Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin
signaling, and PTP1B inhibitors have been seen as promising
therapeutic agents against obesity and type 2 diabetes. Here
we report that the marine natural product hyrtiosal, from the
marine sponge Hyrtios erectus, has been discovered to act as a
PTP1B inhibitor and to show extensive cellular effects on PI3K/
AKT activation, glucose transport, and TGFb/Smad2 signaling.
This inhibitor wad able to inhibit PTP1B activity in dose-dependent
fashion, with an IC50 value of42 mm in a noncompetitive
ACHTUNGTRENUNGinhibition mode. Further study with an IN Cell Analyzer 1000 cellular
fluorescence imaging instrument showed that hyrtiosal displayed
potent activity in abolishing the retardation ofAKT membrane
translocation caused by PTP1B overexpression in CHO
cells. Moreover, it was found that this newly identified PTP1B inhibitor
could dramatically enhance the membrane translocation
ofthe key glucose transporter Glut4 in PTP1B-overexpressed CHO
cells. Additionally, in view ofour recent finding that PTP1B was
able to modulate insulin-mediated inhibition ofSmad2 activation,
hyrtiosal was also tested for its capabilities in the regulation
ofSmad2 activity through the PI3K/AKT pathway. The results
showed that hyrtiosal could effectively facilitate insulin inhibition
ofSmad2 activation. Our current study is expected to supply new
clues for the discovery of PTP1B inhibitors from marine natural
products, while the newly identified PTP1B inhibitor hyrtiosal
might serve as a potential lead compound for further research.