RRC ID 51695
Author Wakita M, Edamatsu H, Li M, Emi A, Kitazawa S, Kataoka T.
Title Phospholipase Cϵ Activates Nuclear Factor-κB Signaling by Causing Cytoplasmic Localization of Ribosomal S6 Kinase and Facilitating Its Phosphorylation of Inhibitor κB in Colon Epithelial Cells.
Journal J Biol Chem
Abstract Phospholipase Cϵ (PLCϵ), an effector of Ras and Rap small GTPases, plays a crucial role in inflammation by augmenting proinflammatory cytokine expression. This proinflammatory function of PLCϵ is implicated in its facilitative role in tumor promotion and progression during skin and colorectal carcinogenesis, although their direct link remains to be established. Moreover, the molecular mechanism underlying these functions of PLCϵ remains unknown except that PKD works downstream of PLCϵ. Here we show by employing the colitis-induced colorectal carcinogenesis model, where Apc(Min) (/+) mice are administered with dextran sulfate sodium, that PLCϵ knock-out alleviates the colitis and suppresses the following tumorigenesis concomitant with marked attenuation of proinflammatory cytokine expression. In human colon epithelial Caco2 cells, TNF-α induces sustained expression of proinflammatory molecules and sustained activation of nuclear factor-κB (NF-κB) and PKD, the late phases of which are suppressed by not only siRNA-mediated PLCϵ knockdown but also treatment with a lysophosphatidic acid (LPA) receptor antagonist. Also, LPA stimulation induces these events in an early time course, suggesting that LPA mediates TNF-α signaling in an autocrine manner. Moreover, PLCϵ knockdown results in inhibition of phosphorylation of IκB by ribosomal S6 kinase (RSK) but not by IκB kinases. Subcellular fractionation suggests that enhanced phosphorylation of a scaffolding protein, PEA15 (phosphoprotein enriched in astrocytes 15), downstream of the PLCϵ-PKD axis causes sustained cytoplasmic localization of phosphorylated RSK, thereby facilitating IκB phosphorylation in the cytoplasm. These results suggest the crucial role of the TNF-α-LPA-LPA receptor-PLCϵ-PKD-PEA15-RSK-IκB-NF-κB pathway in facilitating inflammation and inflammation-associated carcinogenesis in the colon.
Volume 291(24)
Pages 12586-600
Published 2016-6-10
DOI 10.1074/jbc.M116.717561
PII M116.717561
PMID 27053111
PMC PMC4933442
MeSH Adenomatous Polyposis Coli Protein / genetics Adenomatous Polyposis Coli Protein / metabolism Animals Apoptosis Regulatory Proteins Caco-2 Cells Colitis / genetics Colitis / metabolism Colon / metabolism Colon / pathology Colorectal Neoplasms / genetics Colorectal Neoplasms / metabolism Cytoplasm / enzymology Epithelial Cells / metabolism* Humans I-kappa B Proteins / metabolism Immunoblotting Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism Lysophospholipids / pharmacology Mice, Inbred C57BL Mice, Knockout NF-KappaB Inhibitor alpha NF-kappa B / metabolism* Phosphoinositide Phospholipase C / genetics Phosphoinositide Phospholipase C / metabolism* Phosphoproteins / genetics Phosphoproteins / metabolism Phosphorylation / drug effects Protein Kinase C / metabolism RNA Interference Receptors, Lysophosphatidic Acid / genetics Receptors, Lysophosphatidic Acid / metabolism Reverse Transcriptase Polymerase Chain Reaction Ribosomal Protein S6 Kinases / genetics Ribosomal Protein S6 Kinases / metabolism* Signal Transduction* Tumor Necrosis Factor-alpha / genetics Tumor Necrosis Factor-alpha / metabolism Tumor Necrosis Factor-alpha / pharmacology
IF 4.238
Times Cited 5
Human and Animal Cells CACO-2(RCB0988)