Role of pro-IGF-II processing by proprotein convertase 4 in human placental development.
Fetal growth restriction (intrauterine growth restriction, IUGR) is a leading cause of perinatal mortality. However, the causes of aberrant development of the placenta and, thus, of the fetus, are not currently known. Insulin-like growth factor II (IGF-II) has been shown to be an important regulator of fetoplacental growth. This growth factor must undergo posttranslational processing, and, thus, we hypothesized that aberrant processing of pro-IGF-II to IGF-II may be a cause of IUGR. Here, we have found that the proprotein convertase PC4 is expressed in the human placenta and that it cleaves pro-IGF-II to generate the intermediate processed form, IGF-II (1-102) and, subsequently, mature IGF-II (1-67), which are accounted for by the removal of terminal basic residues by carboxypeptidases. This processing confers the ability of IGF-II to activate invasive trophoblast cells through AKT phosphorylation, whereas inhibition of PC4 by a PC4-specific inhibitor blocks pro-IGF-II processing and reduces trophoblast cell migration, which can be partly restored by addition of mature IGF-II. Consistent with the hypothesis that IGF-II processing is implicated in IUGR, sera of patients carrying IUGR fetuses displayed elevated levels of pro-IGF-II. Thus, abnormal processing of IGF-II by PC4 may represent a previously uncharacterized mechanism involved in the pathophysiology of fetoplacental growth restriction, and elevated pro-IGF-II may be a useful clinical marker for risk of IUGR.
Qiu
Qing
Q
Hormones, Growth, and Development and Disease of Aging Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada K1Y 4E9.
Basak
Ajoy
A
Mbikay
Majambu
M
Tsang
Benjamin K
BK
Gruslin
Andrée
A
D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood / Q000209:etiology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D010929:Placentation; D011247:Pregnancy; D043484:Proprotein Convertases; D011498:Protein Precursors / Q000097:blood / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013381:Subtilisins; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D011498:Protein Precursors; C066038:proinsulin-like growth factor II; D007335:Insulin-Like Growth Factor II; C489716:PCSK4 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D013381:Subtilisins