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

被引:26
作者
Guyer, Richard A. [1 ,2 ]
Macara, Ian G. [1 ]
机构
[1] Vanderbilt Univ, Dept Cell & Dev Biol, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Scientist Training Program, Nashville, TN 37232 USA
基金
美国国家卫生研究院;
关键词
NF-KAPPA-B; TUMOR-SUPPRESSOR; ONCOGENIC RAS; ZETA; TUMORIGENESIS; INTERLEUKIN-6; IOTA; PHOSPHORYLATION; EXPRESSION; GROWTH;
D O I
10.1074/jbc.M114.621011
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:8457 / 8468
页数:12
相关论文
共 57 条
[1]   NEOPLASTIC TRANSFORMATION AND ABERRANT CELL-CELL INTERACTIONS IN GENETIC MOSAICS OF LETHAL(2)GIANT LARVAE (LGL), A TUMOR-SUPPRESSOR GENE OF DROSOPHILA [J].
AGRAWAL, N ;
KANGO, M ;
MISHRA, A ;
SINHA, P .
DEVELOPMENTAL BIOLOGY, 1995, 172 (01) :218-229
[2]   Constitutively Active Stat3 Enhances Neu-Mediated Migration and Metastasis in Mammary Tumors via Upregulation of Cten [J].
Barbieri, Isaia ;
Pensa, Sara ;
Pannellini, Tania ;
Quaglino, Elena ;
Maritano, Diego ;
Demaria, Marco ;
Voster, Alessandra ;
Turkson, James ;
Cavallo, Federica ;
Watson, Christine J. ;
Provero, Paolo ;
Musiani, Piero ;
Poli, Valeria .
CANCER RESEARCH, 2010, 70 (06) :2558-2567
[3]   Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression [J].
Basseres, D. S. ;
Baldwin, A. S. .
ONCOGENE, 2006, 25 (51) :6817-6830
[4]   Nf2/Merlin controls progenitor homeostasis and tumorigenesis in the liver [J].
Benhamouche, Samira ;
Curto, Marcello ;
Saotome, Ichiko ;
Gladden, Andrew B. ;
Liu, Ching-Hui ;
Giovannini, Marco ;
McClatchey, Andrea I. .
GENES & DEVELOPMENT, 2010, 24 (16) :1718-1730
[5]   Notch Signaling Regulates Mammary Stem Cell Function and Luminal Cell-Fate Commitment [J].
Bouras, Toula ;
Pal, Bhupinder ;
Vaillant, Francois ;
Harburg, Gwyndolen ;
Asselin-Labat, Marie-Liesse ;
Oakes, Samantha R. ;
Lindeman, Geoffrey J. ;
Visvader, Jane E. .
CELL STEM CELL, 2008, 3 (04) :429-441
[6]   scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila [J].
Brumby, AM ;
Richardson, HE .
EMBO JOURNAL, 2003, 22 (21) :5769-5779
[7]   Emerging role of cell polarity proteins in breast cancer progression and metastasis [J].
Chatterjee, Sudipa June ;
McCaffrey, Luke .
BREAST CANCER-TARGETS AND THERAPY, 2014, 6 :15-27
[8]   STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation [J].
Chung, JK ;
Uchida, E ;
Grammer, TC ;
Blenis, J .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (11) :6508-6516
[9]   Oncogenic Ras Diverts a Host TNF Tumor Suppressor Activity into Tumor Promoter [J].
Cordero, Julia B. ;
Macagno, Juan P. ;
Stefanatos, Rhoda K. ;
Strathdee, Karen E. ;
Cagan, Ross L. ;
Vidal, Marcos .
DEVELOPMENTAL CELL, 2010, 18 (06) :999-1011
[10]   Stat3 regulates genes common to both wound healing and cancer [J].
Dauer, DJ ;
Ferraro, B ;
Song, LX ;
Yu, B ;
Mora, L ;
Buettner, R ;
Enkemann, S ;
Jove, R ;
Haura, EB .
ONCOGENE, 2005, 24 (21) :3397-3408