ArticleJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism2014
The cross-talk between canonical and non-canonical Wnt-dependent pathways regulates P-glycoprotein expression in human blood-brain barrier cells.
Article in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 50 citations in OpenAlex.
- Role of the WNT signalling pathway in physiological and pathological blood-brain barrier.Annals of medicine · 2026Review
- Modeling blood-brain barrier-glioblastoma interactions: implications for chemoresistance and therapeutic targeting.Fluids and barriers of the CNS · 2026Review
- Blood-brain barrier permeability increases with the differentiation of glioblastoma cells in vitro.Fluids and barriers of the CNS · 2024Article
- Suppressing Wnt signaling of the blood‒tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases.Acta pharmaceutica Sinica. B · 2024Article
- ROCK1 deficiency preserves caveolar compartmentalization of signaling molecules and cell membrane integrity.FASEB bioAdvances · 2024Article
- β-catenin inhibitors in cancer therapeutics: intricacies and way forward.Bioengineered · 2023Review
- LGR5 Expression Predicting Poor Prognosis Is Negatively Correlated with WNT5A in Colon Cancer.Cells · 2023Article
- A DLG1-ARHGAP31-CDC42 axis is essential for the intestinal stem cell response to fluctuating niche Wnt signaling.Cell stem cell · 2023Article
- The Molecular Basis of Wnt/International journal of cell biology · 2023Review
- Article
- Lithium attenuates blood-brain barrier damage and brain edema following intracerebral hemorrhage via an endothelial Wnt/β-catenin signaling-dependent mechanism in mice.CNS neuroscience & therapeutics · 2022Article
- FSAP aggravated endothelial dysfunction and neurological deficits in acute ischemic stroke due to large vessel occlusion.Signal transduction and targeted therapy · 2022Article
- Wnt6 plays a complex role in maintaining human limbal stem/progenitor cells.Scientific reports · 2021Article
- Dysregulated Wnt Signalling in the Alzheimer's Brain.Brain sciences · 2020Review
- Multiplexed chemogenetics in astrocytes and motoneurons restore blood-spinal cord barrier in ALS.Life science alliance · 2020Article
- RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/β-catenin signaling pathway.Cell death & disease · 2020Article
- Wnt Pathway: An Emerging Player in Vascular and Traumatic Mediated Brain Injuries.Frontiers in physiology · 2020Review
- Modulation of Wnt/β-catenin signaling promotes blood-brain barrier phenotype in cultured brain endothelial cells.Scientific reports · 2019Article
- Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood-brain barrier dysfunction module.Nature neuroscience · 2019Article
- Drug resistance in papillary RCC: from putative mechanisms to clinical practicalities.Nature reviews. Urology · 2019Review
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In this work, we investigate if and how transducers of the 'canonical' Wnt pathway, i.e., Wnt/glycogen synthase kinase 3 (GSK3)/β-catenin, and transducers of the 'non-canonical' Wnt pathway, i.e., Wnt/RhoA/RhoA kinase (RhoAK), cooperate to control the expression of P-glycoprotein (Pgp) in blood-brain barrier (BBB) cells. By analyzing human primary brain microvascular endothelial cells constitutively activated for RhoA, silenced for RhoA or treated with the RhoAK inhibitor Y27632, we found that RhoAK phosphorylated and activated the protein tyrosine phosphatase 1B (PTP1B), which dephosphorylated tyrosine 216 of GSK3, decreasing the GSK3-mediated inhibition of β-catenin. By contrast, the inhibition of RhoA/RhoAK axis prevented the activation of PTP1B, enhanced the GSK3-induced phosphorylation and ubiquitination of β-catenin, and reduced the β-catenin-driven transcription of Pgp. The RhoAK inhibition increased the delivery of Pgp substrates like doxorubicin across the BBB and improved the doxorubicin efficacy against glioblastoma cells co-cultured under a BBB monolayer. Our data demonstrate that in human BBB cells the expression of Pgp is controlled by a cross-talk between canonical and non-canonical Wnt pathways. The disruption of this cross-talk, e.g., by inhibiting RhoAK, downregulates Pgp and increases the delivery of Pgp substrates across the BBB.
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