title: Pancreatic adenocarcinoma upregulated factor promotes metastasis by regulating TLR/CXCR4 activation.
abstract: Pancreatic adenocarcinoma upregulated factor (PAUF) is overproduced in certain types of cancer. However, little is known of the tumorigenic function of PAUF. In this study, we report the X-ray crystal structure of PAUF and reveal that PAUF is a mammalian lectin normally found in plant lectins. We also identify PAUF as an endogenous ligand of Toll-like receptor 2 (TLR2) and TLR4 by screening extracellular domain receptor pools. We further confirmed the specificity of the PAUF-TLR2 interaction. PAUF induces extracellular signal-regulated kinase (ERK) phosphorylation and activates the IKK-β-mediated TPL2/MEK/ERK signaling pathway through TLR2. In agreement with the result of TLR2-mediated ERK activation by PAUF, PAUF induces increased expression of the protumorigenic cytokines RANTES and MIF in THP-1 cells. However, PAUF does not fully activate Iκ-B-α signaling pathways in THP-1 cells, and fails to translocate the p65 subunit of the nuclear factor-κB (NF-κB) complex into the nucleus, resulting in no NF-κB activation. Surprisingly, we found that PAUF also associated with the CXC chemokine receptor (CXCR4)-TLR2 complex and inhibited CXCR4-dependent, TLR2-mediated NF-κB activation. Together, these findings suggest that the new cancer-associated ligand, PAUF, may activate TLR-mediated ERK signaling to produce the protumorigenic cytokines, but inhibits TLR-mediated NF-κB signaling, thereby facilitating tumor growth and escape from innate immune surveillance.
authors.affiliation: Department of Biological Science, National Creative Research Initiative Center for Cell Division and Differentiation, Daejeon, Korea.
authors.forename: H D
authors.initials: HD
authors.lastname: Park
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.forename: Y K
authors.initials: YK
authors.lastname: Oh
authors.forename: J G
authors.initials: JG
authors.lastname: Jung
authors.forename: Y W
authors.initials: YW
authors.lastname: Park
authors.forename: K
authors.initials: K
authors.lastname: Myung
authors.forename: K-H
authors.initials: KH
authors.lastname: Kim
authors.forename: S S
authors.initials: SS
authors.lastname: Koh
authors.forename: D-S
authors.initials: DS
authors.lastname: Lim
mesh_terms: D000230:Adenocarcinoma / Q000556:secondary*; D000818:Animals; D016466:CHO Cells; D018946:Chemokine CCL5 / Q000032:analysis / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003461:Crystallography; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000032:analysis / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D019746:Intramolecular Oxidoreductases / Q000032:analysis / Q000378:metabolism; D037102:Lectins / Q000737:chemistry / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000032:analysis / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000032:analysis / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D013379:Substrate Specificity; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C483024:CCL5 protein, human; C527276:CXCR4 protein, human; D018946:Chemokine CCL5; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; D008263:Macrophage Migration-Inhibitory Factors; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C517340:ZG16B protein, human; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human
references.citation: Biochimie. 2001 Jul;83(7):645-51
references.pmid: 11522393
references.citation: Cell. 2004 Aug 6;118(3):285-96
references.pmid: 15294155
references.citation: Oncogene. 2008 Jan 7;27(2):225-33
references.pmid: 18176604
references.citation: Ann N Y Acad Sci. 2003 May;995:171-82
references.pmid: 12814949
references.citation: Structure. 1999 Dec 15;7(12):1473-82
references.pmid: 10647178
references.citation: Cancer Res. 2002 Feb 15;62(4):1093-102
references.pmid: 11861388
references.citation: Eur J Immunol. 2008 Jan;38(1):192-203
references.pmid: 18081034
references.citation: J Mol Biol. 2003 Sep 5;332(1):217-28
references.pmid: 12946359
references.citation: Structure. 2001 May 9;9(5):409-17
references.pmid: 11377201
references.citation: Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2658-62
references.pmid: 1826365
references.citation: Oncogene. 2010 Jan 7;29(1):56-67
references.pmid: 19784070
references.citation: J Biol Chem. 2005 May 27;280(21):20442-8
references.pmid: 15778223
references.citation: Nat Rev Immunol. 2004 Jul;4(7):499-511
references.pmid: 15229469
references.citation: J Immunol. 2008 Aug 15;181(4):2781-9
references.pmid: 18684969
references.citation: EMBO J. 1994 Mar 1;13(5):1003-10
references.pmid: 8131734
references.citation: Eur J Cancer. 2006 Apr;42(6):768-78
references.pmid: 16510280
references.citation: Cancer Metastasis Rev. 1987;6(3):433-52
references.pmid: 3319276
references.citation: Cancer Res. 2005 Jun 15;65(12):5009-14
references.pmid: 15958541
references.citation: Cancer Sci. 2009 May;100(5):828-36
references.pmid: 19302292
references.citation: Acta Crystallogr D Biol Crystallogr. 2003 Jan;59(Pt 1):194-6
references.pmid: 12499569
references.citation: CA Cancer J Clin. 2004 Jan-Feb;54(1):8-29
references.pmid: 14974761
references.citation: J Leukoc Biol. 2008 Oct;84(4):1092-100
references.pmid: 18625909
references.citation: Cancer Cell. 2004 Nov;6(5):459-69
references.pmid: 15542430
references.citation: Cancer Lett. 2007 Oct 28;256(2):137-65
references.pmid: 17629396
references.citation: J Natl Cancer Inst. 1990 Jan 3;82(1):4-6
references.pmid: 1688381
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3274-9
references.pmid: 16484370
references.citation: Cancer Res. 2006 Apr 1;66(7):3859-68
references.pmid: 16585214
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13532-7
references.pmid: 18765807
references.citation: Cancer Res. 2007 May 1;67(9):4346-52
references.pmid: 17483348
references.citation: Oncology. 2008;75(3-4):127-33
references.pmid: 18791328
references.citation: J Mol Biol. 2004 May 7;338(4):757-70
references.pmid: 15099743
references.citation: Cancer Metastasis Rev. 2007 Dec;26(3-4):453-67
references.pmid: 17828470
references.citation: J Immunol. 2006 Oct 1;177(7):4679-87
references.pmid: 16982907
references.citation: Nat Rev Cancer. 2005 Jan;5(1):29-41
references.pmid: 15630413