of translational medicine · 2025Article
- Differential Control of Growth and Identity by HNF4α Isoforms in Pancreatic Ductal Adenocarcinoma.Molecular cancer research : MCR · 2025Article
- siRNA Knocking Down in HepG2 Cells Identifies PFKFB4 and HNF4α as Key Genes Important for Cancer Cell Survival.Current gene therapy · 2025Article
- Editorial: Hepatocyte nuclear factor 4 alpha - new insights into an old receptor.Frontiers in endocrinology · 2024Article
- Differential spatial distribution of HNF4α isoforms during dysplastic progression of intraductal papillary mucinous neoplasms of the pancreas.Scientific reports · 2023Article
- Major roles of the circadian clock in cancer.Cancer biology & medicine · 2023Review
- Multiple roles and regulatory mechanisms of the transcription factor HNF4 in the intestine.Frontiers in endocrinology · 2023Review
- HNF4α isoforms: the fraternal twin master regulators of liver function.Frontiers in endocrinology · 2023Review
- Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans.Hepatology (Baltimore, Md.) · 2022Article
- Ssu72-HNF4α signaling axis classify the transition from steatohepatitis to hepatocellular carcinoma.Cell death and differentiation · 2022Article
- Scalable Dual-Fluorescence Assay for Functional Interpretation of HNF-4α Missense Variants.Frontiers in endocrinology · 2022Article
- Review
- Liver fat storage is controlled by HNF4α through induction of lipophagy and is reversed by a potent HNF4α agonist.Cell death & disease · 2021Article
- Article
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
Src tyrosine kinase has long been implicated in colon cancer but much remains to be learned about its substrates. The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) has just recently been implicated in colon cancer but its role is poorly defined. Here we show that c-Src phosphorylates human HNF4α on three tyrosines in an interdependent and isoform-specific fashion. The initial phosphorylation site is a Tyr residue (Y14) present in the N-terminal A/B domain of P1- but not P2-driven HNF4α. Phospho-Y14 interacts with the Src SH2 domain, leading to the phosphorylation of two additional tyrosines in the ligand binding domain (LBD) in P1-HNF4α. Phosphomimetic mutants in the LBD decrease P1-HNF4α protein stability, nuclear localization and transactivation function. Immunohistochemical analysis of approximately 450 human colon cancer specimens (Stage III) reveals that P1-HNF4α is either lost or localized in the cytoplasm in approximately 80% of tumors, and that staining for active Src correlates with those events in a subset of samples. Finally, three SNPs in the human HNF4α protein, two of which are in the HNF4α F domain that interacts with the Src SH3 domain, increase phosphorylation by Src and decrease HNF4α protein stability and function, suggesting that individuals with those variants may be more susceptible to Src-mediated effects. This newly identified interaction between Src kinase and HNF4α has important implications for colon and other cancers.
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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.