Nectin is a calcium-independent cell adhesion molecule, localized to puncta adherentia junctions of the synapse. Nectin-1 interacts with afadin, an actin-binding protein that connects nectin to the actin cytoskeleton. This nectin-afadin intercellular adhesion system plays a role in the formation of synapses. Nectin-1 undergoes a regulated, multi-step set of endoproteolytic cleavage events by several sheddases in an activity-dependent manner. Our data indicates that these multiple process events include b-secretase and intramembranous proteolytic processing mediated by BACE1 and presenilin (PS)-dependent gamma- secretase respectively. This event is analogous to amyloid precursor protein processing. We have identified several amino acid residues that are necessary for these cleavage events through site-directed mutagenesis. Overexpression of these point- mutant polypeptides in primary hippocampal neurons reveals that ectodomain cleavage of nectin- 1 plays a role in maintaining the morphology of dendritic spines and formation of new synapses. In addition, our data also provides that BACE1 and PS-1 are synaptic modulators.