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Shedding of neurexin 3? ectodomain by ADAM10 releases a soluble fragment that affects the development of newborn neurons.

ABSTRACT: Neurexins are transmembrane synaptic cell adhesion molecules involved in the development and maturation of neuronal synapses. In the present study, we report that Nrxn3? is processed by the metalloproteases ADAM10, ADAM17, and by the intramembrane-cleaving protease ?-secretase, producing secreted neurexin3? (sNrxn3?) and a single intracellular domain (Nrxn3?-ICD). We further completed the full characterization of the sites at which Nrxn3? is processed by these proteases. Supporting the physiological relevance of the Nrxn3? processing, we demonstrate in vivo a significant effect of the secreted shedding product sNrxn3? on the morphological development of adult newborn neurons in the mouse hippocampus. We show that sNrxn3? produced by the cells of the dentate gyrus increases the spine density of newborn neurons whereas sNrxn3? produced by the newborn neuron itself affects the number of its mossy fiber terminal extensions. These results support a pivotal role of sNrxn3? in plasticity and network remodeling during neuronal development.

SUBMITTER: Borcel E

PROVIDER: S-EPMC5171655 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Shedding of neurexin 3β ectodomain by ADAM10 releases a soluble fragment that affects the development of newborn neurons.

Borcel Erika E Palczynska Magda M Krzisch Marine M Dimitrov Mitko M Ulrich Giorgio G Toni Nicolas N Fraering Patrick C PC

Scientific reports 20161219

Neurexins are transmembrane synaptic cell adhesion molecules involved in the development and maturation of neuronal synapses. In the present study, we report that Nrxn3β is processed by the metalloproteases ADAM10, ADAM17, and by the intramembrane-cleaving protease γ-secretase, producing secreted neurexin3β (sNrxn3β) and a single intracellular domain (Nrxn3β-ICD). We further completed the full characterization of the sites at which Nrxn3β is processed by these proteases. Supporting the physiolog ...[more]

PMID: 27991559

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Project description:In pancreatic cancer, there is a clear unmet need to identify new serum markers for either early diagnosis, therapeutic stratification or patient monitoring. Proteomic analysis of tumor cell secretomes is a promising approach to indicate proteins released from tumor cells in vitro. Ectodomain shedding of transmembrane proteins has previously been shown to contribute significant fractions the tumor cell secretomes and to generate valuable serum biomarkers. Here we introduce a soluble form of the giant cadherin Fat1 as a novel biomarker candidate. Fat1 expression and proteolytic processing was analyzed by mass spectrometry and Western blotting using pancreatic cancer cell lines as compared to human pancreatic ductal epithelial cells. RNA expression in cancer tissues was assessed by in silico analysis of publically available microarray data. Involvement of ADAM10 (A Disintegrin and metalloproteinase domain-containing protein 10) in Fat1 ectodomain shedding was analyzed by chemical inhibition and knockdown experiments. A sandwich ELISA was developed to determine levels of soluble Fat1 in serum samples. In the present report we describe the release of high levels of the ectodomain of Fat1 cadherin into the secretomes of human pancreatic cancer cells in vitro, a process that is mediated by ADAM10. We confirm the full-length and processed heterodimeric form of Fat1 expressed on the plasma membrane and also show the p60 C-terminal transmembrane remnant fragment corresponding to the shed ectodomain. Fat1 and its sheddase ADAM10 are overexpressed in pancreatic adenocarcinomas and ectodomain shedding is also recapitulated in vivo leading to increased Fat1 serum levels in some pancreatic cancer patients. We suggest that soluble Fat1 may find an application as a marker for patient monitoring complementing carbohydrate antigen 19-9 (CA19-9). In addition, detailed analysis of the diverse processed protein isoforms of the candidate tumor suppressor Fat1 can also contribute to our understanding of cell biology and tumor behavior.

Dataset Information

Shedding of neurexin 3? ectodomain by ADAM10 releases a soluble fragment that affects the development of newborn neurons.

Publications

Shedding of neurexin 3β ectodomain by ADAM10 releases a soluble fragment that affects the development of newborn neurons.

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