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

PAR3suppresses 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 constitutiveSTAT3activity in mouse models, but the mechanism for this is unknown. Wenow 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 iota/lambda (aPKC iota/lambda) mediates this effect by stimulating NF-kappa B signaling and IL-6 expression. Our results suggest that PAR3 restrains aPKC iota/lambda activity and thus prevents aPKC iota/lambda from activating an oncogenic signaling network.