RESUMO
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.
Assuntos
Fosfatase 1 de Especificidade Dupla/antagonistas & inibidores , Humanos , Relação Estrutura-AtividadeAssuntos
Basidiomycota/química , Ergosterol/análogos & derivados , Ergosterol/farmacologia , Elastase de Leucócito/antagonistas & inibidores , Ergosterol/química , Humanos , Concentração Inibidora 50 , Elastase de Leucócito/metabolismo , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Micélio/química , Rotação Ocular , Espectrofotometria InfravermelhoRESUMO
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.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Caseína Quinase 1 épsilon/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Wnt/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Aurora Quinase A , Aurora Quinases , Caseína Quinase 1 épsilon/genética , Proteínas de Ciclo Celular/genética , Cílios/genética , Cílios/metabolismo , Proteínas Desgrenhadas , Células HeLa , Humanos , Células L , Camundongos , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Wnt/genética , Proteína Wnt-5a , Quinase 1 Polo-LikeRESUMO
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.
