title: Ribosomal protein S6 kinase (RSK)-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein.
abstract: BACKGROUND
  Epithelial to mesenchymal transition (EMT) occurs during cancer cell invasion and malignant metastasis. Features of EMT include spindle-like cell morphology, loss of epithelial cellular markers and gain of mesenchymal phenotype. Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein (MSP) has been implicated in cellular EMT program; however, the major signaling determinant(s) responsible for MSP-induced EMT is unknown.
  
  
  RESULTS
  The study presented here demonstrates that RSK2, a downstream signaling protein of the Ras-Erk1/2 pathway, is the principal molecule that links MSP-activated RON signaling to complete EMT. Using MDCK cells expressing RON as a model, a spindle-shape based screen was conducted, which identifies RSK2 among various intracellular proteins as a potential signaling molecule responsible for MSP-induced EMT. MSP stimulation dissociated RSK2 with Erk1/2 and promoted RSK2 nuclear translocation. MSP strongly induced RSK2 phosphorylation in a dose-dependent manner. These effects relied on RON and Erk1/2 phosphorylation, which is significantly potentiated by transforming growth factor (TGF)-β1, an EMT-inducing cytokine. Specific RSK inhibitor SL0101 completely prevented MSP-induced RSK phosphorylation, which results in inhibition of MSP-induced spindle-like morphology and suppression of cell migration associated with EMT. In HT-29 cancer cells that barely express RSK2, forced RSK2 expression results in EMT-like phenotype upon MSP stimulation. Moreover, specific siRNA-mediated silencing of RSK2 but not RSK1 in L3.6pl pancreatic cancer cells significantly inhibited MSP-induced EMT-like phenotype and cell migration.
  
  
  CONCLUSIONS
  MSP-induced RSK2 activation is a critical determinant linking RON signaling to cellular EMT program. Inhibition of RSK2 activity may provide a therapeutic opportunity for blocking RON-mediated cancer cell migration and subsequent invasion.
authors: Division of Cancer Biology at State Key Laboratory for Diagnosis & Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou 310003, China.
authors: Qi
authors: Q
authors: Ma
authors: Sunny
authors: S
authors: Guin
authors: Snehal S
authors: SS
authors: Padhye
authors: Yong-Qing
authors: YQ
authors: Zhou
authors: Rui-Wen
authors: RW
authors: Zhang
authors: Ming-Hai
authors: MH
authors: Wang
references: Nat Rev Cancer. 2002 Apr;2(4):289-300
references: 12001990
references: Biochem Biophys Res Commun. 2007 Aug 17;360(1):219-25
references: 17588532
references: Cancer Res. 2010 May 15;70(10):4174-84
references: 20424117
references: Cancer Res. 2005 Feb 1;65(3):1027-34
references: 15705904
references: Oncogene. 1996 Nov 21;13(10):2167-75
references: 8950984
references: Cancer Res. 2010 Feb 1;70(3):1130-40
references: 20103639
references: Oncogene. 2010 Dec 9;29(49):6485-98
references: 20802523
references: Carcinogenesis. 2008 Mar;29(3):552-9
references: 18204077
references: Oncogene. 2010 Aug 5;29(31):4436-48
references: 20543867
references: Oncogene. 2005 Aug 29;24(37):5764-74
references: 16123809
references: Cell. 2008 May 16;133(4):704-15
references: 18485877
references: Stem Cell Rev. 2007 Jan;3(1):18-29
references: 17873378
references: Scand J Immunol. 2002 Dec;56(6):545-53
references: 12472665
references: Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1124-9
references: 20080645
references: Adv Cancer Res. 2008;100:1-33
references: 18620091
references: J Biol Chem. 1997 Aug 22;272(34):21281-8
references: 9261139
references: J Clin Invest. 2009 Jun;119(6):1420-8
references: 19487818
references: Mol Cell. 2010 Apr 9;38(1):114-27
references: 20385094
references: Science. 1994 Oct 7;266(5182):117-9
references: 7939629
references: Cancer Res. 2010 Sep 1;70(17):6715-24
references: 20736375
references: Mol Cell Biol. 2003 Jul;23(14):4796-804
references: 12832467
references: Mol Cancer. 2010 Nov 29;9:307
references: 21114864
references: Cancer. 2007 Mar 15;109(6):1030-9
references: 17311308
references: Br J Cancer. 2010 Nov 23;103(11):1716-23
references: 21063401
references: J Cell Biol. 2010 Oct 4;191(1):87-99
references: 20876280
references: Mol Cell Biol. 1999 Feb;19(2):1427-37
references: 9891076
references: Genes Dev. 2010 Dec 1;24(23):2654-65
references: 21062900
references: Mol Biol Cell. 2004 Jul;15(7):3106-13
references: 15107468
references: Am J Pathol. 2010 May;176(5):2247-58
references: 20304956
references: Mol Cell Biol. 2004 Mar;24(5):1823-35
references: 14966265
references: Oncogene. 2004 Mar 4;23(9):1668-80
references: 15001985
references: Carcinogenesis. 2011 Feb;32(2):175-81
references: 21081472
references: Cancer Res. 2006 Dec 1;66(23):11271-8
references: 17145872
references: Mol Cell Biol. 2001 Nov;21(21):7470-80
references: 11585927
references: Oncogene. 2008 Nov 24;27(55):6958-69
references: 19029937
references: Cancer Res. 2008 Aug 15;68(16):6680-7
references: 18701492
references: Cancer Cell. 2010 Apr 13;17(4):319-32
references: 20385358
references: Cell. 2009 Nov 25;139(5):871-90
references: 19945376
references: Oncogene. 2010 Aug 26;29(34):4741-51
references: 20531305
references: J Biol Chem. 1993 Jul 25;268(21):15461-8
references: 8393443
references: Oncogene. 2010 Jan 14;29(2):214-26
references: 19838218
references: Cancer Res. 2008 Jul 1;68(13):5185-92
references: 18593918
references: Cancer Lett. 2007 Nov 18;257(2):157-64
references: 17889431
references: Nat Rev Cancer. 2009 Apr;9(4):265-73
references: 19262571
references: J Biol Chem. 2005 Jul 1;280(26):25087-94
references: 15878878
references: J Clin Invest. 2009 Jun;119(6):1417-9
references: 19487817
references: Mol Cell. 2009 Aug 28;35(4):511-22
references: 19716794
references: Cancer Res. 2006 Sep 1;66(17):8319-26
references: 16951136
references: Neoplasia. 2004 Sep-Oct;6(5):603-10
references: 15548370
references: Nat Rev Mol Cell Biol. 2008 Oct;9(10):747-58
references: 18813292
references: Cancer Biol Ther. 2006 Sep;5(9):1179-86
references: 16880737