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Title 

Pancreatic adenocarcinoma upregulated factor promotes metastasis by regulating TLR/CXCR4 activation

Authors 

H D ParkY LeeY K OhJ G JungYoung Woo ParkK MyungK H KimSang Seok KohD S Lim

Publisher 

Nature Publishing Group

Issue Date 

2011

Citation 

Oncogene, vol. 30, no. 2, pp. 201-211

Keywords 

CXCR4ERKNF-κBPAUFTLRTPL2

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 I-B-α signaling pathways in THP-1 cells, and fails to translocate the p65 subunit of the nuclear factor-B (NF-B) complex into the nucleus, resulting in no NF-B activation. Surprisingly, we found that PAUF also associated with the CXC chemokine receptor (CXCR4)-TLR2 complex and inhibited CXCR4-dependent, TLR2-mediated NF-B 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-B signaling, thereby facilitating tumor growth and escape from innate immune surveillance.

ISSN 

0950-9232

Link 

http://dx.doi.org/10.1038/onc.2010.401

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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