Protocadherin-12 Cleavage Is a Regulated Process Mediated by ADAM10 Protein

Autor: Emmanuelle Tillet, Anne-Sophie Gauchez, Francine Cand, Stéphanie Bouillot, Marie-Hélène Prandini, Philippe Huber, Pascale Hoffmann, Nadia Alfaidy, Guillaume Carmona
Přispěvatelé: Alfaidy, Nadia, Laboratoire de développement et vieillissement de l'endothélium, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Plateforme de radioactivité [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie [CHU Grenoble] (IBP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Biologie et de Pathologie - IBP [CHU Grenoble]-Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes)
Rok vydání: 2011
Předmět:
Zdroj: Journal of Biological Chemistry
Journal of Biological Chemistry, 2011, 286 (17), pp.15195-15204. ⟨10.1074/jbc.M111.230045⟩
Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2011, 286 (17), pp.15195-15204. ⟨10.1074/jbc.M111.230045⟩
ISSN: 0021-9258
1083-351X
Popis: International audience; 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.
Databáze: OpenAIRE
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