title: 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.
abstract: 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.
authors: From the Department of Cell and Developmental Biology and Medical-Scientist Training Program, Vanderbilt University, Nashville, Tennessee 37232.
authors: Richard A
authors: RA
authors: Guyer
authors: From the Department of Cell and Developmental Biology and ian.g.macara@vanderbilt.edu.
authors: Ian G
authors: IG
authors: Macara
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019898:Autocrine Communication; D015815:Cell Adhesion Molecules / Q000235:genetics*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; C494200:Il6st protein, mouse; D015850:Interleukin-6; D016328:NF-kappa B; C115084:Pard3 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130; C115015:PKC-3 protein; D011493:Protein Kinase C
keywords: Breast Cancer; Cell Polarity; Cell Signaling; STAT3; Signal Transduction
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