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

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 axono-genesis 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. (C) 2007 Wiley-Liss, Inc.