ABSTRACT
Structure based virtual screening attempts to discover DUSP1 inhibitors have yielded a scaffold featuring benzoxazole and acylthiourea pharmacophore. A series of its analogues were synthesized to explore structure activity relationship (SAR) of DUSP1 inhibition.
Subject(s)
Dual Specificity Phosphatase 1/antagonists & inhibitors , Humans , Structure-Activity RelationshipSubject(s)
Basidiomycota/chemistry , Ergosterol/analogs & derivatives , Ergosterol/pharmacology , Leukocyte Elastase/antagonists & inhibitors , Ergosterol/chemistry , Humans , Inhibitory Concentration 50 , Leukocyte Elastase/metabolism , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Mycelium/chemistry , Optical Rotation , Spectrophotometry, InfraredABSTRACT
Non-motile primary cilium is an antenna-like structure whose defect is associated with a wide range of pathologies, including developmental disorders and cancer. Although mechanisms regulating cilia assembly have been extensively studied, how cilia disassembly is regulated remains poorly understood. Here, we report unexpected roles of Dishevelled 2 (Dvl2) and interphase polo-like kinase 1 (Plk1) in primary cilia disassembly. We demonstrated that Dvl2 is phosphorylated at S143 and T224 in a manner that requires both non-canonical Wnt5a ligand and casein kinase 1 epsilon (CK1É), and that this event is critical to interact with Plk1 in early stages of the cell cycle. The resulting Dvl2-Plk1 complex mediated Wnt5a-CK1É-Dvl2-dependent primary cilia disassembly by stabilizing the HEF1 scaffold and activating its associated Aurora-A (AurA), a kinase crucially required for primary cilia disassembly. Thus, via the formation of the Dvl2-Plk1 complex, Plk1 plays an unanticipated role in primary cilia disassembly by linking Wnt5a-induced biochemical steps to HEF1/AurA-dependent cilia disassembly. This study may provide new insights into the mechanism underlying ciliary disassembly processes and various cilia-related disorders.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Casein Kinase 1 epsilon/metabolism , Cell Cycle Proteins/metabolism , Phosphoproteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Wnt Proteins/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Aurora Kinase A , Aurora Kinases , Casein Kinase 1 epsilon/genetics , Cell Cycle Proteins/genetics , Cilia/genetics , Cilia/metabolism , Dishevelled Proteins , HeLa Cells , Humans , L Cells , Mice , Multienzyme Complexes/genetics , Multienzyme Complexes/metabolism , Phosphoproteins/genetics , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/genetics , Wnt Proteins/genetics , Wnt-5a Protein , Polo-Like Kinase 1ABSTRACT
Activity-guided fractionation of a MeOH extract of the roots of Saussurea lappa C.B.Clarke (Compositae), using an in vitro protein tyrosine phosphatase 1B (PTP1B) inhibition assay, led to the isolation of four active constituents: betulinic acid (1), betulinic acid methyl ester (2), mokko lactone (3) and dehydrocostuslactone (4), along with nine inactive compounds. Our findings indicate that betulinic acid (1) and its methyl ester 2, as well as the two guaiane sesquiterpenoids 3 and 4 are potential lead moieties for the development of new PTP1B inhibitors.
