ArticleThe Biochemical journal2017
Rac1-stimulated macropinocytosis enhances Gβγ activation of PI3Kβ.
Article in The Biochemical journal, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- Acquisition of Resistance to RAS Inhibition Is Associated with the Upregulation of Macropinocytosis through Both PI3K-Dependent and -Independent Signaling.Cancer research communications · 2026Article
- Article
- RAB31 drives extracellular vesicle fusion and cancer-associated fibroblast formation leading to oxaliplatin resistance in colorectal cancer.Journal of extracellular biology · 2024Article
- GNG2 acts as a tumor suppressor in breast cancer through stimulating MRAS signaling.Cell death & disease · 2022Article
- Roles for 3' Phosphoinositides in Macropinocytosis.Sub-cellular biochemistry · 2022Article
- LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes.The EMBO journal · 2020Article
- RAC1mutation is not a predictive biomarker for PI3'-kinase-β-selective pathway-targeted therapy.Pigment cell & melanoma research · 2020Article
- Rac-GEF/Rac Signaling and Metastatic Dissemination in Lung Cancer.Frontiers in cell and developmental biology · 2020Article
- Combined mTORC1/mTORC2 inhibition blocks growth and induces catastrophic macropinocytosis in cancer cells.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- PI3Kβ is selectively required for growth factor-stimulated macropinocytosis.Journal of cell science · 2019Article
- PI3Kβ-A Versatile Transducer for GPCR, RTK, and Small GTPase Signaling.Endocrinology · 2019Review
- The origins and evolution of macropinocytosis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2019Review
- Akt and SGK protein kinases are required for efficient feeding by macropinocytosis.Journal of cell science · 2019Article
- Dorsal ruffles enhance activation of Akt by growth factors.Journal of cell science · 2018Article
- Macropinocytosis, mTORC1 and cellular growth control.Cellular and molecular life sciences : CMLS · 2018Review
- Amplification of PIP3 signalling by macropinocytic cups.The Biochemical journal · 2018Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
Abstract
Phosphoinositide 3-kinases (PI 3-kinases) are regulated by a diverse range of upstream activators, including receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs), and small GTPases from the Ras, Rho and Rab families. For the Class IA PI 3-kinase PI3Kβ, two mechanisms for GPCR-mediated regulation have been described: direct binding of Gβγ subunits to the C2-helical domain linker of p110β, and Dock180/Elmo1-mediated activation of Rac1, which binds to the Ras-Binding Domain of p110β. We now show that the integration of these dual pathways is unexpectedly complex. In breast cancer cells, expression of constitutively activated Rac1 (CA-Rac1) along with either GPCR stimulation or expression of Gβγ led to an additive PI3Kβ-dependent activation of Akt. Whereas CA-Rac1-mediated activation of Akt was blocked in cells expressing a mutated PI3Kβ that cannot bind Gβγ, Gβγ and GPCR-mediated activation of Akt was preserved when Rac1 binding to PI3Kβ was blocked. Surprisingly, PI3Kβ-dependent CA-Rac1 signaling to Akt was still seen in cells expressing a mutant p110β that cannot bind Rac1. Instead of directly binding to PI3Kβ, CA-Rac1 acts by enhancing Gβγ coupling to PI3Kβ, as CA-Rac1-mediated Akt activation was blocked by inhibitors of Gβγ. Cells expressing CA-Rac1 exhibited a robust induction of macropinocytosis, and inhibitors of macropinocytosis blocked the activation of Akt by CA-Rac1 or lysophosphatidic acid. Our data suggest that Rac1 can potentiate the activation of PI3Kβ by GPCRs through an indirect mechanism, by driving the formation of macropinosomes that serve as signaling platforms for Gβγ coupling to PI3Kβ.
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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.