Nectin-1α, an Immunoglobulin-like Receptor Involved in the Formation of Synapses, Is a Substrate for Presenilin/γ-Secretase-like Cleavage*

By Doo Yeon Kim, L. Ingano, D. Kovacs. Journal of Biological Chemistry, 2002

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Nectin-1 is a member of the immunoglobulin superfamily and a Ca2+-independent adherens junction protein involved in synapse formation. Here we show that nectin-1α undergoes intramembrane proteolytic processing analogous to that of the Alzheimer's disease amyloid precursor protein, mediated by a presenilin (PS)-dependent γ-secretase-like activity. 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of Chinese hamster ovary cells activated a first proteolytic event, resulting in ectodomain shedding of nectin-1α. Subsequent cleavage of the remaining 26-kDa membrane-anchored C-terminal fragment (CTF) was inhibited independently by three specific γ−secretase inhibitors and by expression of the dominant negative form of PS1. The PS/γ-secretase-like cleavage product was detected in vivofollowing proteasome inhibitor treatment of cells. An in vitro γ-secretase assay confirmed the generation of a 24-kDa nectin-1α intracellular domain, peripherally associated with the membrane fraction. We also found nectin-1α to interact with the N-terminal fragment of PS1. Finally, γ-secretase inhibition resulted in β-catenin release from cell junctions, concomitantly with the accumulation of the 26-kDa nectin-1α CTF, suggesting that high levels of nectin-1α CTF interfere with TPA-induced remodeling of cell-cell junctions. Our results are consistent with a previously reported role for PS/γ-secretase in adherens junction function involving cleavage of cadherins. Similar to nectin-1, other members of the immunoglobulin superfamily involved in synapse formation may also serve as substrates for PS/γ-secretase-like intramembrane proteolytic activity.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/79d6bf41475388178e9f2a6cd5ef59bb900720e9