Stimulation of Human Extravillous Trophoblast Migration by IGF-II Is Mediated by IGF Type 2 Receptor Involving Inhibitory G Protein(s) and Phosphorylation of MAPK

来自 EBSCO

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作者：

McKinnon Timothy，C Chandan，LM Gleeson，C Peter，PK Lala

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摘要：

We have earlier shown that migration and invasiveness of first trimester extravillous trophoblast cells are stimulated by , independently of type 1 receptor and that migration stimulation is the primary reason for increased extravillous trophoblast cell invasiveness induced by . In the present study we examined the functional role of type II receptor in stimulation of extravillous trophoblast and the underlying signal pathways including the participation of inhibitory G protein(s) and . The migratory ability of a well characterized in vitro propagated first trimester extravillous trophoblast cell line expressing the phenotype of extravillous trophoblast cells in situ was quantitated with a Transwell migration assay under different experimental conditions. We found that the extravillous trophoblast cells expressed an abundance of type 2 receptor as detected by immunostaining and Western blots, and recombinant promoted their migration in a dose- and time-dependent manner. Both polyclonal and monoclonal type 2 receptor-blocking antibodies blocked migration-stimulating effects of . Two synthetic analogs ([Leu27], which can bind to type 2 receptor and -proteins, but not type 1 receptor, and [QAYL-Leu27], which can bind to IGFR-II, but neither IGFR-I nor -proteins) both stimulated extravillous trophoblast to levels higher than those induced by wild-type . These results reveal that action was mediated by type 2 receptor, independently of type 1 receptor and -proteins. Treatment of extravillous trophoblast preparations with decreased activity in a concentration-dependant manner, indicating the participation of inhibitory G proteins in action. This was substantiated further with the findings that increasing cAMP using or (Bu)2cAMP inhibited basal extravillous trophoblast and blocked stimulation of migration. treatment rapidly stimulated of (and -2), which was blocked by pretreatment of extravillous trophoblast cells with the (MEK) inhibitor PD98059. Treatment with this inhibitor also blocked extravillous trophoblast in the presence or absence of . These results, taken together, reveal that stimulates extravillous trophoblast by signaling through type 2 receptor, involving inhibitory G proteins and activating the pathway.

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关键词：

Humans Trophoblasts Cell Line Flavonoids Adenylate Cyclase Insulin-Like Growth Factor II Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinase 1 Receptor, IGF Type 2 Enzyme Inhibitors