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Dendritic Cell Amiloride-Sensitive Channels Mediate Sodium-Induced Inflammation and Hypertension.
Barbaro NR, Foss JD, Kryshtal DO, Tsyba N, Kumaresan S, Xiao L, Mernaugh RL, Itani HA, Loperena R, Chen W, Dikalov S, Titze JM, Knollmann BC, Harrison DG, Kirabo A
(2017) Cell Rep 21: 1009-1020
MeSH Terms: Amiloride, Animals, Cells, Cultured, Cytokines, Dendritic Cells, Epithelial Sodium Channel Blockers, Epithelial Sodium Channels, Hypertension, Inflammation, Male, Mice, Mice, Inbred C57BL, NADPH Oxidases, Oxidative Stress, Prostaglandins E, Protein Kinase C, Sodium, Sodium-Hydrogen Exchanger 1, Superoxides
Show Abstract · Added December 27, 2017
Sodium accumulates in the interstitium and promotes inflammation through poorly defined mechanisms. We describe a pathway by which sodium enters dendritic cells (DCs) through amiloride-sensitive channels including the alpha and gamma subunits of the epithelial sodium channel and the sodium hydrogen exchanger 1. This leads to calcium influx via the sodium calcium exchanger, activation of protein kinase C (PKC), phosphorylation of p47, and association of p47 with gp91. The assembled NADPH oxidase produces superoxide with subsequent formation of immunogenic isolevuglandin (IsoLG)-protein adducts. DCs activated by excess sodium produce increased interleukin-1β (IL-1β) and promote T cell production of cytokines IL-17A and interferon gamma (IFN-γ). When adoptively transferred into naive mice, these DCs prime hypertension in response to a sub-pressor dose of angiotensin II. These findings provide a mechanistic link between salt, inflammation, and hypertension involving increased oxidative stress and IsoLG production in DCs.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
2 Members
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19 MeSH Terms
EGFR signalling controls cellular fate and pancreatic organogenesis by regulating apicobasal polarity.
Löf-Öhlin ZM, Nyeng P, Bechard ME, Hess K, Bankaitis E, Greiner TU, Ameri J, Wright CV, Semb H
(2017) Nat Cell Biol 19: 1313-1325
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Polarity, Epithelial Cells, ErbB Receptors, Insulin-Secreting Cells, Mice, Mice, Knockout, Morphogenesis, Nerve Tissue Proteins, Neuropeptides, Organogenesis, Phosphatidylinositol 3-Kinases, Protein Kinase C, Signal Transduction, rac1 GTP-Binding Protein
Show Abstract · Added November 7, 2017
Apicobasal polarity is known to affect epithelial morphogenesis and cell differentiation, but it remains unknown how these processes are mechanistically orchestrated. We find that ligand-specific EGFR signalling via PI(3)K and Rac1 autonomously modulates apicobasal polarity to enforce the sequential control of morphogenesis and cell differentiation. Initially, EGF controls pancreatic tubulogenesis by negatively regulating apical polarity induction. Subsequently, betacellulin, working via inhibition of atypical protein kinase C (aPKC), causes apical domain constriction within neurogenin3 endocrine progenitors, which results in reduced Notch signalling, increased neurogenin3 expression, and β-cell differentiation. Notably, the ligand-specific EGFR output is not driven at the ligand level, but seems to have evolved in response to stage-specific epithelial influences. The EGFR-mediated control of β-cell differentiation via apical polarity is also conserved in human neurogenin3 cells. We provide insight into how ligand-specific EGFR signalling coordinates epithelial morphogenesis and cell differentiation via apical polarity dynamics.
2 Communities
1 Members
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17 MeSH Terms
Camptothecin resistance is determined by the regulation of topoisomerase I degradation mediated by ubiquitin proteasome pathway.
Ando K, Shah AK, Sachdev V, Kleinstiver BP, Taylor-Parker J, Welch MM, Hu Y, Salgia R, White FM, Parvin JD, Ozonoff A, Rameh LE, Joung JK, Bharti AK
(2017) Oncotarget 8: 43733-43751
MeSH Terms: BRCA1 Protein, Camptothecin, Cell Line, Tumor, DNA Topoisomerases, Type I, DNA-Binding Proteins, Drug Resistance, Neoplasm, Gene Editing, Humans, Ku Autoantigen, Multiprotein Complexes, PTEN Phosphohydrolase, Phosphorylation, Proteasome Endopeptidase Complex, Protein Binding, Protein Kinase C, Proteolysis, RNA Interference, Topoisomerase I Inhibitors, Ubiquitin
Show Abstract · Added November 26, 2018
Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1. A higher basal level of topoI-pS10 ensures rapid topoI degradation leading to CPT resistance. Importantly, PTEN regulates DNA-PKcs kinase activity in this pathway and PTEN deletion ensures DNA-PKcs dependent higher topoI-pS10, rapid topoI degradation and CPT resistance.
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MeSH Terms
Modeling the roles of protein kinase Cβ and η in single-cell wound repair.
Holmes WR, Liao L, Bement W, Edelstein-Keshet L
(2015) Mol Biol Cell 26: 4100-8
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Models, Biological, Oocytes, Protein Kinase C, Protein Kinase C beta, Single-Cell Analysis, Wound Healing, Xenopus laevis, rho GTP-Binding Proteins
Show Abstract · Added February 26, 2016
Wounded cells such as Xenopus oocytes respond to damage by assembly and closure of an array of actin filaments and myosin-2 controlled by Rho GTPases, including Rho and Cdc42. Rho and Cdc42 are patterned around wounds in a characteristic manner, with active Rho concentrating in a ring-like zone inside a larger, ring-like zone of active Cdc42. How this patterning is achieved is unknown, but Rho and Cdc42 at wounds are subject to regulation by other proteins, including the protein kinases C. Specifically, Cdc42 and Rho activity are enhanced by PKCβ and inhibited by PKCη. We adapt a mathematical model of Simon and coworkers to probe the possible roles of these kinases. We show that PKCβ likely affects the magnitude of positive Rho-Abr feedback, whereas PKCη acts on Cdc42 inactivation. The model explains both qualitative and some overall quantitative features of PKC-Rho GTPase regulation. It also accounts for the previous, peculiar observation that ∼ 20% of cells overexpressing PKCη display zone inversions--that is, displacement of active Rho to the outside of the active Cdc42.
© 2015 Holmes, Liao, et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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1 Members
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11 MeSH Terms
"Slow" Voltage-Dependent Inactivation of CaV2.2 Calcium Channels Is Modulated by the PKC Activator Phorbol 12-Myristate 13-Acetate (PMA).
Zhu L, McDavid S, Currie KP
(2015) PLoS One 10: e0134117
MeSH Terms: Animals, Calcium Channel Blockers, Calcium Channels, N-Type, Calcium Signaling, Cattle, Cells, Cultured, Chromaffin Cells, Enzyme Activation, Guanosine Diphosphate, HEK293 Cells, Humans, Kinetics, Patch-Clamp Techniques, Protein Kinase C, Recombinant Proteins, Tetradecanoylphorbol Acetate, Thionucleotides
Show Abstract · Added November 10, 2015
CaV2.2 (N-type) voltage-gated calcium channels (Ca2+ channels) play key roles in neurons and neuroendocrine cells including the control of cellular excitability, neurotransmitter / hormone secretion, and gene expression. Calcium entry is precisely controlled by channel gating properties including multiple forms of inactivation. "Fast" voltage-dependent inactivation is relatively well-characterized and occurs over the tens-to- hundreds of milliseconds timeframe. Superimposed on this is the molecularly distinct, but poorly understood process of "slow" voltage-dependent inactivation, which develops / recovers over seconds-to-minutes. Protein kinases can modulate "slow" inactivation of sodium channels, but little is known about if/how second messengers control "slow" inactivation of Ca2+ channels. We investigated this using recombinant CaV2.2 channels expressed in HEK293 cells and native CaV2 channels endogenously expressed in adrenal chromaffin cells. The PKC activator phorbol 12-myristate 13-acetate (PMA) dramatically prolonged recovery from "slow" inactivation, but an inactive control (4α-PMA) had no effect. This effect of PMA was prevented by calphostin C, which targets the C1-domain on PKC, but only partially reduced by inhibitors that target the catalytic domain of PKC. The subtype of the channel β-subunit altered the kinetics of inactivation but not the magnitude of slowing produced by PMA. Intracellular GDP-β-S reduced the effect of PMA suggesting a role for G proteins in modulating "slow" inactivation. We postulate that the kinetics of recovery from "slow" inactivation could provide a molecular memory of recent cellular activity and help control CaV2 channel availability, electrical excitability, and neurotransmission in the seconds-to-minutes timeframe.
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17 MeSH Terms
mTOR Directs Breast Morphogenesis through the PKC-alpha-Rac1 Signaling Axis.
Morrison MM, Young CD, Wang S, Sobolik T, Sanchez VM, Hicks DJ, Cook RS, Brantley-Sieders DM
(2015) PLoS Genet 11: e1005291
MeSH Terms: Animals, Carrier Proteins, Cell Line, Cell Movement, Cell Survival, Female, Mammary Glands, Animal, Mammary Neoplasms, Animal, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Inbred C57BL, Mice, Transgenic, Morphogenesis, Multiprotein Complexes, Neoplasm Invasiveness, Neuropeptides, Organ Culture Techniques, Phosphorylation, Protein Kinase C-alpha, Proto-Oncogene Proteins c-akt, Rapamycin-Insensitive Companion of mTOR Protein, TOR Serine-Threonine Kinases, rac1 GTP-Binding Protein
Show Abstract · Added April 15, 2019
Akt phosphorylation is a major driver of cell survival, motility, and proliferation in development and disease, causing increased interest in upstream regulators of Akt like mTOR complex 2 (mTORC2). We used genetic disruption of Rictor to impair mTORC2 activity in mouse mammary epithelia, which decreased Akt phosphorylation, ductal length, secondary branching, cell motility, and cell survival. These effects were recapitulated with a pharmacological dual inhibitor of mTORC1/mTORC2, but not upon genetic disruption of mTORC1 function via Raptor deletion. Surprisingly, Akt re-activation was not sufficient to rescue cell survival or invasion, and modestly increased branching of mTORC2-impaired mammary epithelial cells (MECs) in culture and in vivo. However, another mTORC2 substrate, protein kinase C (PKC)-alpha, fully rescued mTORC2-impaired MEC branching, invasion, and survival, as well as branching morphogenesis in vivo. PKC-alpha-mediated signaling through the small GTPase Rac1 was necessary for mTORC2-dependent mammary epithelial development during puberty, revealing a novel role for Rictor/mTORC2 in MEC survival and motility during branching morphogenesis through a PKC-alpha/Rac1-dependent mechanism.
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MeSH Terms
The RNA binding protein FXR1 is a new driver in the 3q26-29 amplicon and predicts poor prognosis in human cancers.
Qian J, Hassanein M, Hoeksema MD, Harris BK, Zou Y, Chen H, Lu P, Eisenberg R, Wang J, Espinosa A, Ji X, Harris FT, Rahman SM, Massion PP
(2015) Proc Natl Acad Sci U S A 112: 3469-74
MeSH Terms: Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cell Line, Tumor, Cell Proliferation, Chromosomes, Human, Pair 3, DNA Copy Number Variations, Gene Expression Regulation, Neoplastic, Humans, Isoenzymes, Lung Neoplasms, Prognosis, Protein Kinase C, Proto-Oncogene Proteins, RNA, Messenger, RNA-Binding Proteins, Survival Analysis, Treatment Outcome
Show Abstract · Added February 16, 2016
Aberrant expression of RNA-binding proteins has profound implications for cellular physiology and the pathogenesis of human diseases such as cancer. We previously identified the Fragile X-Related 1 gene (FXR1) as one amplified candidate driver gene at 3q26-29 in lung squamous cell carcinoma (SCC). FXR1 is an autosomal paralog of Fragile X mental retardation 1 and has not been directly linked to human cancers. Here we demonstrate that FXR1 is a key regulator of tumor progression and its overexpression is critical for nonsmall cell lung cancer (NSCLC) cell growth in vitro and in vivo. We identified the mechanisms by which FXR1 executes its regulatory function by forming a novel complex with two other oncogenes, protein kinase C, iota and epithelial cell transforming 2, located in the same amplicon via distinct binding mechanisms. FXR1 expression is a candidate biomarker predictive of poor survival in multiple solid tumors including NSCLCs. Because FXR1 is overexpressed and associated with poor clinical outcomes in multiple cancers, these results have implications for other solid malignancies.
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1 Members
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17 MeSH Terms
Loss of the polarity protein PAR3 activates STAT3 signaling via an atypical protein kinase C (aPKC)/NF-κB/interleukin-6 (IL-6) axis in mouse mammary cells.
Guyer RA, Macara IG
(2015) J Biol Chem 290: 8457-68
MeSH Terms: Animals, Autocrine Communication, Cell Adhesion Molecules, Cells, Cultured, Cytokine Receptor gp130, Enzyme Activation, Epithelial Cells, Female, Interleukin-6, Mammary Glands, Animal, Mice, Inbred C3H, NF-kappa B, Phosphorylation, Protein Kinase C, Protein Processing, Post-Translational, STAT3 Transcription Factor, Signal Transduction
Show Abstract · Added April 10, 2018
PAR3 suppresses tumor growth and metastasis in vivo and cell invasion through matrix in vitro. We propose that PAR3 organizes and limits multiple signaling pathways and that inappropriate activation of these pathways occurs without PAR3. Silencing Pard3 in conjunction with oncogenic activation promotes invasion and metastasis via constitutive STAT3 activity in mouse models, but the mechanism for this is unknown. We now show that loss of PAR3 triggers increased production of interleukin-6, which induces STAT3 signaling in an autocrine manner. Activation of atypical protein kinase C ι/λ (aPKCι/λ) mediates this effect by stimulating NF-κB signaling and IL-6 expression. Our results suggest that PAR3 restrains aPKCι/λ activity and thus prevents aPKCι/λ from activating an oncogenic signaling network.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
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MeSH Terms
Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways.
Wang S, Amato KR, Song W, Youngblood V, Lee K, Boothby M, Brantley-Sieders DM, Chen J
(2015) Mol Cell Biol 35: 1299-313
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Proliferation, Cells, Cultured, Endothelial Cells, Gene Deletion, Human Umbilical Vein Endothelial Cells, Humans, Mechanistic Target of Rapamycin Complex 2, Mice, Multiprotein Complexes, Neovascularization, Physiologic, Phosphorylation, Protein Kinase C-alpha, Proto-Oncogene Proteins c-akt, Rapamycin-Insensitive Companion of mTOR Protein, Regulatory-Associated Protein of mTOR, Signal Transduction, TOR Serine-Threonine Kinases, Vascular Endothelial Growth Factor A
Show Abstract · Added February 15, 2016
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a diverse array of cellular processes, including cell growth, survival, metabolism, and cytoskeleton dynamics. mTOR functions in two distinct complexes, mTORC1 and mTORC2, whose activities and substrate specificities are regulated by complex specific cofactors, including Raptor and Rictor, respectively. Little is known regarding the relative contribution of mTORC1 versus mTORC2 in vascular endothelial cells. Using mouse models of Raptor or Rictor gene targeting, we discovered that Rictor ablation inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation and assembly in vitro and angiogenesis in vivo, whereas the loss of Raptor had only a modest effect on endothelial cells (ECs). Mechanistically, the loss of Rictor reduced the phosphorylation of AKT, protein kinase Cα (PKCα), and NDRG1 without affecting the mTORC1 pathway. In contrast, the loss of Raptor increased the phosphorylation of AKT despite inhibiting the phosphorylation of S6K1, a direct target of mTORC1. Reconstitution of Rictor-null cells with myristoylated AKT (Myr-AKT) rescued vascular assembly in Rictor-deficient endothelial cells, whereas PKCα rescued proliferation defects. Furthermore, tumor neovascularization in vivo was significantly decreased upon EC-specific Rictor deletion in mice. These data indicate that mTORC2 is a critical signaling node required for VEGF-mediated angiogenesis through the regulation of AKT and PKCα in vascular endothelial cells.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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21 MeSH Terms
Global phosphotyrosine proteomics identifies PKCδ as a marker of responsiveness to Src inhibition in colorectal cancer.
McKinley ET, Liu H, McDonald WH, Luo W, Zhao P, Coffey RJ, Hanks SK, Manning HC
(2013) PLoS One 8: e80207
MeSH Terms: Animals, Antigens, CD, Biomarkers, Tumor, Caco-2 Cells, Cell Adhesion Molecules, Cell Line, Tumor, Colorectal Neoplasms, Dasatinib, HCT116 Cells, Humans, Mice, Mice, Nude, Neoplasm Proteins, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Phosphoric Monoester Hydrolases, Phosphotyrosine, Protein Kinase C-delta, Protein Kinase Inhibitors, Proteome, Proteomics, Pyrimidines, Receptor-Like Protein Tyrosine Phosphatases, Class 5, Thiazoles, src-Family Kinases
Show Abstract · Added March 20, 2014
Sensitive and specific biomarkers of protein kinase inhibition can be leveraged to accelerate drug development studies in oncology by associating early molecular responses with target inhibition. In this study, we utilized unbiased shotgun phosphotyrosine (pY) proteomics to discover novel biomarkers of response to dasatinib, a small molecule Src-selective inhibitor, in preclinical models of colorectal cancer (CRC). We performed unbiased mass spectrometry shotgun pY proteomics to reveal the pY proteome of cultured HCT-116 colonic carcinoma cells, and then extended this analysis to HCT-116 xenograft tumors to identify pY biomarkers of dasatinib-responsiveness in vivo. Major dasatinib-responsive pY sites in xenograft tumors included sites on delta-type protein kinase C (PKCδ), CUB-domain-containing protein 1 (CDCP1), Type-II SH2-domain-containing inositol 5-phosphatase (SHIP2), and receptor protein-tyrosine phosphatase alpha (RPTPα). The pY313 site PKCδ was further supported as a relevant biomarker of dasatinib-mediated Src inhibition in HCT-116 xenografts by immunohistochemistry and immunoblotting with a phosphospecific antibody. Reduction of PKCδ pY313 was further correlated with dasatinib-mediated inhibition of Src and diminished growth as spheroids of a panel of human CRC cell lines. These studies reveal PKCδ pY313 as a promising readout of Src inhibition in CRC and potentially other solid tumors and may reflect responsiveness to dasatinib in a subset of colorectal cancers.
1 Communities
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24 MeSH Terms