PKCα and PKCδ: Friends and Rivals

Black, Jennifer D.; Affandi, Trisiani; Black, Adrian R.; Reyland, Mary E.

doi:10.1016/j.jbc.2022.102194

Cited by 15 publications

(14 citation statements)

References 379 publications

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“…We showed that phosphorylation of FMNL2 at serine 1072 increases the formation of filopodia. These filopodia can further enhance cell motility, migration and invasion as observed in several studies downstream of PKCα signaling in cancer and non-cancerous cells [ 10 , 23 , 42 , 43 , 44 , 45 , 46 ]. FMNL2-dependent filopodia formation is regulated on multiple levels.…”

Section: Discussionmentioning

confidence: 83%

Spatiotemporal Regulation of FMNL2 by N-Terminal Myristoylation and C-Terminal Phosphorylation Drives Rapid Filopodia Formation

et al. 2023

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The actin nucleating and polymerizing formin-like 2 (FMNL2) is upregulated in several cancers and has been shown to play important roles in cell migration, invasion, cell–cell adhesion and filopodia formation. Here, using structured illumination microscopy we show that FMNL2 promotes rapid and highly dynamic filopodia formation in epithelial cells while remaining on the tip of the growing filopodia. This filopodia tip localization depends fully on its N-terminal myristoylation. We further show that FMNL2-dependent filopodia formation requires its serine 1072 phosphorylation within the diaphanous-autoregulatory domain (DAD) by protein kinase C (PKC) α. Consistent with this, filopodia formation depends on PKC activity and PKCα localizes to the base of growing filopodia. Thus, a PKCα–FMNL2 signaling module spatiotemporally controls dynamic filopodia formation.

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Section: Discussionmentioning

confidence: 83%

Spatiotemporal Regulation of FMNL2 by N-Terminal Myristoylation and C-Terminal Phosphorylation Drives Rapid Filopodia Formation

et al. 2023

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“…PKC is a group of nine gene products that encode similar protein kinases, which can be devided into conventional (α, β, γ) novel (δ, ε, η, θ) and atypical (ζ,ι) isoforms [ 56 , 57 ]. Although PKCs are better known for their ability to induce survial/proliferation or, when dysregulated, promote cancer [ 58 ], they were shown to participate in some growth inhibition, apoptosis, and tumor suppressing processes [ 59 , 60 ]. In the current study we show that PKC may induce apoptosis of some cells by inhibiting AKT phosphorylation via PP2Ac.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of PP2Ac by PKC is a key regulatory step in the PP2A-switch-dependent AKT dephosphorylation that leads to apoptosis

Nadel,

Yao,

Hacohen-Lev-Ran

et al. 2024

Cell Commun Signal

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Background Although GqPCR activation often leads to cell survival by activating the PI3K/AKT pathway, it was previously shown that in several cell types AKT activity is reduced and leads to JNK activation and apoptosis. The mechanism of AKT inactivation in these cells involves an IGBP1-coupled PP2Ac switch that induces the dephosphorylation and inactivation of both PI3K and AKT. However, the machinery involved in the initiation of PP2A switch is not known. Methods We used phospho-mass spectrometry to identify the phosphorylation site of PP2Ac, and raised specific antibodies to follow the regulation of this phosphorylation. Other phosphorylations were monitored by commercial antibodies. In addition, we used coimmunoprecipitation and proximity ligation assays to follow protein–protein interactions. Apoptosis was detected by a TUNEL assay as well as PARP1 cleavage using SDS-PAGE and Western blotting. Results We identified Ser24 as a phosphorylation site in PP2Ac. The phosphorylation is mediated mainly by classical PKCs (PKCα and PKCβ) but not by novel PKCs (PKCδ and PKCε). By replacing the phosphorylated residue with either unphosphorylatable or phosphomimetic residues (S24A and S24E), we found that this phosphorylation event is necessary and sufficient to mediate the PP2A switch, which ultimately induces AKT inactivation, and a robust JNK-dependent apoptosis. Conclusion Our results show that the PP2A switch is induced by PKC-mediated phosphorylation of Ser24-PP2Ac and that this phosphorylation leads to apoptosis upon GqPCR induction of various cells. We propose that this mechanism may provide an unexpected way to treat some cancer types or problems in the endocrine machinery.

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“…It is true that the MAPK pathway also plays an important role in OC-genesis and bone resorption by OCs [ 70 , 71 ]. The engagement of PKC-δ and ERK-MAPK in CV-elicited cell signaling indicates that CV may be a ligand for receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) [ 72 ]. Accordingly, a future study will take up the detailed profiling of CV in relation to the initiation of cell signaling in OC precursors as well as the other cell signaling molecules downstream of PKC-δ and ERK-MAPK.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Release of Citrullinated Vimentin Directly Acts on Osteoclasts to Promote Bone Resorption in a Mouse Model of Periodontitis

Shindo

Pierrelus

Ikeda

et al. 2023

Cells

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Elevated osteoclast (OC)-mediated bone resorption, a common pathological feature between periodontitis and rheumatoid arthritis (RA), implicates a possible mutually shared pathogenesis. The autoantibody to citrullinated vimentin (CV), a representative biomarker of RA, is reported to promote osteoclastogenesis (OC-genesis). However, its effect on OC-genesis in the context of periodontitis remains to be elucidated. In an in vitro experiment, the addition of exogenous CV upregulated the development of Tartrate-resistant acid phosphatase (TRAP)-positive multinuclear OCs from mouse bone marrow cells and increased the formation of resorption pits. However, Cl-amidine, an irreversible pan-peptidyl arginine deiminase (PAD) inhibitor, suppressed the production and secretion of CV from RANKL-stimulated OC precursors, suggesting that the citrullination of vimentin occurs in OC precursors. On the other hand, the anti-vimentin neutralizing antibody suppressed in vitro Receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced OC-genesis. The CV-induced upregulation of OC-genesis was abrogated by the Protein kinase C (PKC)-δ inhibitor Rottlerin, accompanied by the downmodulation of OC-genesis-related genes, including Osteoclast stimulatory transmembrane protein (OC-STAMP), TRAP and Matrix Metallopeptidase 9 (MMP9) as well as extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP)-kinase phosphorylation. Elevated levels of soluble CV and vimentin-bearing mononuclear cells were found in the bone resorption lesions of periodontitis induced in mice in the absence of an anti-CV antibody. Finally, local injection of anti-vimentin neutralizing antibody suppressed the periodontal bone loss induced in mice. Collectively, these results indicated that the extracellular release of CV promoted OC-genesis and bone resorption in periodontitis.

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PKCα and PKCδ: Friends and Rivals

Cited by 15 publications

References 379 publications

Spatiotemporal Regulation of FMNL2 by N-Terminal Myristoylation and C-Terminal Phosphorylation Drives Rapid Filopodia Formation

Spatiotemporal Regulation of FMNL2 by N-Terminal Myristoylation and C-Terminal Phosphorylation Drives Rapid Filopodia Formation

Phosphorylation of PP2Ac by PKC is a key regulatory step in the PP2A-switch-dependent AKT dephosphorylation that leads to apoptosis

Extracellular Release of Citrullinated Vimentin Directly Acts on Osteoclasts to Promote Bone Resorption in a Mouse Model of Periodontitis

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