Neuroserpin regulates N‐cadherin‐mediated cell adhesion independently of its activity as an inhibitor of tissue plasminogen activator

Abstract

Neuroserpin is an inhibitor of tissue plasminogen activator (tPA) that is expressed in developing and adult nervous systems. Spatial and temporal analysis of neuroserpin expression suggests that it is involved in regulating the proteolytic balance associated with axonogenesis and synaptogenesis during development and synaptic plasticity in the adult. Here we demonstrate that altered expression of neuroserpin modulates the degree of cell-cell adhesion in pheochromocytoma PC12 cells independently of its role as an inhibitor of tPA. Levels of the homophilic cell-cell adhesion molecule N-cadherin are increased in neuroserpin-overexpressing cell lines. N-cadherin immunoreactivity was detected in a Triton X-100-insoluble fraction and localized to regions of cell contact, consistent with a role in enhancing cell surface adhesion. PC12 cell lines expressing neuroserpin mutants that lack tPA inhibitory activity also showed increased cell-cell adhesion and N-cadherin expression. Our results identify neuroserpin as a novel regulator of cell-cell adhesion and the synaptic adhesion molecule N-cadherin as a key effecter in this response. In nerve cells, neuroserpin may regulate the levels of N-cadherin available for construction, maintenance, and control of synapses and synaptic dynamics.

Neonatal Hypoxia Ischaemia: Mechanisms, Models, and Therapeutic Challenges

“…Cell lines over-expressing neuroserpin demonstrate an increase in N -cadherin protein expression and related cell adhesion, maintained when the tPA binding site of neuroserpin is mutated (Lee et al, 2008). In vitro , neuroserpin has been shown to prevent excitotoxic neuronal death induced by plasmin and kainic acid (Wu et al, 2010), and the 20 methionine residues present within neuroserpin have been claimed to convey protection against oxidative stress (Mohsenifar et al, 2007), and exogenous neuroserpin has been shown to possess anti-inflammatory properties (Munuswamy-Ramanujam et al, 2010).…”

Human Neuroserpin: Structure and Time-Dependent Inhibition

“…1,2 Human neuroserpin (SERPINI1 according to the accepted serpin nomenclature 3 ) is a secretory protein that exerts its recognized physiological role in axonogenesis and synaptogenesis, during development and in synaptic plasticity in the adult, both as an inhibitor of tissue-type plasminogen activator (tPA) and in a tPA-independent way. 1,2,4,5 In Alzheimer's disease models, hNS has been found to interact with the β-amyloid (Aβ) peptide with remarkable effects: first, interaction with Aβ depresses the hNS protease inhibitory activity, and second, Aβ amyloid aggregation is enhanced. Moreover, in cell lines and in a Drosophila model, hNS exerts a protective role against the toxicity of Aβ peptide aggregates.…”

The serine protease inhibitor neuroserpin is required for normal synaptic plasticity and regulates learning and social behavior

“…Overexpression of neuroserpin in primary neurons leads to increased dendritic arborization and altered dendritic spine shape (Borges et al 2010), whereas in rat hippocampus neuroserpin overexpression results in reduced expression of postsynaptic density protein 95 (PSD-95) without impairment in hippocampaldependent learning and memory (Tsang et al 2014). Moreover, expression levels of N-cadherin, an adhesion protein implicated in synapse formation, are modulated by neuroserpin (Lee et al 2008). In the visual cortex, neuroserpin expression is increased during the critical period and decreased following monocular deprivation (Wannier-Morino et al 2003).…”