The Protein-Tyrosine Phosphatase, Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2, Is a Crucial Mediator of Exogenous Insulin-Like Growth Factor Signaling to Human Trophoblast

Adequate fetal growth depends on placental transfer of nutrients and gases from the mother; thus, as pregnancy progresses, the placenta must grow to meet the increasing demands of the developing fetus. IGFs control proliferation, differentiation, and survival of trophoblast in first-trimester placenta via intracellular tyrosine kinase signaling cascades, the activation of which is also regulated by tyrosine phosphatases. The protein-tyrosine phosphatase, Src homology-2 domain containing protein tyrosine phosphatase (SHP)-2, is crucial for mouse placental development and is known to mediate IGF actions in other systems. In this study we examined the role of SHP-2 in regulating IGF-mediated proliferation in human trophoblast. Immunohistochemical analysis demonstrated that SHP-2 is expressed strongly in cytotrophoblast and only weakly in syncytium. After small interfering RNA-mediated knockdown of SHP-2 in BeWo choriocarcinoma cells and human first-trimester placental explants, IGF-induced trophoblast proliferation, examined using immunohistochemical analysis of Ki67 and 5-bromo-2'-deoxyuridine incorporation, was significantly reduced (P < 0.05). Kinase activation assays suggested that SHP-2 interacts with the MAPK pathway to mediate these effects. Markers of trophoblast differentiation were elevated after SHP-2 knockdown. This study demonstrates a role for tyrosine phosphatases in human trophoblast and establishes SHP-2 as a component of the IGF signaling pathway that is required for normal placental growth.