Guyer Richard A, Macara Ian G
From the Department of Cell and Developmental Biology and Medical-Scientist Training Program, Vanderbilt University, Nashville, Tennessee 37232.
From the Department of Cell and Developmental Biology and
J Biol Chem. 2015 Mar 27;290(13):8457-68. doi: 10.1074/jbc.M114.621011. Epub 2015 Feb 5.
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.
PAR3在体内可抑制肿瘤生长和转移，在体外可抑制细胞通过基质的侵袭。我们认为PAR3可组织并限制多种信号通路，且这些通路在没有PAR3的情况下会发生不适当的激活。在小鼠模型中，Pard3基因沉默与致癌激活共同作用可通过组成型STAT3活性促进侵袭和转移，但其机制尚不清楚。我们现在发现，PAR3缺失会触发白细胞介素-6的产生增加，白细胞介素-6以自分泌方式诱导STAT3信号传导。非典型蛋白激酶Cι/λ（aPKCι/λ）的激活通过刺激NF-κB信号传导和IL-6表达介导此效应。我们的结果表明，PAR3抑制aPKCι/λ活性，从而防止aPKCι/λ激活致癌信号网络。
