Identification of circular dorsal ruffles as signal platforms for the AKT pathway in glomerular podocytes

Hua, Rui; Wei, Jinzi; Torres, Mauricio; He, Yuehui; Li, Yanan; Sun, Xiaowei; Wang, Li; Inoki, Ken; Yoshida, Sei

doi:10.1002/jcp.30996

Cited by 4 publications

(3 citation statements)

References 65 publications

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“…The initial and critical step in macropinocytosis involves membrane ruffling or blebbing, which appears to be regulated by various PIPs [25,27]. Inhibitors of phosphoinositide 3-kinases (PI3Ks), responsible for generating PI (3,4,5)P3 from PI(4,5)P 2 , can impair macropinosome formation [28].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

“…Macropinocytosis is a nutrient procurement pathway that aids cells in extracting nutrients from the extracellular environment, fuelling cell growth 24 - 26 . The initial and critical step in macropinocytosis involves membrane ruffling or blebbing, which appears to be regulated by various PIPs 25 , 27 . Inhibitors of phosphoinositide 3-kinases (PI3Ks), responsible for generating PI(3,4,5)P 3 from PI(4,5)P 2 , can impair macropinosome formation 28 .…”

Section: Introductionmentioning

confidence: 99%

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PRL1 and PRL3 promote macropinocytosis via its lipid phosphatase activity

Ye,

Ng,

Liu

et al. 2024

Theranostics

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PRL1 and PRL3, members of the protein tyrosine phosphatase family, have been associated with cancer metastasis and poor prognosis. Despite extensive research on their protein phosphatase activity, their potential role as lipid phosphatases remains elusive. Methods: We conducted comprehensive investigations to elucidate the lipid phosphatase activity of PRL1 and PRL3 using a combination of cellular assays, biochemical analyses, and protein interactome profiling. Functional studies were performed to delineate the impact of PRL1/3 on macropinocytosis and its implications in cancer biology. Results: Our study has identified PRL1 and PRL3 as lipid phosphatases that interact with phosphoinositide (PIP) lipids, converting PI(3,4)P2 and PI(3,5)P2 into PI(3)P on the cellular membranes. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis, facilitating nutrient extraction, cell migration, and invasion, thereby contributing to tumor development. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis. Additionally, we found a correlation between PRL1/3 expression and glioma development, suggesting their involvement in glioma progression. Conclusions: Combining with the knowledge that PRLs have been identified to be involved in mTOR, EGFR and autophagy, here we concluded the physiological role of PRL1/3 in orchestrating the nutrient sensing, absorbing and recycling via regulating macropinocytosis through its lipid phosphatase activity. This mechanism could be exploited by tumor cells facing a nutrient-depleted microenvironment, highlighting the potential therapeutic significance of targeting PRL1/3-mediated macropinocytosis in cancer treatment.

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Section: Ivyspring International Publishermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PRL1 and PRL3 promote macropinocytosis via its lipid phosphatase activity

Ye,

Ng,

Liu

et al. 2024

Theranostics

View full text Add to dashboard Cite

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“…Closure of ruffles is completed by fusion of ruffles, resulting in the formation of large vesicles (>0.2 μm in diameter) called macropinosomes (Conner & Schmid, 2003; Quinn et al, 2021; Swanson, 2008). Significant progress has been made in understanding the responsible genes and molecular mechanisms governing MPC induction and macropinosome maturation in various cell types (Fennell et al, 2015; Freeman et al, 2020; Hua et al, 2023; Kawai et al, 2021; Maekawa et al, 2014; Mylvaganam et al, 2021; Ramirez et al, 2019; Stow et al, 2020; Sun et al, 2022; Yoshida et al, 2018; Zeziulia et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

ATP2B4 is an essential gene for epidermal growth factor‐induced macropinocytosis in A431 cells

Yoshie,

Kuriyama,

Maekawa

et al. 2024

Genes to Cells

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Macropinocytosis (MPC) is a large‐scale endocytosis pathway that involves actin‐dependent membrane ruffle formation and subsequent ruffle closure to generate macropinosomes for the uptake of fluid‐phase cargos. MPC is categorized into two types: constitutive and stimuli‐induced. Constitutive MPC in macrophages relies on extracellular Ca2+ sensing by a calcium‐sensing receptor. However, the link between stimuli‐induced MPC and Ca2+ remains unclear. Here, we find that both intracellular and extracellular Ca2+ are required for epidermal growth factor (EGF)‐induced MPC in A431 human epidermoid carcinoma cells. Through investigation of mammalian homologs of coelomocyte uptake defective (CUP) genes, we identify ATP2B4, encoding for a Ca2+ pump called the plasma membrane calcium ATPase 4 (PMCA4), as a Ca2+‐related regulator of EGF‐induced MPC. Knockout (KO) of ATP2B4, as well as depletion of extracellular/intracellular Ca2+, inhibited ruffle closure and macropinosome formation, without affecting ruffle formation. We demonstrate the importance of PMCA4 activity itself, independent of interactions with other proteins via its C‐terminus known as a PDZ domain‐binding motif. Additionally, we show that ATP2B4‐KO reduces EGF‐stimulated Ca2+ oscillation during MPC. Our findings suggest that EGF‐induced MPC requires ATP2B4‐dependent Ca2+ dynamics.

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Macropinocytic cups function as signal platforms for the mTORC2-AKT pathway to modulate LPS-induced cytokine expression in macrophages

Wang,

Sun,

Chen

et al. 2024

Journal of Leukocyte Biology

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Macropinocytosis is a large-scale endocytosis process that is primarily observed in phagocytes as part of their cellular function to ingest antigens. Once phagocytes encounter gram-negative bacteria, the receptor proteins identify lipopolysaccharides (LPSs), which trigger radical membrane ruffles that gradually change to cup-like structures. The open area of the cups closes to generate vesicles called macropinosomes. The target bacteria are isolated by the cups and engulfed by the cells as the cups close. In addition to its ingestion function, macropinocytosis also regulates the AKT pathway in macrophages. In the current study, we report that macropinocytic cups are critical for LPS-induced AKT phosphorylation (pAKT) and cytokine expression in macrophages. High-resolution scanning electron microscope (SEM) observations detailed the macropinocytic cup structures induced by LPS stimulation. Confocal microscopy revealed that AKT and the kinase molecule mTORC2 were localized in the cups. The biochemical analysis showed that macropinocytosis inhibition blocked LPS-induced pAKT. RNA-Seq, qPCR, and ELISA analyses revealed that the inhibition of macropinocytosis or the AKT pathway causes a decrease in the expression of pro-inflammatory cytokines IL-6 and IL-1α. Moreover, activation of the transcription factor NF-κB, which regulates the cytokine expression downstream of the AKT/IκB pathway, was hindered when macropinocytosis or AKT were inhibited. These results indicate that LPS-induced macropinocytic cups function as signal platforms for the AKT pathway to regulate the cytokine expression by modulating NF-κB activity in LPS-stimulated macrophages. Based on these findings, we propose that macropinocytosis may be a good therapeutic target for controlling cytokine expression.

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Identification of circular dorsal ruffles as signal platforms for the AKT pathway in glomerular podocytes

Cited by 4 publications

References 65 publications

PRL1 and PRL3 promote macropinocytosis via its lipid phosphatase activity

PRL1 and PRL3 promote macropinocytosis via its lipid phosphatase activity

ATP2B4 is an essential gene for epidermal growth factor‐induced macropinocytosis in A431 cells

Macropinocytic cups function as signal platforms for the mTORC2-AKT pathway to modulate LPS-induced cytokine expression in macrophages

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