PKCδ stimulates macropinocytosis via activation of SSH1-cofilin pathway

Singla, Bhupesh; Lin, Hui Ping; Ghoshal, Pushpankur; Cherian‐Shaw, Mary; Csányi, Gábor

doi:10.1016/j.cellsig.2018.09.018

Cited by 17 publications

(17 citation statements)

References 76 publications

(112 reference statements)

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“…A previous study reported that loss of NF1 signaling in Dictyostelium stimulates Ras activity and actin polymerization, leading to macropinocytosis [19]. Relevant to this, previous studies from our laboratory demonstrated that increased Nox2 activity via activation of slingshot phosphatase-1 (SSH1) stimulates cofilin dephosphorylation, leading to membrane ruffling and macropinocytosis [17,39]. With regard to the downstream redox signaling mechanisms stimulating actin remodeling and macropinocytosis in NF1-deficient macrophages, we speculate that PKCδ/Nox2-mediated activation of SSH1 induces activation of cofilin, leading to actin remodeling and macropinocytosis [14,17].…”

Section: Discussionmentioning

confidence: 86%

“…Relevant to this, previous studies from our laboratory demonstrated that increased Nox2 activity via activation of slingshot phosphatase-1 (SSH1) stimulates cofilin dephosphorylation, leading to membrane ruffling and macropinocytosis [17,39]. With regard to the downstream redox signaling mechanisms stimulating actin remodeling and macropinocytosis in NF1-deficient macrophages, we speculate that PKCδ/Nox2-mediated activation of SSH1 induces activation of cofilin, leading to actin remodeling and macropinocytosis [14,17]. In that respect, we expect future studies to investigate the role of SSH1 and cofilin (or other actin binding proteins) in macropinocytosis stimulation in NF1 -deficient macrophages.…”

Section: Discussionmentioning

confidence: 93%

“…Macropinocytosis is an actin-driven process of large-scale, non-specific fluid uptake used for feeding by some cancer cells and eukaryotic bacterivores and antigen sampling by immune cells [[13], [14], [15]]. In mammalian cells and Dictyostelium , active Ras, PI3K, D-3 phosphorylated phosphatidylinositols, protein kinase C (PKC) and actin are important signaling molecules required for efficient fluid-phase macropinocytosis [[16], [17], [18]]. Interestingly, a previous study using whole genome sequencing identified that axenic Dictyostelium carrying inactivating mutations in Nf1 have stimulated macropinocytosis, leading to increased nutrient internalization and their robust proliferation [19].…”

Section: Introductionmentioning

confidence: 99%

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Loss of GTPase activating protein neurofibromin stimulates paracrine cell communication via macropinocytosis

et al. 2019

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Neurofibromin, the protein product of the neurofibromatosis type 1 (NF1) tumor suppressor gene, is a negative regulator of Ras signaling. Patients with mutations in NF1 have a strong predisposition for cardiovascular disease, which contributes to their early mortality. Nf1 heterozygous (Nf1+/−) bone marrow to wild type chimeras and mice with heterozygous recombination of Nf1 in myeloid cells recapitulate many of the vascular phenotypes observed in Nf1+/− mutants. Although these results suggest that macrophages play a central role in NF1 vasculopathy, the underlying mechanisms are currently unknown. In the present study, we employed macrophages isolated from either Nf1+/− or Lysm Cre+/Nf1f/f mice to test the hypothesis that loss of Nf1 stimulates macropinocytosis in macrophages. Scanning electron microscopy and flow cytometry analysis of FITC-dextran internalization demonstrated that loss of Nf1 in macrophages stimulates macropinocytosis. We next utilized various cellular and molecular approaches, pharmacological inhibitors and genetically modified mice to identify the signaling mechanisms mediating macropinocytosis in Nf1-deficient macrophages. Our results indicate that loss of Nf1 stimulates PKCδ-mediated p47phox phosphorylation via RAS activation, leading to increased NADPH oxidase 2 activity, reactive oxygen species generation, membrane ruffling and macropinocytosis. Interestingly, we also found that Nf1-deficient macrophages internalize exosomes derived from angiotensin II-treated endothelial cells via macropinocytosis in vitro and in the peritoneal cavity in vivo. As a result of exosome internalization, Nf1-deficient macrophages polarized toward an inflammatory M1 phenotype and secreted increased levels of proinflammatory cytokines compared to controls. In conclusion, the findings of the present study demonstrate that loss of Nf1 stimulates paracrine endothelial to myeloid cell communication via macropinocytosis, leading to proinflammatory changes in recipient macrophages.

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Loss of GTPase activating protein neurofibromin stimulates paracrine cell communication via macropinocytosis

et al. 2019

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“…Western blot experiments were performed using tissue/cell lysates as described previously using the Odyssey CLx Infrared Imaging System (Li-Cor Biosciences, Lincoln, NE, USA) [ 26 ]. Briefly, protein concentrations in lysate preparations were quantified employing the Pierce BCA Protein Assay Kit (ThermoFisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

Oxidatively Modified LDL Suppresses Lymphangiogenesis via CD36 Signaling

et al. 2021

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Arterial accumulation of plasma-derived LDL and its subsequent oxidation contributes to atherosclerosis. Lymphatic vessel (LV)-mediated removal of arterial cholesterol has been shown to reduce atherosclerotic lesion formation. However, the precise mechanisms that regulate LV density and function in atherosclerotic vessels remain to be identified. The aim of this study was to investigate the role of native LDL (nLDL) and oxidized LDL (oxLDL) in modulating lymphangiogenesis and underlying molecular mechanisms. Western blotting and immunostaining experiments demonstrated increased oxLDL expression in human atherosclerotic arteries. Furthermore, elevated oxLDL levels were detected in the adventitial layer, where LV are primarily present. Treatment of human lymphatic endothelial cells (LEC) with oxLDL inhibited in vitro tube formation, while nLDL stimulated it. Similar results were observed with Matrigel plug assay in vivo. CD36 deletion in mice and its siRNA-mediated knockdown in LEC prevented oxLDL-induced inhibition of lymphangiogenesis. In addition, oxLDL via CD36 receptor suppressed cell cycle, downregulated AKT and eNOS expression, and increased levels of p27 in LEC. Collectively, these results indicate that oxLDL inhibits lymphangiogenesis via CD36-mediated regulation of AKT/eNOS pathway and cell cycle. These findings suggest that therapeutic blockade of LEC CD36 may promote arterial lymphangiogenesis, leading to increased cholesterol removal from the arterial wall and reduced atherosclerosis.

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“…DCs differ from other phagocytic cells in that their primary function is to process antigens and present them to T cells rather than just destroying pathogens. NOX2 activation through PKC-δ promotes pinocytosis and antigen uptake in DCs through the SSH1-Cofilin pathway [ 227 , 228 ]. In addition to promoting antigen uptake, NOX2 plays a key role in antigen processing within the phagosome by modulating the pH and activity of proteolytic enzymes [ 229 ].…”

Section: Nox Enzymes In Immunitymentioning

confidence: 99%

The role of NADPH oxidases in infectious and inflammatory diseases

Taylor

Tse

2021

Redox Biology

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Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) are enzymes that generate superoxide or hydrogen peroxide from molecular oxygen utilizing NADPH as an electron donor. There are seven enzymes in the NOX family: NOX1-5 and dual oxidase (DUOX) 1–2. NOX enzymes in humans play important roles in diverse biological functions and vary in expression from tissue to tissue. Importantly, NOX2 is involved in regulating many aspects of innate and adaptive immunity, including regulation of type I interferons, the inflammasome, phagocytosis, antigen processing and presentation, and cell signaling. DUOX1 and DUOX2 play important roles in innate immune defenses at epithelial barriers. This review discusses the role of NOX enzymes in normal physiological processes as well as in disease. NOX enzymes are important in autoimmune diseases like type 1 diabetes and have also been implicated in acute lung injury caused by infection with SARS-CoV-2. Targeting NOX enzymes directly or through scavenging free radicals may be useful therapies for autoimmunity and acute lung injury where oxidative stress contributes to pathology.

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PKCδ stimulates macropinocytosis via activation of SSH1-cofilin pathway

Cited by 17 publications

References 76 publications

Loss of GTPase activating protein neurofibromin stimulates paracrine cell communication via macropinocytosis

Loss of GTPase activating protein neurofibromin stimulates paracrine cell communication via macropinocytosis

Oxidatively Modified LDL Suppresses Lymphangiogenesis via CD36 Signaling

The role of NADPH oxidases in infectious and inflammatory diseases

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