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
J Biol Chem. 2015 290 (13): 8457-68

PMID: 25657002 · PMCID: PMC4375497 · DOI:10.1074/jbc.M114.621011

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.

MeSH Terms (17)

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 Signal Transduction STAT3 Transcription Factor

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