Self-control of HGF regulation on human trophoblast cell invasion via enhancing c-Met receptor shedding by ADAM10 and ADAM17.
BACKGROUND
Hepatocyte growth factor (HGF)/c-Met signaling has been implicated in mammalian placental development. Integral c-Met can be released from endothelial cell membrane by proteolysis to form a soluble, truncated protein [soluble Met (sMet)], which is biochemically able to bind HGF and may disrupt HGF/c-Met signaling. By far, production of sMet in human placenta has not been reported, and the shedding mechanism remains unclear.


OBJECTIVE
In this study, production of sMet in healthy pregnant placenta and preeclamptic ones was compared, and the role of sMet on trophoblast cell invasion as well as the regulation of c-Met shedding by HGF were investigated in an immortal trophoblast cell line, B6Tert-1.


RESULTS
Placenta productions of sMet, pro- and active forms of a disintegrin and metalloprotease 10 (ADAM10) and ADAM17 in preeclamptic patients were significantly higher than those in normal pregnant women. In B6Tert-1 cells, the HGF-induced promotion on cell invasion and activation of MAPK and AKT could be extensively blocked by sMet. ADAM10 and ADAM17, but not ADAM12, were explored to be sheddases of c-Met. HGF down-regulated c-Met receptor expression, whereas it up-regulated pro- and active/mature forms of ADAM10 and ADAM17 expression, which resulted in enhanced sMet production. Stimulation of H(2)O(2) caused an increase in active ADAM10, pro-ADAM17, and active ADAM17 levels and thus excessive c-Met shedding.


CONCLUSIONS
HGF could negatively self-control its regulatory effect on trophoblast cell invasion via enhancing proteolysis of its receptor. Unbalancing of HGF self-control by oxidative stress may lead to impeding placentation in relevance to preeclampsia.
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Yanyan
Y
Yang
Yongqing
Y
Wang
Xin
X
Zeng
Xiao-jie
XJ
Ma
Yangyu
Y
Zhao
Jie
J
Qiao
Bin
B
Cao
Yu-xia
YX
Li
Lei
L
Ji
Yan-ling
YL
Wang
D051722:ADAM Proteins / Q000502:physiology*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology*; D011225:Pre-Eclampsia / Q000209:etiology; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D014327:Trophoblasts / Q000378:metabolism* / Q000473:pathology
C066855:HGF protein, human; D008565:Membrane Proteins; D017228:Hepatocyte Growth Factor; D006861:Hydrogen Peroxide; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human