ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
DRD4 Interacts with TGF-β Receptors to Drive Colorectal Cancer Metastasis Independently of Dopamine Signaling Pathway.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Neural-tumor interactions: bidirectional regulatory mechanisms and nervous system-targeted tumor therapeutic strategies.Biomarker research · 2026Review
- Targeting the nervous system: Mechanistic insights into neuro-tumor communication and therapeutic opportunities.Acta pharmaceutica Sinica. B · 2026Review
- IGF2BP3 promotes progression of head and neck cancers through the circHECTD2/hsa_miR_4310/7157-5p/Smad2 signaling axis in an mMolecular cancer · 2026Article
- Cancer neuroscience: signaling pathways and new therapeutic strategies for cancer.Signal transduction and targeted therapy · 2026Review
- High dopamine impairs early neuronal identity and morphology in human hippocampal progenitor cells.Frontiers in cell and developmental biology · 2026Article
- Oncolytic adenovirus encoding a TGF-β inhibitor synergizes with PD-1 blockade to potentiate NK cell cytotoxicity against NSCLC.Frontiers in immunology · 2026Article
- Enteric nervous system as a therapeutic target in gastrointestinal disorders.World journal of gastrointestinal pharmacology and therapeutics · 2025Article
- Neurotransmitters and Immunity: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- Association of DRD4 promoter-associated methylation with mild cognitive impairment in Han and Uygur populations.European journal of medical research · 2025Article
- NONO links circadian rhythm disruption and enhanced tumor-fibroblast crosstalk in right-sided colorectal cancer.Biomarker research · 2025Article
- DRD4 Interacts with TGF-β Receptors to Drive Colorectal Cancer Metastasis Independently of Dopamine Signaling Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
The functional and pharmacological significance of dopamine receptor D4 (DRD4) in psychiatric and neurological disorders is well elucidated. However, the roles of DRD4 in colorectal cancer (CRC) remain unclear. This study observes a significant upregulation of DRD4 expression in clinical samples, which is negatively correlated with patient prognosis. In vitro, overexpression of DRD4 causes a constitutive activation of β-Arrestin2/PP2A/AKT independent of dopamine. Interestingly, this classical signaling pathway is not associated with the phenotype of DRD4-promoted migration and invasion in CRC cells. Instead, DRD4 interacts with transforming growth factor beta receptors (TGFBR1 and TGFBR2) to activate Smad2 phosphorylation and promote Smad2/Smad4 complex nucleus translocation. Then, SNAI1 and JAG1 are transcriptionally activated to induce epithelial-mesenchymal transition and enhance the metastatic potential of CRC. Notably, the COOH-terminal domain is identified as the key intracellular region for the pro-metastatic roles of DRD4. Furthermore, treatment with a TGFBR1 inhibitor combined with a BMP inhibitor effectively counteracts the pro-metastatic effects induced by DRD4 both in vitro and in vivo. In conclusion, these findings uncover an unconventional role for DRD4 beyond its classic function as a neurotransmitter receptor. The intracellular signaling of DRD4 interacting with TGFBR1 can be targeted pharmacologically for CRC therapy.
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