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.
Forbes
Karen
K
Maternal and Fetal Health Research Group, University of Manchester, Manchester M13 0JH, United Kingdom.
West
Gemma
G
Garside
Rebecca
R
Aplin
John D
JD
Westwood
Melissa
M
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism*
D034741:RNA, Small Interfering; D013002:Somatomedins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases