ArticleThe Journal of biological chemistry2015
Phosphatidylinositol 3-kinase class II α-isoform PI3K-C2α is required for transforming growth factor β-induced Smad signaling in endothelial cells.
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 26 papers.
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Who cites it
26 citing papers in PubMed, 43 citations in OpenAlex.
- Circulating microRNAs miR-21-5p, miR-23a-3p and miR-26a-5p reflect clinical and molecular features of aging.Scientific reports · 2025Article
- Inactivation of PI3K-C2α deregulates cell death pathways and sensitizes to endotoxic shock.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- PTPN23-dependent activation of PI3KC2α is a therapeutic vulnerability of BRAF-mutant cancers.The Journal of experimental medicine · 2025Article
- Transforming growth factor-β receptors: versatile mechanisms of ligand activation.Acta pharmacologica Sinica · 2024Review
- Discoidin domain receptor 2 signaling through PIK3C2α in fibroblasts promotes lung fibrosis.The Journal of pathology · 2024Article
- Hypoxia activates SREBP2 through Golgi disassembly in bone marrow-derived monocytes for enhanced tumor growth.The EMBO journal · 2023Article
- Structural Basis for Highly Selective Class II Alpha Phosphoinositide-3-Kinase Inhibition.Journal of medicinal chemistry · 2023Article
- Metabolic adaptations of cancer in extreme tumor microenvironments.Cancer science · 2023Review
- Phosphoinositide Conversion Inactivates R-RAS and Drives Metastases in Breast Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- PI3K Isoforms in Vascular Biology, A Focus on the Vascular System-Immune Response Connection.Current topics in microbiology and immunology · 2022Article
- Article
- Class II phosphatidylinositol 3-kinase isoforms in vesicular trafficking.Biochemical Society transactions · 2021Review
- Class II phosphatidylinositol 3-kinase-C2α is essential for Notch signaling by regulating the endocytosis of γ-secretase in endothelial cells.Scientific reports · 2021Article
- B7-H3 in Medulloblastoma-Derived Exosomes; A Novel Tumorigenic Role.International journal of molecular sciences · 2020Article
- Class II phosphatidylinositol 3-kinase α and β isoforms are required for vascular smooth muscle Rho activation, contraction and blood pressure regulation in mice.The journal of physiological sciences : JPS · 2020Article
- TGFβ receptor endocytosis and Smad signaling require synaptojanin1, PI3K-C2α-, and INPP4B-mediated phosphoinositide conversions.Molecular biology of the cell · 2020Article
- PI3K isoforms in cell signalling and vesicle trafficking.Nature reviews. Molecular cell biology · 2019Review
- MicroRNA-744 Inhibits Proliferation of Bronchial Epithelial Cells by Regulating Smad3 Pathway via Targeting Transforming Growth Factor-β1 (TGF-β1) in Severe Asthma.Medical science monitor : international medical journal of experimental and clinical research · 2019Article
- Class II PI3Ks at the Intersection between Signal Transduction and Membrane Trafficking.Biomolecules · 2019Review
- The class II phosphoinositide 3-kinases PI3K-C2α and PI3K-C2β differentially regulate clathrin-dependent pinocytosis in human vascular endothelial cells.The journal of physiological sciences : JPS · 2019Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We have recently demonstrated that the PI3K class II-α isoform (PI3K-C2α), which generates phosphatidylinositol 3-phosphate and phosphatidylinositol 3,4-bisphosphates, plays crucial roles in angiogenesis, by analyzing PI3K-C2α knock-out mice. The PI3K-C2α actions are mediated at least in part through its participation in the internalization of VEGF receptor-2 and sphingosine-1-phosphate receptor S1P1 and thereby their signaling on endosomes. TGFβ, which is also an essential angiogenic factor, signals via the serine/threonine kinase receptor complex to induce phosphorylation of Smad2 and Smad3 (Smad2/3). SARA (Smad anchor for receptor activation) protein, which is localized in early endosomes through its FYVE domain, is required for Smad2/3 signaling. In the present study, we showed that PI3K-C2α knockdown nearly completely abolished TGFβ1-induced phosphorylation and nuclear translocation of Smad2/3 in vascular endothelial cells (ECs). PI3K-C2α was necessary for TGFβ-induced increase in phosphatidylinositol 3,4-bisphosphates in the plasma membrane and TGFβ receptor internalization into the SARA-containing early endosomes, but not for phosphatidylinositol 3-phosphate enrichment or localization of SARA in the early endosomes. PI3K-C2α was also required for TGFβ receptor-mediated formation of SARA-Smad2/3 complex. Inhibition of dynamin, which is required for the clathrin-dependent receptor endocytosis, suppressed both TGFβ receptor internalization and Smad2/3 phosphorylation. TGFβ1 stimulated Smad-dependent VEGF-A expression, VEGF receptor-mediated EC migration, and capillary-like tube formation, which were all abolished by either PI3K-C2α knockdown or a dynamin inhibitor. Finally, TGFβ1-induced microvessel formation in Matrigel plugs was greatly attenuated in EC-specific PI3K-C2α-deleted mice. These observations indicate that PI3K-C2α plays the pivotal role in TGFβ receptor endocytosis and thereby Smad2/3 signaling, participating in angiogenic actions of TGFβ.
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