title: Protocadherin-12 cleavage is a regulated process mediated by ADAM10 protein: evidence of shedding up-regulation in pre-eclampsia.
abstract: Protocadherins are a group of transmembrane proteins with homophilic binding activity, members of the cadherin superfamily. Apart from their role in adhesion, the cellular functions of protocadherins are essentially unknown. Protocadherin (PCDH)12 was previously identified in invasive trophoblasts and endothelial and mesangial cells in the mouse. Invalidation studies revealed that the protein was required for optimal placental development. In this article, we show that its human homolog is abundantly expressed in various trophoblast subtypes of the human placenta and at lower levels in endothelial cells. We demonstrate that PCDH12 is shed at high rates in vitro. The shedding mechanism depends on ADAM10 and results in reduced cellular adhesion in a cell migration assay. PCDH12 is subsequently cleaved by the γ-secretase complex, and its cytoplasmic domain is rapidly degraded by the proteasome. PCDH12 shedding is regulated by interlinked intracellular pathways, including those involving protein kinase C, PI3K, and cAMP, that either increase or inhibit cleavage. In endothelial cells, VEGF, prostaglandin E(2), or histamine regulates PCDH12 shedding. The extracellular domain of PCDH12 was also detected in human serum and urine, thus providing evidence of PCDH12 shedding in vivo. Importantly, we observed an increase in circulating PCDH12 in pregnant women who later developed a pre-eclampsia, a frequent pregnancy syndrome and a major cause of maternal and fetal morbidity and mortality. In conclusion, we speculate that, like in mice, PCDH12 may play an important role in human placental development and that proteolytic cleavage in response to external factors, such as cytokines and pathological settings, regulates its activity.
authors.affiliation: Laboratoire d'Angiogenèse et Physiopathologie Vasculaire, CEA, 38054 Grenoble, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bouillot
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tillet
authors.forename: Guillaume
authors.initials: G
authors.lastname: Carmona
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Prandini
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Gauchez
authors.forename: Pascale
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Nadia
authors.initials: N
authors.lastname: Alfaidy
authors.forename: Francine
authors.initials: F
authors.lastname: Cand
authors.forename: Philippe
authors.initials: P
authors.lastname: Huber
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D042783:Endothelial Cells / Q000737:chemistry; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000097:blood / Q000652:urine; D010929:Placentation; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D000091363:Protocadherins; D014327:Trophoblasts / Q000737:chemistry; D015854:Up-Regulation
chemical_list: D015820:Cadherins; D008565:Membrane Proteins; C113432:PCDH12 protein, human; D010446:Peptide Fragments; D000091363:Protocadherins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human