Pancreatic adenocarcinoma upregulated factor promotes metastasis by regulating TLR/CXCR4 activation.
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.
Park
H D
HD
Department of Biological Science, National Creative Research Initiative Center for Cell Division and Differentiation, Daejeon, Korea.
Lee
Y
Y
Oh
Y K
YK
Jung
J G
JG
Park
Y W
YW
Myung
K
K
Kim
K-H
KH
Koh
S S
SS
Lim
D-S
DS
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
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
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