Abstract
BackgroundTEM8 is a cell membrane protein predominantly expressed in tumor endothelium, which serves as a receptor for the protective antigen (PA) of anthrax toxin. However, the physiological ligands for TEM8 remain unknown.ResultsHere we identified uPA as an interacting partner of TEM8. Binding of uPA stimulated the phosphorylation of TEM8 and augmented phosphorylation of EGFR and ERK1/2. Finally, TEM8-Fc, a recombinant fusion protein comprising the extracellular domain of human TEM8 linked to the Fc portion of human IgG1, efficiently abrogated the interaction between uPA and TEM8, blocked uPA-induced migration of HepG2 cells in vitro and inhibited the growth and metastasis of human MCF-7 xenografts in vivo. uPA, TEM8 and EGFR overexpression and ERK1/2 phosphorylation were found co-located on frozen cancer tissue sections.ConclusionsTaken together, our data provide evidence that TEM8 is a novel receptor for uPA, which may play a significant role in the regulation of tumor growth and metastasis.
Highlights
Tumor endothelial marker 8 (TEM8) is a cell membrane protein predominantly expressed in tumor endothelium, which serves as a receptor for the protective antigen (PA) of anthrax toxin
The region of Urokinase-type plasminogen activator (uPA) responsible for binding to TEM8 is distinct from the interaction domain for uPAR As mentioned above, there are three forms of uPA, namely HMW-scuPA, HMW-tcuPA, and low molecular weight urokinase-type plasminogen activator (LMW-uPA). uPA is initially translated as pro-urokinase containing 431 amino acid residues
To clarify whether the region within uPA that binds to TEM8 is the same region that interacts with uPAR, direct ELISA was used to measure the ability of TEM8 to interact with three different forms of recombinant uPA
Summary
TEM8 is a cell membrane protein predominantly expressed in tumor endothelium, which serves as a receptor for the protective antigen (PA) of anthrax toxin. The physiological ligands for TEM8 remain unknown. Tumor endothelial marker 8 (TEM8), a type I membrane protein, was originally identified by virtue of its elevated expression during tumor angiogenesis [1], and subsequently discovered to be a receptor for anthrax toxin, its official name, anthrax toxin receptor 1 (ANTXR1) [2]. The most well-known function of TEM8 is its role as a cell surface receptor for anthrax toxin PA. TEM8 mediates the entry of anthrax toxin into the cells of host organisms, and its role in the pathogenic process has been well described.
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