Natural products with distinct
biological activities are very promising
molecular probes to dissect the novel pathways of biology.
FR177391, a product of bacteria, was obtained as a natural compound possessing anti-hyperlipidemic effects.
FR177391 enhances differentiation of mouse 3T3-L1 fibroblasts to adipocytes and reduces the circulating levels of
triglyceride in C57BL/KsJ-db/db mice, a obese
non-insulin-dependent diabetes mellitus animal model, although its mechanism of actions remained to be unknown. We report here that the target
protein for
FR177391 was identified to be
protein phosphatase 2A (PP2A) by employing the method of affinity chromatography.
FR177391 potently inhibited PP2A activity at nano molar concentration, and shared its binding pocket with a
phosphatase inhibitor,
okadaic acid. In addition to the phenotypic alterations, the enhancement for phosphorylation of
extracellular signal-regulated kinase (ERK)
protein was observed in the FR177391-treated 3T3-L1 cells. These results suggest that prolonged activation of ERK
protein due to inhibition of its dephosphorylation by PP2A plays an important role in adipocyte maturation and regulation of the blood revels of
lipids.