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

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 ␥-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.The cadherin superfamily is composed of membrane proteins with Ca 2ϩ -dependent cell adhesion properties and homologous sequence repeats located in their extracellular domains (1-3). These repeats are responsible for the homophilic adhesive behavior of members of the cadherin family. Four groups of cadherins have been identified so far: the "classical" type I and type II cadherins; the desmosomal cadherins; and the most recently discovered protocadherin family. Protocadherins were initially discovered by PCR cloning using cadherin homology sequences (4). With genome sequencing, more than 70 different protocadherin genes have been identified altogether. This makes protocadherins the largest subgroup within the cadherin superfamily (5). Most protocadherin genes are clustered in three loci: protocadherin (Pcdh) 3 ␣, ␤, and ␥.

Characterization of protocadherin‐1 expression in primary bronchial epithelial cells: association with epithelial cell differentiation

“…This 50‐kDa product could be the protein product of the putative novel isoform, although we can not exclude the possibility that this product is the result of a full‐length isoform modified by post‐translational cleavage or shedding. Such a shedding process was previously identified for the clustered γ‐protocadherins and the nonclustered protocadherin‐12 (30, 31) but is yet unknown for δ1‐protocadherins. Future studies will be directed at the characterization of this novel PCDH1 protein.…”

Sfrp1 deficiency makes retinal photoreceptors prone to degeneration

“…This model is supported by the appropriate localization of the required molecular machinery -ADAM10, SFRP1 and different cell adhesion molecules-within the retina (46,47,55,67) and this study) and by the increased shedding of N-cadherin and PCDH21 in the Sfrp1 -/retinas. Increased proteolysis of these molecules has been shown to weaken cell-cell interactions (53,54) and thus may well explain the intermittent breakage of the OLM in the Sfrp1 -/retinas, with the consequent disorganization of the ONL and rhodopsin distribution. The latter defect is considered both a consequence and a further cause of rod degenerative signs, including the decompaction of the OS disc membrane stacks (68), as we observed in the Sfrp1 -/mutants.…”

Characterization of exosomal release in bovine endometrial intercaruncular stromal cells

“…Up-regulation of ADAM10 could induce placental release of soluble vascular endothelial growth factor receptor-1 (sFlt-1) and this cascade is associated with endothelial dysfunction, suggesting the significant role of oxidative change in preeclamptic placentas. ADAM10 is also a sheddase [53] that could induce CD46 shedding attributed to cell apoptotic processes [54], as well as mediate E-cadherin shedding affecting cellular adhesion and cell migration [55]. …”