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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenocarcinoma / secondary*
-
Animals
-
CHO Cells
-
Chemokine CCL5 / analysis
-
Chemokine CCL5 / metabolism
-
Cricetinae
-
Cricetulus
-
Crystallography
-
Extracellular Signal-Regulated MAP Kinases / analysis
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
HEK293 Cells
-
Humans
-
I-kappa B Kinase / analysis
-
I-kappa B Kinase / metabolism
-
Intercellular Signaling Peptides and Proteins
-
Intramolecular Oxidoreductases / analysis
-
Intramolecular Oxidoreductases / metabolism
-
Lectins / chemistry
-
Lectins / metabolism*
-
MAP Kinase Kinase Kinases / analysis
-
MAP Kinase Kinase Kinases / metabolism
-
Macrophage Migration-Inhibitory Factors / analysis
-
Macrophage Migration-Inhibitory Factors / metabolism
-
Pancreatic Neoplasms / metabolism
-
Pancreatic Neoplasms / pathology*
-
Phosphorylation
-
Protein Binding
-
Protein Structure, Tertiary
-
Proto-Oncogene Proteins / analysis
-
Proto-Oncogene Proteins / metabolism
-
Receptors, CXCR4 / metabolism*
-
Substrate Specificity
-
Toll-Like Receptor 2 / metabolism*
-
Toll-Like Receptor 4 / metabolism*
-
Up-Regulation
Substances
-
CCL5 protein, human
-
CXCR4 protein, human
-
Chemokine CCL5
-
Intercellular Signaling Peptides and Proteins
-
Lectins
-
Macrophage Migration-Inhibitory Factors
-
Proto-Oncogene Proteins
-
Receptors, CXCR4
-
TLR2 protein, human
-
TLR4 protein, human
-
Toll-Like Receptor 2
-
Toll-Like Receptor 4
-
ZG16B protein, human
-
I-kappa B Kinase
-
Extracellular Signal-Regulated MAP Kinases
-
MAP Kinase Kinase Kinases
-
MAP3K8 protein, human
-
Intramolecular Oxidoreductases
-
MIF protein, human